Journal articles on the topic 'Antigeni tumore associati'
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Polito, M., L. Possati, G. Muzzonigro, and V. Beatrici. "Identificazione Di Antigeni Tumore Associati Con La Tecnica Dell'Immunofluorescenza Su Cellule Uroteliali Neoplastiche." Urologia Journal 57, no. 5 (October 1990): 546–48. http://dx.doi.org/10.1177/039156039005700516.
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Krishnan, Lakshmi, Lise Deschatelets, Felicity C. Stark, Komal Gurnani, and G. Dennis Sprott. "Archaeosome Adjuvant Overcomes Tolerance to Tumor-Associated Melanoma Antigens Inducing Protective CD8+T Cell Responses." Clinical and Developmental Immunology 2010 (2010): 1–13. http://dx.doi.org/10.1155/2010/578432.
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Vesicles comprised of the ether glycerolipids of the archaeonMethanobrevibacter smithii(archaeosomes) are potent adjuvants for evoking CD8+T cell responses. We therefore explored the ability of archaeosomes to overcome immunologic tolerance to self-antigens. Priming and boosting of mice with archaeosome-antigen evoked comparable CD8+T cell response and tumor protection to an alternate boosting strategy utilizing live bacterial vectors for antigen delivery. Vaccination with melanoma antigenic peptides TRP181-189and Gp10025-33delivered in archaeosomes resulted in IFN-γproducing antigen-specific CD8+T cells with strong cytolytic capability and protection against subcutaneous B16 melanoma. Targeting responses against multiple antigens afforded prolonged median survival against melanoma challenge. Entrapment of multiple peptides within the same vesicle or admixed formulations were both effective at evoking CD8+T cells against each antigen. Melanoma-antigen archaeosome formulations also afforded therapeutic protection against established B16 tumors when combined with depletion of T-regulatory cells. Overall, we demonstrate that archaeosome adjuvants constitute an effective choice for formulating cancer vaccines.
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Yang, Changlin, Kyle Dyson, Oleg Yegorov, and Duane Mitchell. "IMMU-24. A COMPREHENSIVE IN SILICO APPROACH TO DISCOVERING TUMOR REJECTION ANTIGENS IN MALIGNANT BRAIN TUMORS." Neuro-Oncology 21, Supplement_6 (November 2019): vi124. http://dx.doi.org/10.1093/neuonc/noz175.517.
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Abstract BACKGROUND Proteins that can serve as effective tumor rejection antigens within brain tumors are poorly characterized. Current prediction algorithms relying on identification of mutated epitopes as neoantigens are limited in low mutational burden tumors. We have developed a multi-faceted computer algorighm for identifying tumor rejection antigens called the Open Reading Frame Antigen Network (ORAN). This pipeline provides a comprehensive solution for predicting brain tumor immunogenic targetable epitopes/transcripts. METHODS Human and murine RNASeq and WES data were QCed. Patients individual HLA-I and HLA-II haplotypes were predicted by highly customized Optitype and Phlat Algorithms. SNPs and Indels were called from tumors WES and read through matched RNASeq data. 19,131 transcripts expression were counted per TOIL algorithm. Tumor associate antigens(TAA) of individual patient or murine tumors were selected by setting a cutoff of Transcripts Per Million (TPM) > 1 on individual patient’s tumor, while RNA Seq data from 7000 normal tissues was used to identify tumor unique transcripts. Actual sequence of HLA and SNPed Consenses TAA(CTAA) were called. Only expressed mutations and personalized TAAs were used for antigenic epitope predictions. All neoepitopes were screened against a human reference proteomic library to guarantee that epitopes were not shared by other expressed isoforms or genes. In silico validation were preformed to cross validate predictions made by ORAN. RESULTS In medullobastoma (N=121 samples), ORAN gives an average of 15.6 MHC class I restricted neoepitopes,11.9 epitopes encoded by Indels and with 33.2 MHC class II restricted neoepitopes and 16.2 Indel antigens per patient. The TAAs of each patient reaches average 256 antigenic epitopes per patient. ORAN also predicts the exact HLA and neo-antigens from a validated neoantigens vaccine dataset (Gros A Nat Med 2016). CONCLUSION ORAN accurately identifies validated neoantigens and provides a comprehensive list of potential tumor rejection antigens within human and murine brain tumors.
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Zhao, Jiaxuan, Guangsheng Du, and Xun Sun. "Tumor Antigen-Based Nanovaccines for Cancer Immunotherapy: A Review." Journal of Biomedical Nanotechnology 17, no. 11 (November 1, 2021): 2099–113. http://dx.doi.org/10.1166/jbn.2021.3178.
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As an important means of tumor immunotherapy, tumor vaccines have achieved exciting results in the past few decades. However, there are still many obstacles that hinder tumor vaccines from achieving maximum efficacy, including lack of tumor antigens, low antigen immunogenicity and poor delivery efficiency. To overcome these challenges, researchers have developed and investigated various new types of tumor antigens with higher antigenic specificity and broader antigen spectrum, such as tumor-specific peptide antigens, tumor lysates, tumor cell membrane, tumor associated exosomes, etc. At the same time, different nanoparticulate delivery platforms have been developed to increase the immunogenicity of the tumor antigens, for example by increasing their targeting efficiency of antigen-presenting cells and lymph nodes, and by co-delivering antigens with adjuvants. In this review, we summarized different types of the tumor antigens that have been reported, and introduced several nanovaccine strategies for increasing the immunogenicity of tumor antigens. The review of recent progress in these fields may provide reference for the follow-up studies of tumor antigen-based cancer immunotherapy.
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Haupt, Katharina, Michael Roggendorf, and Klauss Mann. "The Potential of DNA Vaccination against Tumor-Associated Antigens for Antitumor Therapy." Experimental Biology and Medicine 227, no. 4 (April 2002): 227–37. http://dx.doi.org/10.1177/153537020222700403.
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Conventional treatment approaches for malignant tumors are highly invasive and sometimes have only a palliative effect. Therefore, there is an increasing demand to develop novel, more efficient treatment options. Increased efforts have been made to apply immunomodulatory strategies in antitumor treatment. In recent years, immunizations with naked plasmid DNA encoding tumor-associated antigens have revealed a number of advantages. By DNA vaccination, antigen-specific cellular as well as humoral immune responses can be generated. The induction of specific immune responses directed against antigens expressed in tumor cells and displayed e.g., by MHC class I complexes can inhibit tumor growth and lead to tumor rejection. The improvement of vaccine efficacy has become a critical goal in the development of DNA vaccination as antitumor therapy. The use of different DNA delivery techniques and coadministration of adjuvants including cytokine genes may influence the pattern of specific immune responses induced. This brief review describes recent developments to optimize DNA vaccination against tumor-associated antigens. The prerequisite for a successful antitumor vaccination is breaking tolerance to tumor-associated antigens, which represent “self-antigens.” Currently, immunization with xenogeneic DNA to induce immune responses against self-molecules is under intensive investigation. Tumor cells can develop immune escape mechanisms by generation of antigen loss variants, therefore, it may be necessary that DNA vaccines contain more than one tumor antigen. Polyimmunization with a mixture of tumor-associated antigen genes may have a synergistic effect in tumor treatment. The identification of tumor antigens that may serve as targets for DNA immunization has proceeded rapidly. Preclinical studies in animal models are promising that DNA immunization is a potent strategy for mediating antitumor effects in vivo. Thus, DNA vaccines may offer a novel treatment for tumor patients. DNA vaccines may also be useful in the prevention of tumors with genetic predisposition. By DNA vaccination preventing infections, the development of viral-induced tumors may be avoided.
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Fischer, Duncan K., Terence L. Chen, and Raj K. Narayan. "Immunological and biochemical strategies for the identification of brain tumor-associated antigens." Journal of Neurosurgery 68, no. 2 (February 1988): 165–80. http://dx.doi.org/10.3171/jns.1988.68.2.0165.
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✓ Various strategies have been used to identify and characterize the antigens associated with human brain tumors. These approaches have included the raising of polyclonal and monoclonal antibodies against tumor antigens and, more recently, efforts toward the direct biochemical identification of such proteins. This review summarizes the progress made in this area, suggests reasons for the broad antigenic cross-reactivity and heterogeneity revealed by these studies, and proposes additional methods for deciphering the complex antigenic composition of human brain tumors.
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Craig, Vanessa J., Isabelle Arnold, Christiane Gerke, Minh Q. Huynh, Thomas Wündisch, Andreas Neubauer, Christoph Renner, Stanley Falkow, and Anne Müller. "Gastric MALT lymphoma B cells express polyreactive, somatically mutated immunoglobulins." Blood 115, no. 3 (January 21, 2010): 581–91. http://dx.doi.org/10.1182/blood-2009-06-228015.
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Abstract Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) arises against a background of chronic inflammation caused by persistent Helicobacter pylori infection. The clinical and histopathologic features of the human tumor can be reproduced by Helicobacter infection of BALB/c mice. In this study, we have analyzed the antibody sequences and antigen specificity of a panel of murine and human MALT lymphoma–derived antibodies. We find that a majority of tumors in patients as well as experimentally infected mice are monoclonal. The tumor immunoglobulin heavy chain genes have undergone somatic hypermutation, and approximately half of all tumors show evidence of intraclonal variation and positive and/or negative selective pressure. Recombinantly expressed MALT lymphoma antibodies bind with intermediate affinity to various unrelated self- and foreign antigens, including Helicobacter sonicate, immunoglobulin G (IgG), DNA, and stomach extract; antigen binding is blocked in a dose-dependent manner in competitive enzyme-linked immunosorbent assays. A strong bias toward the use of VH gene segments previously linked to autoantibodies and/or polyreactive antibodies in B-cell malignancies or autoimmune pathologies supports the experimental finding of polyreactivity. Our results suggest that MALT lymphoma development may be facilitated by an array of local self- and foreign antigens, providing direct antigenic stimulation of the tumor cells via their B-cell receptor.
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Fu, C., H. Zhao, Y. Wang, H. Cai, Y. Xiao, Y. Zeng, and H. Chen. "Tumor-associated antigens: Tn antigen, sTn antigen, and T antigen." HLA 88, no. 6 (September 28, 2016): 275–86. http://dx.doi.org/10.1111/tan.12900.
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Karan, Dev, Seema Dubey, and Brantley Thrasher. "Dual antigen target based immunotherapy for prostate cancer eliminates the growth of established tumors in mice (155.3)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 155.3. http://dx.doi.org/10.4049/jimmunol.186.supp.155.3.
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Abstract Generation of antigen-specific CD8 T cells is considered optimal for an effective immunotherapy against cancer. Knowing that heterogeneity of prostate cancer limits the therapeutic benefit, we developed a recombinant adenovirus type 5 (rAd5) co-expressing a fusion of PSA (prostate-specific antigen) and PSCA (prostate stem cell antigen) genes. The selection of these genes is based on their restricted distribution within the prostate and their association with the development and progression of prostate cancer. Immunization of mice with rAd5 vector co-expressing PSA and PSCA antigens (Ad5-PSPA) simultaneously induces the expansion of anti-PSA, and anti-PSCA T cells as measured by intracellular cytokine staining for IFN-y. To analyze the impact on therapeutic efficacy of Ad5-PSPA vaccine against the tumor cells co-expressing cognate antigens (RM11-PSA/PSCA cells), injection of mice with Ad5-PSPA vaccine inhibited the growth of established tumors. Initially, the mice developed slow growing tumors and eventually upto 80% of the mice remain tumor free following immunization with Ad5-PSPA vaccine. These data provide useful information that antigen-specific effector T cells can be generated simultaneously and their additive anti-tumor effect has the ability to eliminate the growth of established tumors. Therefore, the immunotherapy approach of using the simultaneous targeting of dual antigens associated with prostate cancer may have important implications for human clinical trials.
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Dyson, Kyle, Changlin Yang, Vrunda Trivedi, Tyler Wildes, Adam Grippin, and Duane Mitchell. "IMMU-49. PREDICTING PATIENT-SPECIFIC ANTIGENS FOR MEDULLOBLASTOMA IMMUNOTHERAPY." Neuro-Oncology 22, Supplement_2 (November 2020): ii115. http://dx.doi.org/10.1093/neuonc/noaa215.479.
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Abstract BACKGROUND Identification of tumor rejection antigens remains a major barrier to the development of effective immunotherapeutics and their application to pediatric brain tumors. To identify candidate antigen targets for medulloblastoma adoptive cellular therapy, we performed a comprehensive immunogenomic analysis of medulloblastoma transcription profiles and in silico antigen prediction across a broad array of antigen classes. We hypothesized that medulloblastomas are immunologically heterogeneous and express genes with limited normal tissue expression that may serve as targets for immunotherapy. METHODS Immunologic heterogeneity was assessed using several published algorithms and approaches implemented within the R programming language. Patient-specific HLA haplotypes were called via customized Optitype and Phlat algorithms. Patient-specific tumor associated antigens (TAA) were selected only if expressed >1 transcript per million (TPM) in tumor and the standardized expression across a human tissue database was below 1 TPM. Patient-specific HLA and TAA sequences were extracted from RNA-seq data for prediction with eight MHC class I and four MHC class II affinity algorithms. Only expressed mutations and personalized TAAs were used for antigenic epitope predictions. All epitopes were screened against a human reference proteomic library to guarantee that epitopes were not shared by other expressed isoforms or genes. Public mass-spec data was also screened for protein-level antigen expression. RESULTS Although absolute immune cell content is predicted to be low, immune gene-signature analysis revealed subgroup-specific differences. Antigen prediction analysis revealed most patients express few candidate neoantigen targets passing all filtering criteria. Importantly, cancer testis antigens as well as previously unappreciated neurodevelopmental antigens were found expressed across all medulloblastoma subgroups and most patients. Protein level antigen expression was confirmed for some predicted TAAs. CONCLUSION Medulloblastomas are immunologically cold yet subgroups have distinct immune cell gene-signatures. Using a custom antigen prediction pipeline, we identified potential tumor rejection antigens with important implications for development of medulloblastoma cellular therapies.
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Malchow, Sven, Daniel Leventhal, Saki Nishi, Benjamin Fischer, Nicholas Socci, and Peter Savage. "Murine prostate tumors recruit and expand thymic-derived regulatory T cell populations (P2191)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 170.52. http://dx.doi.org/10.4049/jimmunol.190.supp.170.52.
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Abstract For some human cancers, elevated densities of Foxp3+ regulatory T cells (Tregs) in the tumor tissue correlate with poor prognosis, suggesting that Tregs may play a functional role in cancer progression. Despite considerable interest in the modulation of tumor-associated Tregs for therapeutic benefit, little is known about the developmental origins of these cells and the nature of the antigens that they recognize. By a TCR sequencing approach of T cells isolated from tumors of mice with oncogene-driven prostate cancer (TRAMP), we identified an endogenous population of antigen-specific Tregs found recurrently enriched in the tumors. These Tregs were not reactive to a tumor-specific antigen, but instead recognized a prostate-associated antigen that is present in tumor-free mice. Transgenic T cells expressing this Treg-derived TCR underwent Treg development in the thymus, but inefficient development in the periphery, indicating a thymic origin of these cells. Taken together, our data support a model in which organ-specific Tregs reactive to peripheral tissue antigens develop as Tregs in the thymus and are co-opted by tumors arising within the associated organ.
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Contegiacomo, A., R. Mariani Costantini, R. Muraro, P. Battista, C. Valli, L. Frati, R. Calderopoli, et al. "Cell Kinetics and Tumor-Associated Antigen Expression in Human Mammary Carcinomas." International Journal of Biological Markers 6, no. 3 (July 1991): 159–66. http://dx.doi.org/10.1177/172460089100600304.
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Twenty-six primary breast carcinomas were studied to evaluate cell proliferation as assessed by thymidine labeling index (TLI), and antigenic phenotype, as defined by immunohistochemistry using eight monoclonal antibodies (MAbs) to tumor-associated antigens (TAAs). The majority of tumors had low TLI values. Reactivity to MAbs B72.3, CC49, CC83 (anti TAG 72), COL-12 (anti CEA) and MOv2 (against a tumor-associated mucoprotein) was restricted to < 50% of the tumors studied, while MAbs B1.1 (anti CEA), MBrl and MBr8 (to tumor-associated carbohydrates) reacted with > 50% of the cases. Correlations between expression of TAAs and proliferative activity showed that the tumors could be divided into three groups, two characterized by either high proliferative activity and absence of antigenic expression or low proliferative activity and strong antigenic expression, and the third showing no relation between these two biological features. We defined two antigenic phenotypes associated with specific cellular kinetics: one characterized by negative immunoreaction with MAbs, CC49, CC83 and COL-12 and high proliferative activity; the other characterized by intense immunoreactivity with these antibodies and low proliferative activity. The data suggest that cell proliferation and antigenic phenotype may define biologic subsets of breast carcinomas
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Xu, Lijun, Bingyu Li, Chenyu Pi, Zhaohua Zhu, Fei Tao, Kun Xie, Yan Feng, et al. "Targeting CD89 on tumor-associated macrophages overcomes resistance to immune checkpoint blockade." Journal for ImmunoTherapy of Cancer 10, no. 12 (December 2022): e005447. http://dx.doi.org/10.1136/jitc-2022-005447.
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BackgroundDespite the survival benefits observed with immune checkpoint blockade (ICB) treatment—programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1), many patients with cancer have not benefited from these agents because of impaired antigen presentation and other resistance mechanisms. To overcome resistance to checkpoint therapy, we designed bispecific antibodies (BsAbs) targeting CD89 and tumor antigens. We demonstrated their immunomodulatory efficacy as a separate treatment strategy or combined with immune checkpoint inhibitors.MethodsWe have previously generated a heterodimeric one-arm IgG1 Fc-based bispecific antibody. For animal efficacy studies, murine tumors in a humanized transgenic mice model were used to determine the effects of CD89-bispecific antibodies on antigen presentation and immune cell recruitment. The efficacy of the CD89 bispecific antibody against tumors resistant to pembrolizumab was evaluated in double-transgenic mice.ResultsBsAbs targeting CD89 on tumor-associated macrophages (TAMs) increased the ratio of M1:M2 and activated the antigen presentation, leading to increased cytotoxic T cell-mediated tumor regression. CD89-BsAbs also potentiated a combinational antitumor effect with PD-1/PD-L1 inhibitors and overcame the ICB resistance by augmenting cytotoxic T-cell infiltration and reshaping tumor immune microenvironment. In an hCD89/hPD-1 double transgenic mouse model engrafted with pembrolizumab-resistant B16-HER2 tumor cells, the HER2-CD89 bispecific antibody potently inhibited tumor growth.ConclusionsCD89 BsAbs targeting tumor antigens and TAMs controlled tumor growth in animal models by improving antigen presentation and T-cell infiltration. Our results suggest a general strategy for overcoming resistance to ICB.
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Han, Xiao, Shufang Shen, Qin Fan, Guojun Chen, Edikan Archibong, Gianpietro Dotti, Zhuang Liu, Zhen Gu, and Chao Wang. "Red blood cell–derived nanoerythrosome for antigen delivery with enhanced cancer immunotherapy." Science Advances 5, no. 10 (October 2019): eaaw6870. http://dx.doi.org/10.1126/sciadv.aaw6870.
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Erythrocytes or red blood cells (RBCs) represent a promising cell-mediated drug delivery platform due to their inherent biocompatibility. Here, we developed an antigen delivery system based on the nanoerythrosomes derived from RBCs, inspired by the splenic antigen-presenting cell targeting capacity of senescent RBCs. Tumor antigens were loaded onto the nanoerythrosomes by fusing tumor cell membrane–associated antigens with nanoerythrosomes. This tumor antigen–loaded nanoerythrosomes (nano-Ag@erythrosome) elicited antigen responses in vivo and, in combination with the anti–programmed death ligand 1 (PD-L1) blockade, inhibited the tumor growth in B16F10 and 4T1 tumor models. We also generated a tumor model showing that “personalized nano-Ag@erythrosomes” could be achieved by fusing RBCs and surgically removed tumors, which effectively reduced tumor recurrence and metastasis after surgery.
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Flyer, D. C., S. J. Burakoff, and D. V. Faller. "The immune response to Moloney murine leukemia virus-induced tumors: induction of cytolytic T lymphocytes specific for both viral and tumor-associated antigens." Journal of Immunology 137, no. 12 (December 15, 1986): 3968–72. http://dx.doi.org/10.4049/jimmunol.137.12.3968.
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Abstract The specificity of CTL generated against tumors induced by murine leukemia viruses (MuLV) has been reported to parallel the expression of two serologically defined tumor cell surface antigens--the cross-reactive FMR antigen expressed on the surface of tumors induced by Friend, Moloney, and Rauscher MuLV, and the Gross cell surface antigen (GCSA) expressed on tumors induced by AKV/Gross MuLV. We examined the specificity of CTL generated against MuLV-induced tumors and identified two distinct patterns of reactivity. The first follows the traditional pattern of FMR vs GCSA reactivity as assessed on a panel of established MuLV-induced lymphomas. However, CTL exhibiting this pattern of reactivity are incapable of lysing MuLV-infected fibroblasts. CTL exhibiting the second pattern of reactivity are capable of lysing MuLV-induced lymphomas as well as MuLV-infected fibroblasts. In addition, these CTL exhibit extensive cross-reactivity between lymphomas and fibroblasts infected by both groups of MuLV. Our results suggest that CTL exhibiting the traditional FMR vs GCSA pattern of reactivity are directed against a tumor-associated antigen and not against virus-encoded antigens, and that CTL directed against MuLV-encoded antigens demonstrate extensive cross-reactivity, including the ability to lyse AKV-infected cells.
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Wang, Yange, Chenyang Li, Xinlei Qi, Yafei Yao, Lu Zhang, Guosen Zhang, Longxiang Xie, Qiang Wang, Wan Zhu, and Xiangqian Guo. "A Comprehensive Prognostic Analysis of Tumor-Related Blood Group Antigens in Pan-Cancers Suggests That SEMA7A as a Novel Biomarker in Kidney Renal Clear Cell Carcinoma." International Journal of Molecular Sciences 23, no. 15 (August 8, 2022): 8799. http://dx.doi.org/10.3390/ijms23158799.
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Blood group antigen is a class of heritable antigenic substances present on the erythrocyte membrane. However, the role of blood group antigens in cancer prognosis is still largely unclear. In this study, we investigated the expression of 33 blood group antigen genes and their association with the prognosis of 30 types of cancers in 31,870 tumor tissue samples. Our results revealed that blood group antigens are abnormally expressed in a variety of cancers. The high expression of these antigen genes was mainly related to the activation of the epithelial-mesenchymal transition (EMT) pathway. High expression of seven antigen genes, i.e., FUT7, AQP1, P1, C4A, AQP3, KEL and DARC, were significantly associated with good OS (Overall Survival) in six types of cancers, while ten genes, i.e., AQP1, P1, C4A, AQP3, BSG, CD44, CD151, LU, FUT2, and SEMA7A, were associated with poor OS in three types of cancers. Kidney renal clear cell carcinoma (KIRC) is associated with the largest number (14 genes) of prognostic antigen genes, i.e., CD44, CD151, SEMA7A, FUT7, CR1, AQP1, GYPA, FUT3, FUT6, FUT1, SLC14A1, ERMAP, C4A, and B3GALT3. High expression of SEMA7A gene was significantly correlated with a poor prognosis of KIRC in this analysis but has not been reported previously. SEMA7A might be a putative biomarker for poor prognosis in KIRC. In conclusion, our analysis indicates that blood group antigens may play functional important roles in tumorigenesis, progression, and especially prognosis. These results provide data to support prognostic marker development and future clinical management.
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Wang, R. F., M. R. Parkhurst, Y. Kawakami, P. F. Robbins, and S. A. Rosenberg. "Utilization of an alternative open reading frame of a normal gene in generating a novel human cancer antigen." Journal of Experimental Medicine 183, no. 3 (March 1, 1996): 1131–40. http://dx.doi.org/10.1084/jem.183.3.1131.
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Tumor infiltrating lymphocytes (TILs) derived from tumor-bearing patients recognize tumor-associated antigens presented by major histocompatibility complex (MHC) class I molecules. The infusion of TIL586 along with interleukin (IL) 2 into an autologous patient with metastatic melanoma resulted in the objective regression of tumor. A gene encoding a tumor antigen recognized by TIL586 was recently isolated and shown to encode gp75. Here we report that an antigenic peptide, MSLQRQFLR, recognized by TIL586 was not derived from the normal gp75 protein. Instead, this nonamer peptide resulted from translation of an alternative open reading frame of the same gene. Thus, the gp75 gene encodes two completely different polypeptides, gp75 as an antigen recognized by immunoglobulin G antibodies in sera from a patient with cancer, and a 24-amino acid product as a tumor rejection antigen recognized by T cells. This represents the first demonstration that a human tumor rejection antigen can be generated from a normal cellular gene using an open reading frame other than that used to encode the normal protein. These findings revealed a novel mechanism for generating tumor antigens, which may be useful as vaccines to induce tumor-specific cell-mediated immunity against cancer.
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Wang, Guanmeng, Xin Zhou, Giovanni Fucà, Elena Dukhovlinova, Peishun Shou, Hongxia Li, Colette Johnston, Brian Mcguinness, Gianpietro Dotti, and Hongwei Du. "Fully human antibody VH domains to generate mono and bispecific CAR to target solid tumors." Journal for ImmunoTherapy of Cancer 9, no. 4 (April 2021): e002173. http://dx.doi.org/10.1136/jitc-2020-002173.
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BackgroundChimeric antigen receptor (CAR) T cells are effective in B-cell malignancies. However, heterogeneous antigen expression and antigen loss remain important limitations of targeted immunotherapy in solid tumors. Therefore, targeting multiple tumor-associated antigens simultaneously is expected to improve the outcome of CAR-T cell therapies. Due to the instability of single-chain variable fragments, it remains challenging to develop the simultaneous targeting of multiple antigens using traditional single-chain fragment variable (scFv)-based CARs.MethodsWe used Humabody VH domains derived from a transgenic mouse to obtain fully human prostate-specific membrane antigen (PSMA) VH and mesothelin (MSLN) VH sequences and redirect T cell with VH based-CAR. The antitumor activity and mode of action of PSMA VH and MSLN VH were evaluated in vitro and in vivo compared with the traditional scFv-based CARs.ResultsHuman VH domain-based CAR targeting PSMA and MSLN are stable and functional both in vitro and in vivo. VH modules in the bispecific format are capable of binding their specific target with similar affinity as their monovalent counterparts. Bispecific CARs generated by joining two human antibody VH domains can prevent tumor escape in tumor with heterogeneous antigen expression.ConclusionsFully human antibody VH domains can be used to generate functional CAR molecules, and redirected T cells elicit antitumoral responses in solid tumors at least as well as conventional scFv-based CARs. In addition, VH domains can be used to generate bispecific CAR-T cells to simultaneously target two different antigens expressed by tumor cells, and therefore, achieve better tumor control in solid tumors.
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Molino, Annamaria, Gabriella Stevanoni, Pamela Lorenzi, Bruno Dipasquale, Romano Colombari, Marco Chilosi, Gian Luigi Cetto, Guido Forni, Massimo Gerosa, and Giuseppe Tridente. "Establishment and Characterization of a New Human Melanoma Cell Line (HU 214) with a High Growth Potential and Stable Properties." Tumori Journal 74, no. 2 (April 1988): 151–55. http://dx.doi.org/10.1177/030089168807400205.
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A human melanoma cell line (HU 214) with high growth potential was established from a lymph node metastasis of a patient with advanced cutaneous melanoma. The cells of this line were able to grow in monolayer (according to the Rosenblum technique) and in agar (according to the Courtenay-Mills method), and formed tumors when injected in nude mice. The line has been maintained in culture for more than 47 passages. The cell cultures were periodically characterized (every 6-8 passages) by immunohistochemistry using a panel of monoclonal antibodies (MoAbs) including MoAbs against tumor-associated antigens (antimelanoma, antiglioma and anti-LLA), against vimentin, and against major histocompatibility antigens, and including also Ki 67, a MoAb which reacts with a nuclear antigen associated with cell proliferation. The results of this characterization indicate that we have established a human melanoma cell line with a stable antigenic phenotype during subculturing, poorly differentiated cells, and a high growth potential.
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Hyrenius-Wittsten, Axel, Yang Su, Minhee Park, Julie M. Garcia, Josef Alavi, Nathaniel Perry, Garrett Montgomery, Bin Liu, and Kole T. Roybal. "SynNotch CAR circuits enhance solid tumor recognition and promote persistent antitumor activity in mouse models." Science Translational Medicine 13, no. 591 (April 28, 2021): eabd8836. http://dx.doi.org/10.1126/scitranslmed.abd8836.
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The first clinically approved engineered chimeric antigen receptor (CAR) T cell therapies are remarkably effective in a subset of hematological malignancies with few therapeutic options. Although these clinical successes have been exciting, CAR T cells have hit roadblocks in solid tumors that include the lack of highly tumor-specific antigens to target, opening up the possibility of life-threatening “on-target/off-tumor” toxicities, and problems with T cell entry into solid tumor and persistent activity in suppressive tumor microenvironments. Here, we improve the specificity and persistent antitumor activity of therapeutic T cells with synthetic Notch (synNotch) CAR circuits. We identify alkaline phosphatase placental-like 2 (ALPPL2) as a tumor-specific antigen expressed in a spectrum of solid tumors, including mesothelioma and ovarian cancer. ALPPL2 can act as a sole target for CAR therapy or be combined with tumor-associated antigens such as melanoma cell adhesion molecule (MCAM), mesothelin, or human epidermal growth factor receptor 2 (HER2) in synNotch CAR combinatorial antigen circuits. SynNotch CAR T cells display superior control of tumor burden when compared to T cells constitutively expressing a CAR targeting the same antigens in mouse models of human mesothelioma and ovarian cancer. This was achieved by preventing CAR-mediated tonic signaling through synNotch-controlled expression, allowing T cells to maintain a long-lived memory and non-exhausted phenotype. Collectively, we establish ALPPL2 as a clinically viable cell therapy target for multiple solid tumors and demonstrate the multifaceted therapeutic benefits of synNotch CAR T cells.
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Sugiura, Tosihiko, Koichi Kato, and Teruyuki Nagamune. "Antibody opsonization of tumor cell membranes using hapten-PEG-lipid conjugates." Journal of Biomedical Engineering and Informatics 2, no. 2 (November 16, 2015): 1. http://dx.doi.org/10.5430/jbei.v2n2p1.
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Dendritic cell (DC) immunotherapy is a newly developed type of tumor immunotherapy. As a method for generating antigen-presenting DCs, the phagocytosis of whole tumor cells (WTCs) opsonized with antibodies by DCs (antibody-dependent cellular phagocytosis, ADCP) is especially efficient. To opsonize tumor cells, tumor-specific antibodies are usually required. Therefore conventional ADCP was limited to tumor types for which antigens have been identified and antigen-specific antibodies are available. Herein, we developed a general method to promote ADCP by DCs using an arbitrary antibody and evaluated its antitumor effects. To opsonize tumor cells with a tumor-nonspecific antibody, we modified tumor cell surfaces with PEG-lipid-hapten conjugates and a conjugated anti-hapten antibody. By co-culturing DCs with the antibody-opsonized tumor cells, the phagocytosis and DC maturation rates were enhanced by ~20% and ~10%, respectively, compared with co-cultured non-opsonized tumor cells. The administration of tumor antigen-loaded matured DCs to mice resulted in enhanced tumor rejection and long-term survival. The advantages of this method are that tumor-specific antibodies are not required and DCs can present uncharacterized antigens by phagocytosing WTCs and associated antigens. Therefore, this method might be applicable to various types of tumors for which specific antigens have not yet been identified.
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Tegeler, Christian M., Jonas Scheid, Hans-Georg Rammensee, Helmut R. Salih, Juliane S. Walz, Jonas S. Heitmann, and Annika Nelde. "HLA-DR Presentation of the Tumor Antigen MSLN Associates with Clinical Outcome of Ovarian Cancer Patients." Cancers 14, no. 9 (April 30, 2022): 2260. http://dx.doi.org/10.3390/cancers14092260.
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T-cell recognition of HLA-presented antigens is central for the immunological surveillance of malignant disease and key for the development of novel T-cell-based immunotherapy approaches. In recent years, large-scale immunopeptidome studies identified naturally presented tumor-associated antigens for several malignancies. Regarding ovarian carcinoma (OvCa), Mucin-16 (MUC16) and Mesothelin (MSLN) were recently described as the top HLA class I- and HLA class II-presented tumor antigens, respectively. Here, we investigate the role and impact of immunopeptidome-presented tumor antigens on the clinical outcomes of 39 OvCa patients with a follow-up time of up to 50 months after surgery. Patients with a HLA-restricted presentation of high numbers of different MSLN-derived peptides on their tumors exhibited significantly prolonged progression-free (PFS) and overall survival (OS), whereas the presentation of MUC16-derived HLA class I-restricted peptides had no impact. Furthermore, a high HLA-DRB gene expression was associated with increased PFS and OS. In line , in silico prediction revealed that MSLN-derived HLA class II-presented peptides are predominantly presented on HLA-DR allotypes. In conclusion, the correlation of MSLN tumor antigen presentation and HLA-DRB gene expression with prolonged survival indicates a central role of CD4+ T-cell responses for tumor immune surveillance in OvCa, and highlights the importance of immunopeptidome-guided tumor antigen discovery.
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Lendvai, Nikoletta, Sacha Gnjatic, Erika Ritter, Yao-Tseng Chen, Christina Coughlin, Robert H. Vonderheide, Ruben Niesvizky, et al. "Host Immune Responses Against CT Antigens in Multiple Myeloma Patients." Blood 108, no. 11 (November 16, 2006): 3492. http://dx.doi.org/10.1182/blood.v108.11.3492.3492.
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Abstract The type I Melanoma Antigen GEne (MAGE) proteins belong to the Cancer-Testis (CT) family of tumor-associated antigens and are widely expressed in solid and hematologic malignancies. They are immunogenic and frequently elicit spontaneous immune responses in patients with CT antigen-expressing tumors, particularly in malignant melanoma. In melanoma patients, there is high concordance between humoral and cellular immunity. Based on these findings, CT antigens are widely investigated as potential antigenic targets for tumor-specific therapeutic vaccines. We previously showed that the type I MAGE proteins CT7 (MAGE-C1), CT10 (MAGE-C2) and MAGE-A3 were commonly detected in primary myeloma specimens, and expression of CT7 and MAGE-A3 was correlated with abnormally elevated plasma cell proliferation. These findings suggest that type I MAGE may be rational targets for vaccine therapy in multiple myeloma. Therefore, it is important to determine if type I MAGE elicit cellular or humoral immune responses in myeloma patients. To investigate this hypothesis, we assessed cellular immunity against CT7 and humoral immunity against a broad panel of CT antigens. To quantify CT7-specific cellular immunity, expanded, polyclonal pools of T cells from the bone marrow, the tumor microenvironment, were co-cultured in interferon gamma (IFNγ) ELISpot assays with autologous antigen-presenting cells (APC) transduced with in vitro transcribed mRNA coding for CT7 or control antigens. CT antigen-specific humoral immunity was examined by ELISA assay using patient serum or plasma and recombinant CT antigens. This analysis demonstrated that 2/9 patients exhibited specific T cell immunity against CT7 in their bone marrow lymphocytes as measured by IFNγ secretion. These same two patients had positive titers for other CT antigens; one for MAGE-A1 (another type I MAGE), the other for SSX-1 (a structurally distinct CT antigen). Interestingly, neither patient had positive serology for CT7. Serum from 16 other myeloma patients did not have detectible antibody titers for a broad panel of CT antigens. These results show that CT antigens are immunogenic in myeloma patients, with cellular responses against CT7 and humoral responses against MAGE-A1 and SSX-1. However, unlike other types of cancer, there appears to be discordance between humoral and cellular immunity against CT7 in multiple myeloma. This may be due in part to the significant derangements of humoral immunity in this disease. These results support further investigation of immunologic therapies targeting type I MAGE in myeloma, especially therapeutic vaccine strategies.
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Rudd, Christopher E., Youg Raj Thaker, Monika Raab, and Klaus Strebhardt. "GTPase-activating protein (RASAL1) associates with ZAP-70 of the TCR and negatively regulates T-cell proliferation and anti-tumor immunity." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 184.4. http://dx.doi.org/10.4049/jimmunol.202.supp.184.4.
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Abstract T-cell activation is needed for responses to antigen and controls responses to foreign antigen and cancer neo-antigens in immunotherapy. The full range of signaling events that inhibit T-cell activation and limit anti-tumor reactivity is unclear. Previous studies have identified the importance of phosphatases and E-3 ligases as inhibitors of activation. In this study, we show by a combination of tandem affinity chromatography, co-precipitation and proximity ligation analysis (PLA) that RASAL1, a novel GTPase-activating protein (GAP), binds to ZAP-70 of the TCR complex and inhibits anti-CD3 activation of ERKs and proliferation in T-cells. RASAL1 inhibited via two pathways where it binds and inhibits ZAP-70 activity, and acts as a GAP to inhibit the p21ras-ERK pathway. As a negative regulator, its expression is induced as a consequence of T-cell activation, where it reduced in vitro responses to anti-CD3 and to antigenic peptides presented by dendritic cells (DCs), while having no effect on T-cell dwell times. Further, we show that siRNA knock-down of RASAL1 expression increased in vivo CD4+ T-cell responses to peptide antigen while reducing the pulmonary metastasis of B16 melanoma and the growth of solid EL-4 lymphoma tumors. This anti-tumor effect was accompanied by a marked increase in CD8+ tumor-infiltrating T-cells (TILs) expressing effector molecules granzyme B (GZMB) and interferon γ-1 (IFNγ1). These findings identify RASAL1 as a new negative regulator of T-cell activation and tumor immunity.
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Houke, Haley, Xiaoyan Zhu, Kimberly S. Mercer, Jennifer L. Stripay, Jason Chiang, Suzanne Baker, Martine F. Roussel, Stephen Gottschalk, and Giedre Krenciute. "EXTH-73. HETEROGENEITY IN CELL SURFACE ANTIGEN AND HLA CLASS I EXPRESSION IN PEDIATRIC BRAIN TUMORS AND ITS IMPACT ON T-CELL IMMUNOTHERAPY." Neuro-Oncology 22, Supplement_2 (November 2020): ii103. http://dx.doi.org/10.1093/neuonc/noaa215.427.
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Abstract Immunotherapy with tumor antigen-specific chimeric antigen receptor (CAR) and/or ab (T-cell receptor) TCR T-cells has the potential to improve clinical outcomes of patients with pediatric brain tumors. As a prerequisite for successful T-cell therapies, we must determine which cell surface antigens are expressed and targetable in these tumors, and if HLA Class I is present, which is necessary for ab TCR T-cell recognition. Therefore, in this study we systematically analyzed pediatric patient-derived orthotopic xenograft (PDOX) brain tumor samples for cell surface expression of five known CAR targets: IL13Ra2, HER2, EphA2, B7-H3, and GD2, as well as HLA Class I. We established and validated a flow cytometry-based method of profiling tumor-associated antigens. Fifty-three PDOX samples have been profiled to date, including medulloblastoma, high grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), atypical teratoid rhabdoid tumor (ATRT), and ependymoma, among others. Our results showed high variability within and between individual samples. B7-H3 was the most consistently expressed, seen in 98% of the samples tested. We validated these results by conventional immunohistochemistry staining for B7-H3 and found comparable RESULTS: HLA Class I was highly expressed on all HGG samples but was undetectable on 47.8% of other brain tumor samples. This suggests that down-regulation of HLA class I is one mechanism by which brain tumors evade conventional T-cells, and that HLA-independent CAR T-cells would be useful therapies. We also compared expression of antigens in fresh patient samples and corresponding PDOX tumors and saw that they were indeed similar. To our knowledge, this is the largest group of pediatric brain tumor PDOX samples methodically analyzed for potential CAR target antigens and HLA Class I. Taken together, our data demonstrate that elimination of tumors by CAR T-cell immunotherapies will require targeting multiple antigens, and our profiling method could inform how to circumvent antigen-negative relapse.
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Trivedi, Vrunda, Changlin Yang, Oleg Yegorov, Kyle Dyson, and Duane Mitchell. "EXTH-47. PRECISION IMMUNOTHERAPY VACCINES FOR GLIOBLASTOMA USING CANCER IMMUNOGENOMICS AND SELECTIVE GENE ENRICHMENT STRATEGY." Neuro-Oncology 22, Supplement_2 (November 2020): ii97. http://dx.doi.org/10.1093/neuonc/noaa215.401.
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Abstract BACKGROUND Development of successful immunotherapy targeting antigens in Glioblastoma (GBM) remains a challenge owing to the heterogeneous nature of GBM and the low mutation burden. It is therefore important to identify multiple tumor antigens that can be targeted simultaneously. Our goal is to develop a personalized RNA vaccination approach that employs the use of cancer immunogenomics in identifying tumor immunogenic epitopes and target enrichment strategies that allow for targeting only the tumor specific antigens. APPROACH RNAseq and WES was performed for murine GBM tumors KR158 and GL261. Using our Open Reading Frame Antigen Network (O.R.A.N.) algorithm, we identified neoantigens and tumor-associated antigens (TAAs) which includes cancer testis and developmental antigens that are aberrantly over-expressed in the KR158 and GL261 tumors. The genes identified as harboring the target epitopes were subjected to a gene enrichment strategy which included hybridization, capture and amplification of our identified genes from a pool of total tumor cDNA. The precision RNA libraries generated from the enriched cDNA samples were then validated for enrichment of target genes using RNAseq. RESULTS We predicted 12 neoantigens and 15 TAAs as immunogenic targets for the KR158 tumor and 192 neoantigens and 37 TAAs for GL261. Pre-capture and amplification, the 27 KR158 tumor genes constituted only 1.14% of the total tumor cDNA pool, however, we were able to enrich the selected genes to up to 95% of the cDNA pool. The IVT RNA library generated from the enriched cDNA templates also consisted of a 90–95% majority of the predicted tumor-specific genes and only 5–10% of the genes were background. CONCLUSION We have demonstrated the ability to generate tumor antigen specific personalized RNA libraries for murine GBM tumors. RNA vaccines targeting specifically and simultaneously numerous tumor antigens, will pave way for the future of immunotherapy vaccines without the induction of intolerable autoimmunity.
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Giorgadze, Tina, Henning Fischel, Ansel Tessier, and Kerri-Ann Norton. "Investigating Two Modes of Cancer-Associated Antigen Heterogeneity in an Agent-Based Model of Chimeric Antigen Receptor T-Cell Therapy." Cells 11, no. 19 (October 9, 2022): 3165. http://dx.doi.org/10.3390/cells11193165.
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Chimeric antigen receptor (CAR) T-cell therapy has been successful in treating liquid tumors but has had limited success in solid tumors. This work examines unanswered questions regarding CAR T-cell therapy using computational modeling, such as, what percentage of the tumor must express cancer-associated antigens for treatment to be successful? The model includes cancer cell and vascular and CAR T-cell modules that interact with each other. We compare two different models of antigen expression on tumor cells, binary (in which cancer cells are either susceptible or are immune to CAR T-cell therapy) and gradated (where each cancer cell has a probability of being killed by a CAR T-cell). We vary the antigen expression levels within the tumor and determine how effective each treatment is for the two models. The simulations show that the gradated antigen model eliminates the tumor under more parameter values than the binary model. Under both models, shielding, in which the low/non-antigen-expressing cells protect high antigen-expressing cells, reduced the efficacy of CAR T-cell therapy. One prediction is that a combination of CAR T-cell therapies that targets the general population of cells as well as one that specifically targets cancer stem cells should increase its efficacy.
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Li, Claire Y., Hyeung Ju Park, Jinyeon Shin, Jung Eun Baik, Babak J. Mehrara, and Raghu P. Kataru. "Tumor-Associated Lymphatics Upregulate MHC-II to Suppress Tumor-Infiltrating Lymphocytes." International Journal of Molecular Sciences 23, no. 21 (November 3, 2022): 13470. http://dx.doi.org/10.3390/ijms232113470.
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Steady-state lymphatic endothelial cells (LECs) can induce peripheral tolerance by presenting endogenous antigens on MHC class I (MHC-I) molecules. Recent evidence suggests that lymph node LECs can cross-present tumor antigens on MHC-I to suppress tumor-specific CD8+ T cells. Whether LECs can act as immunosuppressive cells in an MHC-II dependent manner in the local tumor microenvironment (TME) is not well characterized. Using murine heterotopic and spontaneous tumor models, we show that LECs in the TME increase MHC-II expression in the context of increased co-inhibitory signals. We provide evidence that tumor lymphatics in human melanoma and breast cancer also upregulate MHC-II compared to normal tissue lymphatics. In transgenic mice that lack LEC-specific MHC-II expression, heterotopic tumor growth is attenuated, which is associated with increased numbers of tumor-specific CD8+ and effector CD4+ T cells, as well as decreased numbers of T regulatory CD4+ cells in the TME. Mechanistically, we show that murine and human dermal LECs can take up tumor antigens in vitro. Antigen-loaded LECs in vitro can induce antigen-specific proliferation of CD8+ T cells but not CD4+ T cells; however, these proliferated CD8+ T cells have reduced effector function in the presence of antigen-loaded LECs. Taken together, our study suggests LECs can act as immunosuppressive cells in the TME in an MHC-II dependent manner. Whether this is a result of direct tumor antigen presentation on MHC-II requires additional investigation.
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Trivedi, Vrunda, Changlin Yang, Graeme Fenton, Oleg Yegorov, Christina Von Roemeling, Kelena Klippel, Elizabeth Ogando-Rivas, et al. "EXTH-44. PERSONALIZED IMMUNOTHERAPY VACCINES FOR GLIOBLASTOMA AND THEIR TREATMENT EFFICACY." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii219. http://dx.doi.org/10.1093/neuonc/noac209.842.
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Abstract BACKGROUND Glioblastoma multiforme (GBM) remains a disease with debilitating survival outcomes. Cancer immunogenomics represents a complementary approach to the application of genomics in developing novel immunotherapies for brain malignancies. Using a cancer immunogenomics approach that we developed, called the Open Reading Frame Antigen Network (O.R.A.N.), we identified the immunogenic neoantigens and tumor-associated antigens (TAAs) including cancer-testis and developmental antigens, that are aberrantly overexpressed in murine models of GBM. The aim of this study is to evaluate the immunologic effects and safety of immunotherapy vaccines targeting neoantigens and TAAs in preclinical models of GBM. METHODS RNAseq and WES were performed for murine glioblastoma tumors- KR158-Luc and GL261, and the results were fed to the O.R.A.N pipeline for antigen prediction. A tumor antigen-specific RNA library was created for each tumor using a gene enrichment strategy and validated by RNAseq. Tumor-bearing animals were treated with adoptively transferred ex vivo expanded lymphocytes and dendritic cell vaccines loaded with the tumor antigen-specific RNA. Tumor volume, and thus progress, was determined using in vivo luciferase imaging technique and the survival outcomes were noted. We also evaluated the efficacy of the tumor vaccines in combination with checkpoint blockade therapy by treating tumor-bearing animals with dendritic cell vaccines loaded with the tumor antigen-specific RNA combined with an anti-PD-1 antibody. RESULTS The dendritic cell vaccines loaded with tumor antigen-specific RNA were significantly effective in slowing the progression of murine GBM tumors in combination with both the adoptive cellular therapy as well as checkpoint blockade therapy. Additionally, we identified antigen-specific T cells targeting several of our predicted antigens and an increase in tumor-infiltrating lymphocytes and memory T cells in the treated animals. CONCLUSION We developed a dendritic cell-based vaccination approach targeting neoantigens and TAAs identified as being tumor-specific and evaluated the efficacy of immunotherapy vaccines in preclinical models of GBM.
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Singhi, Naina, Carolyn Shasha, Sylvia Lee, Julia Szeto, Ata Moshiri, Teresa Kim, John Thompson, et al. "661 Neoantigen-specific CD4+ T cells in human melanoma have diverse differentiation states and correlate with CD8+ T cell, macrophage, and B cell function." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A689. http://dx.doi.org/10.1136/jitc-2021-sitc2021.661.
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BackgroundTumor-antigen specific CD4+ T cells are crucial for the efficacy of antibodies that block immune checkpoint proteins in mouse tumor models, but their activities in human tumor immunity are less clear. CD8+ T cells infiltrating human tumors, including those specific for tumor antigens, have been studied using single cell profiling techniques and exist in a variety of dysfunctional states. The transcriptional states of tumor-specific CD4+ T cells present in tumors and their potential contributions to the tumor microenvironment are less well understood.MethodsWe used targeted single cell RNA sequencing and matching of T cell receptor (TCR) sequences to identify phenotypic signatures that discriminated tumor antigen- and viral antigen-specific CD4+ T cells infiltrating human melanoma tumors in four patients. The presence of CD4+ T cells with these signatures was correlated with the number and phenotype of other immune cells in the tumor microenvironment in an extended cohort of 20 patients.ResultsWe identified 259 CD4+ T cells representing 40 different TCR clonotypes specific for 13 neoantigens and 108 cells representing 14 TCR clonotypes specific for self-antigens in four melanoma patients. High expression of CXCL13 defined conventional CD4+ T cells that recognize tumor associated neoantigens and self-antigens from bystander and viral antigen-specific CD4+ T cells. Tumor-reactive CD4+ T cells could be subdivided into clusters expressing memory and T follicular helper markers, and those expressing cytolytic markers and IFN-g. In an extended cohort of 20 patients with melanoma, the frequency of CXCL13+ CD4+ T cells in the tumor microenvironment correlated with the presence and proliferation of CD8+ T cells, the presence and maturation of B cells, the activation of interferon responsive genes in tumor associated macrophages, and patient survival. CD4+ T cells with similar transcriptional signatures were identified in data sets from breast and non-small cell lung cancer, suggesting these markers may enrich for tumor-reactive CD4+ T cells in many cancers.ConclusionsThese results identify a subset of tumor infiltrating conventional CD4+ T cells in melanoma that are enriched for reactivity to tumor antigens and exist in multiple phenotypic states. Correlations of the presence of these cells with the frequency and phenotype of other immune cells suggest roles for these tumor antigen-specific CD4+ T cells in providing CD8+ T cell help, driving recruitment and maturation of B cells, and activating macrophages. Isolating such cells based on their unique phenotype and utilizing them for adoptive therapy could alter the tumor microenvironment for therapeutic benefit.Ethics ApprovalAll Patient samples in this study were obtained from patients who signed informed consent in a study approved by the institutional review board of the Fred Hutchinson Cancer Research Center (protocol #2643).
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Tegeler, Christian M., Jonas S. Heitmann, Helmut R. Salih, Juliane S. Walz, and Annika Nelde. "Abstract 1972: Clinical implications of HLA expression and immunopeptidome-presented tumor antigens in ovarian carcinoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1972. http://dx.doi.org/10.1158/1538-7445.am2022-1972.
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Abstract Ovarian carcinoma (OvCa) is the seventh most common malignancy in women and the eighth leading cause of cancer-related deaths worldwide. In a previous study, we characterized the antigenic landscape of ovarian carcinoma by mass spectrometry-based immunopeptidomics and identified novel OvCa-associated tumor antigens, including Mucin-16 (MUC-16) and Mesothelin (MSLN) with the aim to develop novel T cell-based immunotherapies (Schuster et al. PNAS 2017). Here, we analyzed the immunopeptidomics data of this OvCa cohort in relation to clinical patient characteristics and disease outcome. Analysis included 43 OvCa patients with respective immunopeptidomics and RNA sequencing data, comprising immunopeptidome diversity, tumor antigen presentation and expression (MUC16, MSLN) as well as HLA mRNA expression.Analyzing HLA class I-restricted tumor antigen presentation in relation to clinical data, we could show that nodal-positive patients presented more frequently HLA-restricted peptides derived from the tumor antigen MUC16 (p = 0.0087) and showed significantly increased numbers of unique MUC16-derived HLA-presented peptides within the total immunopeptidome (p = 0.042) compared to nodal-negative patients. No significant difference in HLA class I immunopeptidome diversity, overall tumor antigen presentation, and expression was observed for histological subtypes, grading, or the prevalence of distant metastases. For HLA class II-restricted tumor antigen presentation and HLA expression in relation to clinical data, we observed a more diverse HLA class II immunopeptidome in terms of different HLA class II-presented peptides (p = 0.011) for patients with high tumor grading (G3) compared to low/intermediate (G1/G2) grading. In line, the tumors of these patients also presented an increased number of different MSLN-derived HLA class II-restricted peptides (p = 0.021). No significant difference in HLA class II immunopeptidome diversity, tumor antigen presentation and expression was seen for the prevalence of distant metastasis, histological subtypes, or nodal positivity.Of note, patients presenting MSLN-derived peptides in their immunopeptidome showed a significantly prolonged recurrence-free survival (RFS, p = 0.011). In addition, patients exhibiting a high expression of HLA-DR showed a significantly increased RFS (p = 0.018 for HLA-DRA, p = 0.0031 for HLA-DRB).In conclusion, this work provides first insights on the relation of immunopeptidomic characteristics, comprising HLA expression and tumor antigen presentation, with clinical characteristics and disease outcome of OvCa patients. The observed correlation of HLA-DR expression and HLA class II tumor antigen presentation with prolonged RFS indicates a central role of CD4+ T cell responses for anti-tumor immune surveillance in ovarian cancer. Citation Format: Christian M. Tegeler, Jonas S. Heitmann, Helmut R. Salih, Juliane S. Walz, Annika Nelde. Clinical implications of HLA expression and immunopeptidome-presented tumor antigens in ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1972.
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D’Souza, Reena Reshma, Paraskevi Dimou, Reyisa Bughda, Elizabeth Hawkins, Clara Leboreiro Babe, and Astero Klampatsa. "Overcoming tumor antigen heterogeneity in CAR-T cell therapy for malignant mesothelioma (MM)." Journal of Cancer Metastasis and Treatment 8, no. 5 (2022): 28. http://dx.doi.org/10.20517/2394-4722.2022.51.
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Malignant mesothelioma (MM) is a rare, aggressive solid tumor with limited therapeutic options and poor therapeutic response. The role of immunotherapy in MM is now well established and therapeutic options, such as checkpoint inhibitors, are increasingly being approved. Chimeric antigen receptor (CAR)-T cell therapy is successfully implemented in several hematologic cancers, but currently has inadequate effect in solid tumors, owing to several limitations, such as trafficking and infiltration, limited T cell persistence and exhaustion, the immunosuppressive TME and tumor antigen heterogeneity. The lack of uniform and universal expression of tumor-associated antigens (TAAs) on tumor cells, as well as TAA heterogeneity following tumor editing post-therapy, are issues of significant importance to CAR-T cell and associated antigen-targeting therapies. Our review discusses the concept of tumor antigen heterogeneity in MM, the consequences for CAR-T cell therapies and the strategies to overcome it.
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Ito, Tomoko, Kikuya Sugiura, Aya Hasegawa, Wakana Ouchi, Takayuki Yoshimoto, Izuru Mizoguchi, Toshio Inaba, Katsuyuki Hamada, Masazumi Eriguchi, and Yoshiyuki Koyama. "Microbial Antigen-Presenting Extracellular Vesicles Derived from Genetically Modified Tumor Cells Promote Antitumor Activity of Dendritic Cells." Pharmaceutics 13, no. 1 (January 4, 2021): 57. http://dx.doi.org/10.3390/pharmaceutics13010057.
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Tumor-derived extracellular vesicles (EVs), as tumor vaccines, carry tumor-associated antigens (TAAs), and were expected to transfer TAAs to antigen-presenting cells. However, treatment with tumor-derived EVs exhibited no obvious antitumor effect on the established tumors, likely due to their immuno-suppressive functions, and also to the poor immunogenicity of TAAs. In order to improve the immune stimulating properties, EVs expressing a highly immunogenic bacterial antigen, 6 kDa early secretory antigenic target (ESAT-6), from Mycobacterium tuberculosis were prepared by genetically modifying the parent tumor cells with a plasmid coding for ESAT-6. Cultured B16 tumor cells were transfected with a ternary complex system consisting of pDNA, polyethylenimine (PEI), and chondroitin sulfate. The cells that were transfected with the ternary complex secreted EVs with a higher number of ESAT-6 epitopes than those transfected by a conventional DNA/PEI binary complex, due to the low cytotoxicity, and durable high expression efficiency of the ternary complex systems. The EVs presenting the ESAT-6 epitope (ESAT-EV) were collected and explored as immune modulatory agents. Dendritic cells (DCs) were differentiated from mouse bone marrow cells and incubated with ESAT-EV. After incubating with the EVs for one day, the DCs expressed a significantly higher level of DC maturation marker, CD86. The DCs treated with ESAT-EV showed a significantly improved antitumor activity in tumor-bearing mice.
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Borrok, M. Jack, Yonghai Li, Paul B. Harvilla, Bharathikumar Vellalore Maruthachalam, Ninkka Tamot, Christine Prokopowitz, Jun Chen, et al. "Conduit CAR: Redirecting CAR T-Cell Specificity with A Universal and Adaptable Bispecific Antibody Platform." Cancer Research Communications 2, no. 3 (March 2022): 146–57. http://dx.doi.org/10.1158/2767-9764.crc-21-0150.
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The success of chimeric antigen receptor (CAR) T-cell therapy against hematologic malignancies has altered the treatment paradigm for patients with these diseases. Nevertheless, the occurrence of relapse due to antigen escape or heterogeneous antigen expression on tumors remains a challenge for first-generation CAR T-cell therapies as only a single tumor antigen can be targeted. To address this limitation and to add a further level of tunability and control to CAR T-cell therapies, adapter or universal CAR T-cell approaches use a soluble mediator to bridge CAR T cells with tumor cells. Adapter CARs allow simultaneous or sequential targeting of multiple tumor antigens, control of immune synapse geometry, dose control, and the potential for improved safety. Herein, we described a novel CAR T-cell adapter platform that relies on a bispecific antibody (BsAb) targeting both a tumor antigen and the GGGGS (G4S) linker commonly used in single-chain Fv (ScFv) domains expressed on CAR T-cell surfaces. We demonstrated that the BsAb can bridge CAR T cells to tumor cells and potentiate CAR T-cell activation, proliferation, and tumor cell cytolysis. The cytolytic activity of CAR T-cells was redirected to different tumor antigens by changing the BsAb in a dose-dependent manner. This study highlights the potential of G4S-displaying CAR T cells to be redirected to engage alternative tumor-associated antigens (TAA). Significance: New approaches are needed to address relapsed/refractory disease and manage potential toxicities associated with CAR T-cell therapy. We describe an adapter CAR approach to redirect CAR T cells to engage novel TAA-expressing cells via a BsAb targeting a linker present on many clinical CAR T-cell therapeutics. We anticipate the use of such adapters could increase CAR T-cell efficacy and reduce potential CAR-associated toxicities.
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Bessell, Catherine Ami, Ariel Isser, Jonathan Havel, Timothy Chan, and Jonathan P. Schneck. "Cross Reactivity of CD8+ T Cell Neo-epitopes to Bifidobacterium Boosts the Tumor Specific Population." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 57.33. http://dx.doi.org/10.4049/jimmunol.200.supp.57.33.
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Abstract The interplay between the microbiome and the anti-tumor T cell specific response is a rising field in cancer immunotherapy. The effect of antigen homology between commensal bacteria and neo-antigen specific responses in tumors has, in concept, a high degree of targeted application. The neo-antigen response is a tumor specific antigen rising from mutation in the tumor cells has been associated with an increased anti-tumor ability with immunotherapy. Using a model of neo-antigen specificity with Kb-SIY in B16-SIY melanoma and commensal bacteria Bifidobacterium we identified a model of antigen mimicry for neo-antigen. Commensal bacteria antigen “Kb-SVY” is not inhibited from binding into the MHC molecule and leads to stable peptide MHC interactions. T cell populations for Kb-SIY and Kb-SVY show cross-reactivity for homologous antigens. And the impact of Bifidobacterium on the developing response show an in vivo priming to create a robust commensal bacteria response that contributes to the anti-tumor activity.
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Yang, Changlin, Vrunda Trivedi, and Duane Mitchell. "CTIM-30. THE PRIVATE AND RECURRING ANTIGENIC PROFILE OF HUMAN MEDULLOBLASTOMA." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii67. http://dx.doi.org/10.1093/neuonc/noac209.262.
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Abstract BACKGROUND Identifying tumor rejection antigens remains a major barrier to developing effective immunotherapeutics and their application to pediatric brain tumors. We performed a multi-faceted computer algorithm, the Open Reading Frame Antigen Network (O.R.A.N.), on medulloblastoma transcription profiles and predicted antigens across a broad array of antigen classes. METHODS Patient-specific HLA haplotypes were called via customized Optitype and Phlat algorithms. Only expressed mutations such as single nucleotide variations, small indels, gene fusions, and Tumor Associated Antigens (TAAs) were used for antigenic epitope predictions. TAAs were selected only if expressed > 1 transcript per million (TPM) in tumor and the standardized expression across a human tissue database. Immunogenic TAA epitopes were screened against a customized human proteomic library to guarantee that epitopes were not shared by other expressed isoforms or genes. Immune deconvolution with single cell RNASeq integration was leveraged for teasing out medulloblastoma immunologic landscape. RESULTS We hypothesized that medulloblastomas are immunologically heterogeneous and express genes with limited normal tissue expression that may serve as targets for immunotherapy. In this study, most neoantigens from medulloblastoma patients were found private suggesting a personalized neoantigen based therapy was on demand. In addition, recurring neoantigens were common in SHH but composed only a small proportion of putative antigens in WNT, Group 3 and Group 4 patients. However, recurring TAAs were found to be more commonly expressed in the latter three molecular subgroups but not in SHH. Together, combining personalized neoantigen vaccine and taking advantage of recurring TAAs approach may maximize anti medulloblastoma effect. CONCULSION Medulloblastoma is a heterogeneous disease, and the current standard of care treatments don’t take that into account. Newer, and safer, patient-specific treatment approaches are required to treat high-risk patients who are not cured by the standard therapies .Cellular immunotherapy might be key to improving survival and avoiding morbidity.
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Abbott, Rebecca C., Hannah E. Hughes-Parry, and Misty R. Jenkins. "To go or not to go? Biological logic gating engineered T cells." Journal for ImmunoTherapy of Cancer 10, no. 4 (April 2022): e004185. http://dx.doi.org/10.1136/jitc-2021-004185.
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Genetically engineered T cells have been successfully used in the treatment of hematological malignancies, greatly increasing both progression-free and overall survival in patients. However, the outcomes of patients treated with Chimeric Antigen Receptor (CAR) T cells targeting solid tumors have been disappointing. There is an unmet clinical need for therapies which are specifically designed to overcome the challenges associated with solid tumors such as tumor heterogeneity and antigen escape. Genetic engineering employing the use of biological logic gating in T cells is an emerging and cutting-edge field that may address these issues. The advantages of logic gating include localized secretion of anti-tumor proteins into the tumor microenvironment, multi antigen targeting of tumors and a potential increase in safety when targeting tumor antigens which may not be exclusively tumor specific. In this review, we introduce the concept of biological logic gating and how this technology addresses some of the challenges of current CAR T treatment. We outline the types of logic gating circuits and finally discuss the application of this new technology to engineered T cells, in the treatment of cancer.
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Leitner, Wolfgang W., Matthew C. Baker, Thomas L. Berenberg, Michael C. Lu, P. Josef Yannie, and Mark C. Udey. "Enhancement of DNA tumor vaccine efficacy by gene gun–mediated codelivery of threshold amounts of plasmid-encoded helper antigen." Blood 113, no. 1 (January 1, 2009): 37–45. http://dx.doi.org/10.1182/blood-2008-01-136267.
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AbstractNucleic acid–based vaccines are effective in infectious disease models but have yielded disappointing results in tumor models when tumor-associated self-antigens are used. Incorporation of helper epitopes from foreign antigens into tumor vaccines might enhance the immunogenicity of DNA vaccines without increasing toxicity. However, generation of fusion constructs encoding both tumor and helper antigens may be difficult, and resulting proteins have unpredictable physical and immunologic properties. Furthermore, simultaneous production of equal amounts of highly immunogenic helper and weakly immunogenic tumor antigens in situ could favor development of responses against the helper antigen rather than the antigen of interest. We assessed the ability of 2 helper antigens (β-galactosidase or fragment C of tetanus toxin) encoded by one plasmid to augment responses to a self-antigen (lymphoma-associated T-cell receptor) encoded by a separate plasmid after codelivery into skin by gene gun. This approach allowed adjustment of the relative ratios of helper and tumor antigen plasmids to optimize helper effects. Incorporation of threshold (minimally immunogenic) amounts of helper antigen plasmid into a DNA vaccine regimen dramatically increased T cell–dependent protective immunity initiated by plasmid-encoded tumor-associated T-cell receptor antigen. This simple strategy can easily be incorporated into future vaccine trials in experimental animals and possibly in humans.
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Trivedi, Vrunda, Changlin Yang, Oleg Yegorov, Kyle Dyson, and Duane Mitchell. "IMMU-32. IDENTIFICATION OF TUMOR-ANTIGEN SPECIFIC T CELLS AND THE EFFICACY OF IMMUNOTHERAPY VACCINES FOR GLIOBLASTOMA ANTIGENS DETERMINED USING CANCER IMMUNOGENOMICS APPROACH." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi99. http://dx.doi.org/10.1093/neuonc/noab196.391.
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Abstract BACKGROUND Glioblastoma multiforme (GBM) remains a disease with debilitating survival outcomes. Owing to the heterogeneous nature and low mutation burden, identifying multiple antigens inherent to GBM that may serve as targets for immune-based therapies is attractive. Our aim is to develop a personalized immunotherapy approach using cancer immunogenomics for prospectively identifying neoantigens and uniquely expressed tumor proteins and then selectively expanding T cells against these truly tumor-specific antigens and dendritic cell vaccines to boost the T cell responses. METHODS RNAseq and WES was performed for murine KR158-luc GBM tumor. Using a cancer immunogenomics approach that we developed, called the O pen R eading Frame A ntigen N etwork (O.R.A.N.), we identified the immunogenic neoantigens and tumor-associated antigens (TAAs) including cancer testis and developmental antigens, that are aberrantly over-expressed in KR158-luc tumor. All predicted genes were subjected to a gene enrichment strategy and an mRNA library was generated containing predominantly only the target genes but had some background non-specific genes (validated by RNAseq). KR158-luc tumor bearing animals were then treated with dendritic cells loaded with the tumor antigen specific mRNA library. Tumor volume and thus progress was determined using in vivo luciferase imaging technique. Additionally, tetramers specific to several of the predicted antigens were manufactured and the frequency of antigen specific T cells was determined using flow cytometry. RESULTS The dendritic cell vaccines were effective in delaying the progression of KR158-luc tumors and we identified T cells targeting several of our predicted antigens in the tumor bearing animals. The antigen specific T cells were detected in the tumor infiltrating lymphocytes as well as in the peripheral lymph organs. CONCLUSION We developed a dendritic cell-based vaccination approach targeting all neoantigens and TAAs identified as being tumor-specific and validated our developed immunogenomics pipeline by identifying antigen-specific T cells in the tumor bearing animals against novel GBM antigens.
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Freire, Teresa, Xiaoming Zhang, Edith Dériaud, Christelle Ganneau, Sophie Vichier-Guerre, Elie Azria, Odile Launay, Richard Lo-Man, Sylvie Bay, and Claude Leclerc. "Glycosidic Tn-based vaccines targeting dermal dendritic cells favor germinal center B-cell development and potent antibody response in the absence of adjuvant." Blood 116, no. 18 (November 4, 2010): 3526–36. http://dx.doi.org/10.1182/blood-2010-04-279133.
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AbstractIn vivo targeting of C-type lectin receptors is an effective strategy for increasing antigen uptake and presentation by dendritic cells (DCs). To induce efficient immune response, glycosylated tumor-associated Tn antigens were used to target DCs through binding to macrophage galactose-type lectin (MGL). The capacity of Tn-glycosylated antigens—and the multiple antigenic glycopeptide Tn3 therapeutic candidate vaccine—to target mouse and human MGL+ DCs are demonstrated, especially regarding dermal DCs. In mice, MGL+ CD103− dermal DCs efficiently captured and processed glycosylated Tn antigen in vivo, inducing a potent major histocompatibility complex (MHC) class II–restricted T-cell response. Intradermal immunization with Tn-glycopeptides induced high levels of Th2 cytokines—even in the presence of unmethylated cytosine-phosphate-guanosine—and was associated with increased expansion of the germinal center B-cell population. Therefore, MGL acts as an efficient endocytic antigen receptor on dermal DCs in vivo, able to prime Tn-specific T- and B-cell responses. Moreover, even in the absence of adjuvant, immunization with this glycosidic Tn-based vaccine induced high levels of anti-Tn antibody responses, recognizing human tumor cells. In vivo DC-targeting strategies, based on Tn-MGL interactions, constitute a promising strategy for enhancing antigen presentation and inducing potent antibody response.
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Wongthida, Phonphimon, Kalli Catcott, Kelly Lancaster, Keith Bentley, Anouk Dirksen, Bingfan Du, Timothy Eitas, et al. "785 STING-agonist ADCs targeting tumor-associated antigens coordinate immune-mediated killing of antigen-negative cancer cells." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A820. http://dx.doi.org/10.1136/jitc-2021-sitc2021.785.
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BackgroundThe tumor microenvironment is a complex, multicellular system, composed not only of malignant cancer cells but also of a diversity of stromal cells including vascular cells, immune cells, and fibroblasts that support tumorigenesis. Antigens expressed on these cells tend to be widely expressed across a range of malignancies, presenting unique opportunities for development of anti-cancer therapies.MethodsWe have previously demonstrated that STING-agonist antibody-drug conjugates (Immunosynthen ADCs) targeting tumor cell antigens induce target-dependent anti-tumor immune responses in vitro and in vivo. To that effect, we hypothesized that Immunosynthen ADCs targeting tumor-associated antigens would coordinate immune-mediated killing of cancer cells not expressing the tumor-associated antigens (antigen-negative cancer cells) and induce anti-tumor activity.ResultsHerein, we demonstrate that targeting tumor-associated antigens with STING-agonist ADCs activate the STING pathway in immune cells via Fcγ receptor-mediated uptake. In addition, due to the intrinsic ability of certain tumor-associated cells to activate the STING pathway, STING-agonist ADCs targeting those cells can induce STING signaling in both the targeted cells and the immune cells, which constitutes a therapeutic advantage of ADCs that activate the STING pathway. In triple co-cultures of antigen-positive tumor-associated cells, antigen-negative cancer cells, and immune cells, the STING-agonist ADC specifically induced potent cell killing of the antigen-negative cancer cells with minimal impact on the immune and tumor-associated cells, thus representing a non-traditional, yet highly effective mechanism of ADC targeting. In vivo efficacy studies showed that STING-agonist ADCs developed for two tumor-associated antigens induced complete, sustained tumor regressions in syngeneic tumor models and exhibited immunological memory after rechallenge. CD8+ T cells contributed to the anti-tumor activity of the STING-agonist ADCs.ConclusionsIn summary, Immunosynthen STING-agonist ADCs targeting tumor-associated antigens represent a novel approach for ADC-mediated cancer immunotherapy and enable the multifaceted activation of the STING pathway in a tumor-targeted manner beyond tumor antigens.
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Saya, Hideyuki, Takashi Masuko, Takashi Kokunai, Hideo Yagita, Akihiro Ijichi, Katsushi Taomoto, Norihiko Tamaki, Satoshi Matsumoto, and Yoshiyuki Hashimoto. "Detection of human glioma-associated antigen by rat monoclonal antibody raised against syngeneic rat glioma cells." Journal of Neurosurgery 65, no. 4 (October 1986): 495–502. http://dx.doi.org/10.3171/jns.1986.65.4.0495.
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✓ A monoclonal antibody termed “FR77” was obtained from a hybridoma clone established by fusion between P3x63Ag8.653 mouse myeloma cells and spleen cells of a Fischer F344 rat hyperimmune to syngeneic 9L/R3 glioma cells. Immunoperoxidase staining of various cultured cells showed that FR77 was reactive to both rat and human glioma cells, but was not reactive with other nonglioma cells. Immunohistochemical examination of paraffin-embedded or cryostat-frozen sections of various human tissues revealed that FR77 was strongly reactive with glioblastoma, grade III astrocytoma, and craniopharyngioma; partially reactive with intracerebral primitive neuroectodermal tumor, pineoblastoma, and desmoplastic medulloblastoma; and weakly reactive with low-grade astrocytoma. It was not reactive with other types of brain tumors and normal human tissues tested. The FR77-defined antigen was observed to be predominantly localized in the cytoplasm of antigen-bearing cells as suggested by the immunostaining pattern, but part of it was also expressed on the cell surface of glioma cells as demonstrated by a complement-mediated cytotoxic test. Fractionation of the antigenic component and periodic acid treatment of tumor tissue bearing the FR77-defined antigen indicated that the antigen is of a neutral glycolipid nature and that the antigenic determinant to FR77 is present on its sugar portion.
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Mrass, Paulus, Hajime Takano, Lai Guan Ng, Sachin Daxini, Marcio O. Lasaro, Amaya Iparraguirre, Lois L. Cavanagh, et al. "Random migration precedes stable target cell interactions of tumor-infiltrating T cells." Journal of Experimental Medicine 203, no. 12 (November 20, 2006): 2749–61. http://dx.doi.org/10.1084/jem.20060710.
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The tumor microenvironment is composed of an intricate mixture of tumor and host-derived cells that engage in a continuous interplay. T cells are particularly important in this context as they may recognize tumor-associated antigens and induce tumor regression. However, the precise identity of cells targeted by tumor-infiltrating T lymphocytes (TILs) as well as the kinetics and anatomy of TIL-target cell interactions within tumors are incompletely understood. Furthermore, the spatiotemporal conditions of TIL locomotion through the tumor stroma, as a prerequisite for establishing contact with target cells, have not been analyzed. These shortcomings limit the rational design of immunotherapeutic strategies that aim to overcome tumor-immune evasion. We have used two-photon microscopy to determine, in a dynamic manner, the requirements leading to tumor regression by TILs. Key observations were that TILs migrated randomly throughout the tumor microenvironment and that, in the absence of cognate antigen, they were incapable of sustaining active migration. Furthermore, TILs in regressing tumors formed long-lasting (≥30 min), cognate antigen–dependent contacts with tumor cells. Finally, TILs physically interacted with macrophages, suggesting tumor antigen cross-presentation by these cells. Our results demonstrate that recognition of cognate antigen within tumors is a critical determinant of optimal TIL migration and target cell interactions, and argue against TIL guidance by long-range chemokine gradients.
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Chinnasamy, Dhanalakshmi, Pawel Muranski, Manuel Franco-Colon, Sawa Ito, Nancy F. Hensel, Catherine M. Bollard, and A. John Barrett. "Generation Of Anti-Tumor CD4+ T Helper Cells Using Genetically-Engineered Dendritic Cells Expressing Leukemia-Associated Antigens." Blood 122, no. 21 (November 15, 2013): 2027. http://dx.doi.org/10.1182/blood.v122.21.2027.2027.
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Abstract Adoptive transfer of antigen-specific T cells is a potentially curative strategy for patients with solid tumors and leukemia. Most clinical trials of adoptive T cell therapy have used cytotoxic CD8+ T cells recognizing MHC class I-restricted tumor antigens. Despite overwhelming evidence suggesting the fundamental influence of CD4+ T cells on the immune system, clinical experience with tumor-specific CD4+ Th cells is almost non-existent. Unlike most other tissues, bone marrow-derived cells constitutively express MHC class II and CD4+ T cells play crucial role in mediating the curative GVL effect after allogeneic SCT and donor lymphocyte infusion (DLI). Furthermore, experimental evidences suggest that MHC class II-restricted antigenic targets recognized by CD4+ T cells exist in both solid cancers and in hematological malignancies. Therefore adoptive immunotherapy using CD4+ T cells in the setting of leukemia might be especially relevant. The goal of this study is to establish a simplified non-individualized protocol of generating LAA-reactive CD4+ T cells from patients and normal donors for adoptive immunotherapy directed against common leukemia-associated antigens (LAA) expressed in acute myeloid leukemias (AML) and myelodysplastic syndrome (MDS). We isolated naïve and memory CD4+ T cells from 3 normal donors and stimulated with twice at weekly interval with autologous monocytes pulsed with libraries of overlapping 15-amino acid length peptides (pepmixes) derived from WT-1, MAGE A3 and A4, PRAME and SSX2 antigens. At the end of the experiment CD4+ T cells were evaluated for reactivity against each LAA by analyzing their ability to specifically release cytokines (IL-2, TNF-α, and IFNγ) using flow cytometry. LAA-specific cells were found in either naïve or memory-derived CD4+ T cells upon stimulation with relevant pepmixes in all donors tested. However specific cytokine production could not be demonstrated when the same T cells were exposed to LAA-transduced autologous targets (LCL and T cells), raising the possibility that the majority of pepmix-reactive cells recognized epitopes that were not naturally processed. Therefore, as an alternative strategy to induce LAA-specific cells capable of targeting only therapeutically-relevant epitopes, we used autologous dendritic cells (DCs) transduced with a lentiviral vector encoding MAGE A3 antigen. Autologous CD4+ T cells were stimulated with MAGE A3 or mock-transduced DCs at an interval of 7-10 days and tested for their antigen-specific cytokine secretion. At the end of the culture we observed that Th cells expanded in presence of MAGE A3-expressing DCs and contained a significant number of cells possessing specific reactive against MAGE A3 pepmix (Figure), but not to unrelated antigenic targets, suggesting induction of LAA-reactivity against naturally-processed MAGE A3 epitopes. In summary, we demonstrate the feasibility of generating specific anti-tumor CD4+ T cells using autologous DCs engineered to express a full-length tumor antigen. This approach allows for selective expansion of polyclonal Th cells recognizing only naturally processed MHC class II-restricted epitopes. Therefore, this strategy circumvents the limitation inherent to usage of overlapping peptide libraries that might induce the expansion of high-avidity T cells specific to epitopes that are irrelevant to in vivo recognition of tumor targets. Furthermore, this approach does not rely on a particular pre-defined MHC class II restriction element, thus it is applicable to majority of donors or patients irrespective of their MHC haplotype. Disclosures: No relevant conflicts of interest to declare.
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Gaffrey, Matthew, and Joan Redd. "Characterization of a tumor-associated antigen on 9L gliosarcoma (101.31)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 101.31. http://dx.doi.org/10.4049/jimmunol.184.supp.101.31.
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Abstract Cell surface antigens play a distinct role in the process of cell transformation and proliferation. The malignant, transformed counterparts of glial cells are referred to as glioma cells. Tumors or cancers resulting from the proliferation of these glioma cells constitute some of the most lethal types of cancer. We have characterized a tumor-associated antigen (TAA) expressed on the cell membrane of the 9L rat glisoarcoma (9L-Ag). Previous work has identified this antigen as a glycoprotein. In this study, we further characterize expression of 9L-Ag by normal brain cells, 9L cells, and a non-glial tumor cell line (P3X3Ag8.653). Characterization of 9L-Ag may provide a better understanding of the transformation processes from a normal to a malignant cell, and the role that 9L-Ag and similar TAAs may play in these processes.
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Lu, Yong-Chen, Xin Yao, Jessica Crystal, Yong Li, Mona El-Gamil, Colin Gross, Lindy Davis, et al. "Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions (TUM2P.878)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 71.2. http://dx.doi.org/10.4049/jimmunol.192.supp.71.2.
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Abstract Cancer immunotherapy with adoptive transfer of tumor infiltrating lymphocytes (TILs) represents an effective treatment for patients with metastatic melanoma, with the objective regressions in up to 72% of patients in three sequential pilot clinical trials. However, the antigen targets recognized by effective TILs remain largely unclear. Melanoma patients 2359 and 2591 both experienced durable complete regressions of metastases ongoing beyond five years following adoptive TIL transfer. A novel approach was developed to identify mutated T-cell antigens by screening a tandem minigene library, which comprised non-synonymous mutation sequences identified by whole-exome sequencing of autologous tumors. The screening of tandem minigene libraries resulted in the identification of mutated kinesin family member 2C (KIF2C) antigen as a target of TIL 2359, and mutated DNA polymerase alpha subunit B (POLA2) antigen as a target of TIL 2591. Both KIF2C and POLA2 have been found to play important roles in cell proliferation. These findings suggest that the minigene screening approach may facilitate the antigen repertoire analysis of tumor reactive T cells, and lead to the development of novel adoptive cell therapies based on the in vitro stimulation of T cells that recognize candidate mutated antigens derived from genes essential for the carcinogenesis.
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Dyachenko, Lada, Kristina Havrysh, Anita Lytovchenko, Irina Dosenko, Stepan Antoniuk, Valeriy Filonenko, and Ramziya Kiyamova. "Autoantibody Response to ZRF1 and KRR1 SEREX Antigens in Patients with Breast Tumors of Different Histological Types and Grades." Disease Markers 2016 (2016): 1–8. http://dx.doi.org/10.1155/2016/5128720.
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Purpose. To investigate a frequency of antibody response to SEREX-identified medullary breast carcinoma autoantigens ZRF1 and KRR1 in sera of breast cancer patients taking into account clinical and molecular characteristics of tumors for opening of new perspectives in creation of minimally invasive immunological tests for cancer diagnostics. Methods. Enzyme-linked immunosorbent assay and bioinformatics analysis. Results. Increased frequency of antibody response was found in sera of breast cancer patients to ZRF and KRR1 antigens. The antibody response to these antigens was higher in sera of patients with invasive ductal carcinoma than in sera of patients with other histological types of breast tumors. Moreover, more frequent antibody response to ZRF antigen was found in sera of patients with less aggressive tumors. The sequence analysis of ZRF1 antigen SEREX clones obtained from cDNA libraries of different tumors demonstrates that they encode different protein isoforms. Conclusion. Tumor-associated antigens KRR1 and ZRF1 and their cognate autoantibodies could be considered as potential molecular markers of breast cancer which need to be further investigated.
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Rius Ruiz, Irene, Rocio Vicario, Beatriz Morancho, Cristina Bernadó Morales, Enrique J. Arenas, Sylvia Herter, Anne Freimoser-Grundschober, et al. "p95HER2–T cell bispecific antibody for breast cancer treatment." Science Translational Medicine 10, no. 461 (October 3, 2018): eaat1445. http://dx.doi.org/10.1126/scitranslmed.aat1445.
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T cell bispecific antibodies (TCBs) are engineered molecules that include, within a single entity, binding sites to the T cell receptor and to tumor-associated or tumor-specific antigens. The receptor tyrosine kinase HER2 is a tumor-associated antigen in ~25% of breast cancers. TCBs targeting HER2 may result in severe toxicities, likely due to the expression of HER2 in normal epithelia. About 40% of HER2-positive tumors express p95HER2, a carboxyl-terminal fragment of HER2. Using specific antibodies, here, we show that p95HER2 is not expressed in normal tissues. We describe the development of p95HER2-TCB and show that it has a potent antitumor effect on p95HER2-expressing breast primary cancers and brain lesions. In contrast with a TCB targeting HER2, p95HER2-TCB has no effect on nontransformed cells that do not overexpress HER2. These data pave the way for the safe treatment of a subgroup of HER2-positive tumors by targeting a tumor-specific antigen.
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Carey, Thomas E., Gregory T. Wolf, S. Hsu, J. Poore, K. Peterson, and K. D. Mcclatchey. "Expression of A9 Antigen and Loss of Blood Group Antigens as Determinants of Survival in Patients with Head and Neck Squamous Carcinoma." Otolaryngology–Head and Neck Surgery 96, no. 3 (March 1987): 221–30. http://dx.doi.org/10.1177/019459988709600301.
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The murine monoclonal antibody (A9), raised to the human squamous cell carcinoma (SCC) cell-line UM-SCC-1, defines a squamous cell antigen associated with aggressive biologic behavior of SCC cell lines in vivo and in vitro. In the present investigation, A9 antigen was detected in tissue sections from 37 consecutive, previously untreated patients with SCC of the head and nack. All tumors were positive for A9 binding, although three distinct patterns (reflecting different intensities of A9 expression) were identified. The intensity of A9 expression was independent of primary tumor site, tumor differentiation, keratinization, or growth pattern. The frequency of high expression (Pattern 1) grew with increasing T class, N class, and tumor stage, and was associated with loss of blood group expression in the tumor and with low levels of lymphocyte infiltration In the tumor. Strong A9 expression had a statistically signification association with low nuclear grade (i.e., tumors with more mature and fewer enlarged nuclei, P = 0.019), low vascular/stromal response (i.e., patchy response rather than continuous, P = 0.014), and impaired in vitro lymphokine production by peripheral blood leukocytes ( P = 0.0011). Of greatest interest, however, was the strong association of high A9 expression with shortened disease-free interval (DFI) ( P = 0.085) and survival ( P = 0.081) relative to patients with weak A9 tumor staining (Patterns 2 and 3). Similarly, the loss of blood group antigen expression was strongly associated with decreased DFI ( P = 0.038) and survival ( P = 0.062). While neither Pattern 1 A 9 expression nor loss of blood group reach statistical significance in prediction of survival, the combination of Pattern 1 A 9 expression and loss of blood group expression in primary tumors was significantly associated, both with decreased disease-free interval ( P = 0.017) and with decreased overall survival ( P = 0.011) (median length of follow-up = 22 months). The length of follow-up (LFU) ranged from 2 to 38 months, with a median LFU of 22 months. While the number of patients (37) is small, the significant association between the expression of these cell-surface markers with relapse and survival indicates that immunohistologic staining of the primary tumor will be an important prognostic indicator useful in identification of individual patients at greatest risk of recurrence or early death from head and neck cancer, independent of tumor size, site, or stage at presentation. These markers may thus provide means of selecting patients who should receive adjuvant therapy and more intensive monitoring for the early detection of recurrent disease.
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Bruno, Tullia Carmela, Peggy Ebner, Brandon Moore, Olivia Squalls, Katherine Waugh, Evgeniy B. Eruslanov, Sunil Singhal, et al. "Antigen-presenting tumor B cells impact the phenotype of CD4 tumor infiltrating T cells in lung cancer patients." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 130.26. http://dx.doi.org/10.4049/jimmunol.198.supp.130.26.
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Abstract The focus of immunotherapy has been on CD8 and CD4 tumor infiltrating lymphocytes (TILs), however, tumor infiltrating B cells (TIL-Bs) are understudied with no focus on their role as antigen presenting cells. We hypothesize that TIL-Bs help generate potent, long-term immune responses against cancer by presenting tumor antigens to CD4 TILs. Using un-manipulated, primary human B cells from fresh tumor, we generated a specific in vitro antigen presentation assay and observed three types of CD4 TIL responses when TIL-Bs presented autologous tumor antigens. There were activated responder CD4 TILs that proliferated when combined with TIL-Bs alone, which indicates stimulation with endogenous tumor antigens. There were antigen-associated responders that required autologous tumor lysate to elicit a CD4 TIL response, and there were patient CD4 TILs that did not respond to antigen presentation. Exhausted B cells have been described in chronic infection i.e. HIV, and thus, to parallel our studies to a model of chronic infection, we analyzed activated and exhausted TIL-Bs with our antigen presentation assay. If TIL-Bs were activated (HLADR+CD69+CD27+CD21+), the resultant CD4 TILs were T helper (anti-tumor) CD4 T cells and if the TIL-Bs were exhausted (HLADR+CD69+CD27−CD21−), the resultant CD4 TILs were T regulatory cells (pro-tumor). These data suggest that TIL-Bs influence CD4 TILs in NSCLC patient tumors. In conclusion, determining if TIL-Bs are activated or exhausted in NSCLC patients will determine the extent of their anti-tumor function in human cancer. Ultimately, results from this study will dictate how to target TIL-Bs in future immunotherapies.