Journal articles: 'Immunocheckpoint'

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Rizzo, Mimma, Matteo Santoni, and Camillo Porta. "Treatment sequencing strategies in metastatic renal cell carcinoma: A critical interpretation of available data." Journal of Onco-Nephrology 4, no. 3 (August 18, 2020): 153–64. http://dx.doi.org/10.1177/2399369320943609.

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Therapeutic sequencing strategies for metastatic renal cell carcinoma have evolved significantly over time. For about 10 years, vascular endothelial growth factor receptor-targeted therapies and mammalian target of rapamycin inhibitors have been the standard of care. About 5 years ago an immunocheckpoint inhibitor, nivolumab, has opened new therapeutic perspectives. Recent clinical studies have confirmed the biological rationale of combining two immunocheckpoint inhibitors or vascular endothelial growth factor-targeted therapies plus immunocheckpoint inhibitors, demonstrating an improvement in clinical outcomes. We are still unable to recognize immunocheckpoint inhibitors responder patients from vascular endothelial growth factor-targeted therapies responder patients and, therefore, to quantify in a certain patient the benefits/harms ratio of upfront combination over sequence therapy in a certain patient. However, the metastatic renal cell carcinoma records of high-volume cancer centers could reveal the effectiveness and tolerability of combined treatments and indicate the potentially predictive factors and the management strategies in the real-world population.

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Singh, Navdeep, Sandeep Singh Lubana, George Constantinou, and Andrea N. Leaf. "Immunocheckpoint Inhibitor- (Nivolumab-) Associated Hypereosinophilia in Non-Small-Cell Lung Carcinoma." Case Reports in Oncological Medicine 2020 (May 15, 2020): 1–5. http://dx.doi.org/10.1155/2020/7492634.

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Immunocheckpoint inhibitor (ICI) therapy has provided significant clinical improvements in the treatment of several malignancies. The purpose of this report is to increase awareness of hypereosinophilia associated with checkpoint inhibitors, a topic that has been rarely reported. Hypereosinophilia may need to be addressed especially if eosinophil counts increase to levels where hypereosinophilic visceral complications can occur. We are presenting a case of a 57-year-old male with hypereosinophilia that was seen in the setting of progression of metastatic non-small-cell lung cancer during and after nivolumab treatment.

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Borghaei, Hossein. "Emerging evidence of immunocheckpoint inhibitors in non-small cell lung cancer." Annals of Oncology 28 (October 2017): ix20. http://dx.doi.org/10.1093/annonc/mdx552.

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Cazzato, Gerardo, Eliano Cascardi, Anna Colagrande, Teresa Lettini, Alessandra Filosa, Francesca Arezzo, Carmelo Lupo, et al. "T Cell Immunoglobulin and Mucin Domain 3 (TIM-3) in Cutaneous Melanoma: A Narrative Review." Cancers 15, no. 6 (March 10, 2023): 1697. http://dx.doi.org/10.3390/cancers15061697.

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T cell immunoglobulin and mucin domain 3 (TIM-3) is an inhibitory immunocheckpoint that belongs to the TIM gene family. Monney et al. first discovered it about 20 years ago and linked it to some autoimmune diseases; subsequent studies have revealed that some tumours, including melanoma, have the capacity to produce inhibitory ligands that bind to these receptor checkpoints on tumour-specific immune cells. We conducted a literature search using PubMed, Web of Science (WoS), Scopus, Google Scholar, and Cochrane, searching for the following keywords: “T cell immunoglobulin and mucin-domain containing-3”, “TIM-3” and/or “Immunocheckpoint inhibitors” in combination with “malignant melanoma” or “human malignant melanoma” or “cutaneous melanoma”. The literature search initially turned up 117 documents, 23 of which were duplicates. After verifying eligibility and inclusion criteria, 17 publications were ultimately included. A growing body of scientific evidence considers TIM-3 a valid inhibitory immuno-checkpoint with a very interesting potential in the field of melanoma. However, other recent studies have discovered new roles for TIM-3 that seem almost to contradict previous findings in this regard. All this demonstrates how common and valid the concept of ‘pleiotropism’ is in the TME field, in that the same molecule can behave completely or partially differently depending on the cell type considered or on temporary conditions. Further studies, large case series, and a special focus on the immunophenotype of TIM-3 are absolutely necessary in order to explore this highly promising topic in the near future.

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Santoni, Matteo, Daniel Y. C. Heng, Gaetano Aurilio, Andrea Iozzelli, Lucilla Servi, Andrea Fabiani, Massimo Giannini, et al. "Combining Radiotherapy with Immunocheckpoint Inhibitors or CAR-T in Renal Cell Carcinoma." Current Drug Targets 21, no. 4 (March 2, 2020): 416–23. http://dx.doi.org/10.2174/1389450120666191017113051.

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Radiotherapy is considered a second life in Renal Cell Carcinoma (RCC) patients, mainly due to the introduction of immune checkpoint inhibitors, such as anti-Programmed-death (PD)-1, alone or in combination with anti-Cytotoxic T-Lymphocyte Antigen (CTLA)-4. Several trials are investigating the efficacy/safety of immune checkpoint inhibitors in sequential or combined strategies with radiotherapy. Chimeric Antigen Receptor (CAR)-T cells therapy as a promising approach in cancer patients has opened the way to novel possibilities of integrating therapies. The identification of biomarkers of tumor response to these combinations represents a challenge in RCC, together with the research for the best partner for immunotherapy in metastatic patients. In this review we illustrated preclinical/clinical data on the integration of radiotherapy with immunocheckpoint inhibitors or CART cells in RCC.

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Mejías, Claudia, and Osmany Guirola. "Pharmacophore model of immunocheckpoint protein PD-L1 by cosolvent molecular dynamics simulations." Journal of Molecular Graphics and Modelling 91 (September 2019): 105–11. http://dx.doi.org/10.1016/j.jmgm.2019.06.001.

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Ebata, T., T. Shimizu, S. Iizumi, T. Koyama, A. Shimomura, S. Iwasa, S. Kondo, et al. "Prognostic factors of patients received immunocheckpoint inhibitors in oncology phase 1 trials." Annals of Oncology 28 (November 2017): x40. http://dx.doi.org/10.1093/annonc/mdx658.004.

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Sonmez, Ozlem, Ozlem Nuray Sever, Basak Oyan, and Osman Gokhan Demir. "Immunotherapy releated cardiomyopathy." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e14601-e14601. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e14601.

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e14601 Background: Side effects of immunotherapies also differ from classical cytoxic chemotherapy agents such as effects. Cardiomyopathy is a relatively rare complication. Studies have shown that the risk of developing myocarditis is higher when the ipilimumab / nivolumab combination is used than when the single agent nivolumab is used. ImmunoCheckpoint inhibitors are associated with an increase in immunologic response and immunosuppressives such as corticosteroids, TNF-alpha antagonists and mycophenolate acetate are used in treatment.In this study, we aimed to report cardiac toxicity in patients who treated with immune checkpoint inhibitors. Methods: Forty patients who were treated with immunocheckpoint inhibitors were screened retrospectively at two centers in Turkey between August 2015 and January 2017 . Results: Twenty-eight of the patients were male (70%), 12 were female (30%); The median age was 61 (32-81) years. 23 (57.5%) patients received nivolumab and 16 (40 %) patients received pembrolizumab and 1(2.5%) patient received pembrolizumab/ipilimumab combination. Seven of the cases had immuno-related side effects (17.5%).In two of our patients, after the second cure of the treatment, diffuse edema and shortness of breath due to heart failure was detected. Echocardiography revealed a low ejection fraction. Methylprednisolone was started by cessation of treatment. One week after the symptoms improved rapidly and control ejection fractions normalized. One of these patients was diagnosed with malignant melanoma and the other with RCC , they using pembrolizumab and nivolumab respectively. Conclusions: In conclusion, side effects that may occur may lead to fatal outcomes, while immunotherapy, which is increasingly used in oncology practice, may result in satisfactory success in treatment. Patients and their relatives should be adequately informed about side effects caused by these agents, complaints should be carefully evaluated and treatment should be started without spending time.

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Saigi, Maria, Juan J. Alburquerque-Bejar, and Montse Sanchez-Cespedes. "Determinants of immunological evasion and immunocheckpoint inhibition response in non-small cell lung cancer: the genetic front." Oncogene 38, no. 31 (June 28, 2019): 5921–32. http://dx.doi.org/10.1038/s41388-019-0855-x.

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Takamori, S., T. Komiya, and E. Powell. "P75.06 Survival Benefit From Immunocheckpoint Inhibitors in Stage IV Non-Small Cell Lung Cancer Patients With Brain Metastases." Journal of Thoracic Oncology 16, no. 3 (March 2021): S575—S576. http://dx.doi.org/10.1016/j.jtho.2021.01.1040.

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Zheng, Aixian, Yanlin Du, Yiru Wang, Youshi Zheng, Zhaoyu Ning, Ming Wu, Cuilin Zhang, Da Zhang, Jingfeng Liu, and Xiaolong Liu. "CD16/PD-L1 bi-specific aptamer for cancer immunotherapy through recruiting NK cells and acting as immunocheckpoint blockade." Molecular Therapy - Nucleic Acids 27 (March 2022): 998–1009. http://dx.doi.org/10.1016/j.omtn.2022.01.010.

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Tuca, Albert, Rosa Gallego, Ismael Ghanem, Mireia Gil-Raga, and Jaime Feliu. "Chemotherapy and Targeted Agents in the Treatment of Elderly Patients with Metastatic Colorectal Cancer." Journal of Clinical Medicine 9, no. 12 (December 11, 2020): 4015. http://dx.doi.org/10.3390/jcm9124015.

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Colorectal cancer (CRC) is one of the main causes of cancer death in the elderly. The older patients constitute a heterogeneous group in terms of functional status, comorbidities, and aging-related conditions. Therefore, therapeutic decisions need to be individualized. Additionally, a higher toxicity risk comes from the fact that pharmacokinetics and pharmacodynamics of the drugs as well as the tissue tolerance can be altered with aging. Although the chemotherapy efficacy in metastatic colorectal cancer (mCRC) is similar for older and young patients, more toxicity is presented in the elderly. While the mono-chemotherapy provides the same benefit for young and older patients, doublets front-line chemotherapy improves progression-free survival (PFS) but not overall survival (OS) in the elderly. Furthermore, the benefit of the addition of bevacizumab to chemotherapy in older patients has been shown in several clinical trials, while the clinical data for the benefit of anti-epidermal growth factor antibodies are scarcer. Immunocheckpoint inhibitors could be an appropriate option for patients with microsatellite instability (MSI) tumors. A prior geriatric assessment is required before deciding the type of treatment in order to offer the best therapeutic option.

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Gambini, Donatella, Stefano Ferrero, and Elisabetta Kuhn. "Lynch Syndrome: From Carcinogenesis to Prevention Interventions." Cancers 14, no. 17 (August 24, 2022): 4102. http://dx.doi.org/10.3390/cancers14174102.

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Lynch syndrome (LS) is the most common inherited disorder responsible for an increased risk of developing cancers at different sites, most frequently in the gastrointestinal and genitourinary tracts, caused by a germline pathogenic variant affecting the DNA mismatch repair system. Surveillance and risk-reducing procedures are currently available and warranted for LS patients, depending on underlying germline mutation, and are focused on relevant targets for early cancer diagnosis or primary prevention. Although pharmacological approaches for preventing LS-associated cancer development were started many years ago, to date, aspirin remains the most studied drug intervention and the only one suggested by the main surveillance guidelines, despite the conflicting findings. Furthermore, we also note that remarkable advances in anticancer drug discovery have given a significant boost to the application of novel immunological strategies such as immunocheckpoint inhibitors and vaccines, not only for cancer treatment, but also in a preventive setting. In this review, we outline the clinical, biologic, genetic, and morphological features of LS as well as the recent three-pathways carcinogenesis model. Furthermore, we provide an update on the dedicated screening, surveillance, and risk-reducing strategies for LS patients and describe emerging opportunities of harnessing the immune system.

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Tessema, Belay, Andreas Boldt, Brigitte König, Melanie Maier, and Ulrich Sack. "Flow-Cytometry Intracellular Detection and Quantification of HIV1 p24 Antigen and Immunocheckpoint Molecules in T Cells among HIV/AIDS Patients." HIV/AIDS - Research and Palliative Care Volume 14 (August 2022): 365–79. http://dx.doi.org/10.2147/hiv.s374369.

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Takamori, S., T. Komiya, and E. Powell. "MA15.07 Survival Benefit From Immunocheckpoint Inhibitors in Stage IV Non-small Cell Lung Cancer Patients ≥75 Years Old of Age." Journal of Thoracic Oncology 16, no. 10 (October 2021): S936. http://dx.doi.org/10.1016/j.jtho.2021.08.193.

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Liu, Jinhui, Xing Chen, Yi Jiang, and Wenjun Cheng. "Development of an immune gene prognostic classifier for survival prediction and respond to immunocheckpoint inhibitor therapy/chemotherapy in endometrial cancer." International Immunopharmacology 86 (September 2020): 106735. http://dx.doi.org/10.1016/j.intimp.2020.106735.

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Ma, Xiaoting, Yujian Zhang, Shan Wang, and Jing Yu. "Predictive value of tumor mutation burden (TMB) with targeted next-generation sequencing in immunocheckpoint inhibitors for non-small cell lung cancer (NSCLC)." Journal of Cancer 12, no. 2 (2021): 584–94. http://dx.doi.org/10.7150/jca.48105.

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Kakizaki, Masatoshi, Yuichiro Yamamoto, Motoyuki Otsuka, Kouichi Kitamura, Masatoshi Ito, Hideki Derek Kawai, Masamichi Muramatsu, Tatehiro Kagawa, and Ai Kotani. "Extracellular vesicles secreted by HBV-infected cells modulate HBV persistence in hydrodynamic HBV transfection mouse model." Journal of Biological Chemistry 295, no. 35 (July 10, 2020): 12449–60. http://dx.doi.org/10.1074/jbc.ra120.014317.

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Hepatitis B, a viral infection that affects the liver, is thought to affect over 257 million people worldwide, and long-term infection can lead to life-threatening issues such as cirrhosis or liver cancer. Chronic hepatitis B develops by the interaction between hepatitis B virus (HBV) and host immune response. However, questions of how HBV-infected cells thwart immune system defenses remain unanswered. Extracellular vesicles (EVs) are used for cellular communication, carrying cargoes such as RNAs, proteins, and lipids and delivering them intracellularly after being endocytosed by target cells. HBV-infected liver cells secrete several types of EVs into body fluids such as complete and incomplete virions, and exosomes. We previously demonstrated that monocytes that incorporated EVs moved to immunoregulatory phenotypes via up-regulation of PD-L1, an immunocheckpoint molecule, and down-regulation of CD69, a leukocyte activation molecule. In this study, we transfected mice with HBV using hydrodynamic injection and studied the effects of EVs secreted by HBV-infected liver cells. EVs secreted from cells with HBV replication strongly suppressed the immune response, inhibiting the eradication of HBV-replicating cells in the mice transfected with HBV. EVs were systemically incorporated in multiple organs, including liver, bone marrow (BM), and intestine. Intriguingly, the BM cells that incorporated EVs acquired intestinal tropism and the dendritic cell populations in the intestine increased. These findings suggest that the EVs secreted by HBV-infected liver cells exert immunosuppressive functions, and that an association between the liver, bone marrow, and intestinal tract exists through EVs secreted from HBV-infected cells.

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Zhang, Geng, Yi Xu, Sen Zhang, and Huifang Zhou. "The ICOSL Expression Predicts Better Prognosis for Nasopharyngeal Carcinoma via Enhancing Oncoimmunity." BioMed Research International 2020 (January 9, 2020): 1–9. http://dx.doi.org/10.1155/2020/9756732.

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Nasopharyngeal carcinoma (NPC) is a malignant tumor with poor prognosis, high morbidity, and mortality. Currently, immunocheckpoint therapy has led to new treatment strategies for almost all cancers, including nasopharyngeal carcinoma. Inducible T-cell aggregation ligand (ICOSL) belongs to the b7-cd28 immunoglobulin superfamily, which is a ligand of ICOS, and also begins to draw attention for its potential usage in cancer treatment. Previous studies from our laboratory have suggested that ICOS expression in tumor-infiltrating lymphocytes is correlated with beneficial outcome, but little is known about the role of ICOSL in NPC. In the current study, ICOSL expression in NPC tumor sections was stained by immunohistochemistry (IHC), and both lymphatic metastasis and distant metastasis showed decreased expression, which was negatively correlated with TNM stage of nasopharyngeal carcinoma. Importantly, high ICOSL expression was significantly associated with overall survival (OS) in patients with NPC (n = 225, p<0.001), and multivariate analysis confirmed that high ICOSL expression was an independent prognostic factor. Fresh nasopharyngeal carcinoma specimens were excised, and the specific expression of cytokines was analyzed by enzyme-linked immunosorbent assay (ELISA). The expression level of ICOSL is positively correlated with interferon-gamma (IFN-γ) concentration in tumor tissues, which is characteristic of T helper 1 (Th1) cells. Knocking down ICOSL by RNAi did not influence the proliferation, migration, and invasion ability of NPC cells. Conclusively, ICOSL expression is associated with increased survival rate in patients with nasopharyngeal carcinoma, which may be a clinical biomarker for prognosis of nasopharyngeal carcinoma.

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Huang, Wan-Ting, Chee Ho Chew, Amanda Chen, Kang-Yuan Lee, Hsing-Lun Lee, Po-Hao Feng, Jeng-Fong Chiou, Kuan-Chou Lin, Po-Li Wei, and Chien-Chung Chen. "Abstract 200: Microtube Array Membrane-Hollow Fiber Assay (MTAM-HFA): A combination of immunocheckpoint blocker (ICBs) and secondary drug anti-cancer drug screening system with significant clinical value propositions for personalized medicine and pre-clinical drug development." Cancer Research 82, no. 12_Supplement (June 15, 2022): 200. http://dx.doi.org/10.1158/1538-7445.am2022-200.

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Abstract Despite modern advances in technology, significant challenges still plague the development of new cancer drugs and cancer care. To address these issue, we are introducing our novel platform technology- Microtube Array Membrane-Hollow Fiber Assay (MTAM-HFA) that is based on combination of the patented MTAM membrane with unique microstructures; replacing the role of traditional hollow fibers enabled the entire HFA assay to be significantly improved in terms of clinical relevance, accuracy, reliability and cost resulting in unprecedented value propositions as an anti-cancer drug screening platform. In the current work, we have clinically demonstrated in several cases where the MTAM-HFA system is capable of accurately predicting clinical response in several Cancers-Lung, Breast and Colon cancers; with unprecedented flexibility of being screened against multiple drug class (including anti-PD1/PDL1) in monotherapy and combination therapy settings. Despite being a phenotypic based assay, the test cycle of MTAM-HFA is only 7-10 days while maintaining a very low cost of up to 60% savings when compared to traditional models such as Patient Derived Xenografts (PDX). When screening ICBs, without the need to use Genetically Engineered Mice (GEM) translates to a cost savings of 98% just for the animal model alone. The combined value proposition of MTAM-HFA makes is a suitable system fulfilling the needs of multiple stakeholders. Citation Format: Wan-Ting Huang, Chee Ho Chew, Amanda Chen, Kang-Yuan Lee, Hsing-Lun Lee, Po-Hao Feng, Jeng-Fong Chiou, Kuan-Chou Lin, Po-Li Wei, Chien-Chung Chen. Microtube Array Membrane-Hollow Fiber Assay (MTAM-HFA): A combination of immunocheckpoint blocker (ICBs) and secondary drug anti-cancer drug screening system with significant clinical value propositions for personalized medicine and pre-clinical drug development [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 200.

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Salabert, Laura, Marine Gross-Goupil, Thibaud Haaser, Jean-Christophe Bernhard, Jean Palussière, and Alain Ravaud. "Impact of metastatic local treatment in the strategy of metastatic renal cell carinoma including sterotactic radiotherapy, surgery, and radiofrequency in an expert center." Journal of Clinical Oncology 36, no. 6_suppl (February 20, 2018): 596. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.596.

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596 Background: Standard treatment of metastatic renal clear cell carcinoma is based upon nephrectomy, and systemic treatment with targeted agents. These drugs induce frequent side effects that may compromise observance and quality of life. Considering a focal treatment of one or more metastases can lead to a drug-holidays, or allow to postpone systemic treatment start in oligometastatic disease. Such focal treatment techniques are surgery, radiofrequency ablation (RFA) or stereotactic radiotherapy (SRT). Methods: In this retrospective, monocentric and analytic study, we analyzed progression-free survival (PFS) and overall survival (OS) after a focal treatment in a cohort of patients from Bordeaux University Hospital, involving similar staff members along time. We have also reported local control, complications and potential predictive factors associated with a better outcome. Results: Seventy-one patients with 78 focal treatments (23 RFA, 47 metastasectomy and 8 SRT) have been included in our study. For 44 patients, the disease was oligometastatic, (1 to sites, less than 5 metastases) including 15 patients with a partial response to systemic treatment before the focal approach, and 12 patients with a dissociated response to systemic treatment. Progression post focal treatment occurred in 53 (74.6 %) of patients. Median PFS was 14 months (95 % confidence interval [CI], - 8-16 months); and median OS was 77 months (95 % CI, 41 months-not reach). Local control rate was 83.3 %, and complication rate was 36.3 % due to local treatments, without death related to iatrogenic events. A diagnosis of metachrone metastases and a disease-free interval between the first diagnosis and the occurrence of the metastases of at least one year seemed to be associated with better outcomes. Conclusions: Data observed in our study are consistent with those reported in literature. The prolonged OS and PFS post focal treatment should encourage clinical oncologists to discuss this multimodal approach (association of systemic and focal treatments). This approach should be also evaluated in the context of the immunocheckpoint inhibitor in the future.

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Zhou, Chengzhi, Zhanhong Xie, Yinyin Qin, Laiyu Liu, Hua Zhang, Weineng Feng, Xiaohong Xie, et al. "Genomic profiling of pulmonary lymphoepithelioma-like carcinoma (PLELC)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 1572. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.1572.

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1572 Background: PLELC, a rare and distinct type of primary lung cancer, is characterized by Epstein-Barr virus (EBV) infection. Histologically, it resembles undifferentiated nasopharyngeal carcinomas (NPC). Only a few hundred cases have been reported since its discovery. Due to the extreme rareness, its genomic landscape remains elusive. Methods: Tissue samples of 27 PLELC patients (13 males and 14 females) with various stages (Ib to IV) were subjected to targeted sequencing using a panel consisting of 520 cancer-related genes, spanning 1.6Mb of human genome. Results: Collectively, we identified 184 somatic mutations spanning 109 genes, including 107 SNVs, 12 insertions or deletions (INDELs) and 65 copy-number amplifications (CNAs). Approximately, 50% of patients had CNAs. One patient had no mutation detected from this panel. Except for 2 patients, 1 with HER2 amplification and another with KRAS mutation, no other classic NSCLC driver genes were detected. The most frequently mutated genes were CCND1, TP53, DAXX and NF kBIA, occurring in 30%, 26%, 22% and 22% of patients, respectively. Interestingly, 78% (21/27) patients had mutations in epigenetic regulators. Of the 184 mutations identified, 51 occurred in epigenetics-related genes. Pathway analysis also revealed an enrichment of genes participating in chromatin remodeling and organization. Next, we compared the genomic profile of PLELC with lung adenocarcinoma and EBV positive NPC. The frequency of TP53 mutations was significantly higher in lung adenocarcinoma (68% vs 26%, p = 0.021). Comparing to NPC, PLELC had significantly more mutations in epigenetic regulators. TMB analysis revealed a median TMB of 1.6/Mb, significantly lowered than lung adenocarcinomas (p < 0.01). We also assessed PD-L1expression and revealed that 67% had an overexpression of PD-L1. Interestingly, TP53-mutant patients were more likely to associated low PD-L1 expression (p < 0.01). Conclusions: In this study, we elucidated a distinct genomic landscape associated with PLELC with no classic NSCLC driver mutation but an enrichment of mutations in epigenetic regulators. The observation of high expression of PD-L1 and lack of canonical druggable driver mutation raises the potential of immunocheckpoint blockade therapy for PLELC.

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Massari, Francesco, Matteo Santoni, Chiara Ciccarese, and Daniele Santini. "The immunocheckpoints in modern oncology: the next 15 years." Expert Opinion on Biological Therapy 15, no. 7 (June 10, 2015): 917–21. http://dx.doi.org/10.1517/14712598.2015.1035251.

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Ndembe, Gloriana, Mirko Marabese, Ilenia Intini, Alessandra Fabbri, Massimo Moro, Mario Occhipinti, Elisa Sottotetti, Giuseppe Lo Russo, Monica Ganzinelli, and Massimo Broggini. "Abstract 2380: The effect of metabolic alterations on chemo-immunotherapy response in non-small-cell lung cancer model." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2380. http://dx.doi.org/10.1158/1538-7445.am2022-2380.

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Abstract Introduction: Lung cancer is one of the leading cause of cancer death worldwide, with an estimate incidence of about 2 million new cases per year. Among all lung cancers, non-small-cell lung cancer (NSCLC) is the most frequent (nearly 85%) with a 5-year survival of about 25% when all stages are considered.NSCLCs are frequently mutated in KRAS or STK11/LKB1 and co-mutation is often reported. Considering the key role of STK11/LKB1 in controlling cell metabolism, we hypothesized that NSCLC harboring mutations in this gene could be vulnerable to metabolic stresses. Different studies in the last years have highlighted how is possible to interfere with cancer metabolism using metformin and caloric restriction.Our work aimed at investigating the role of metabolic stress in determining response to chemotherapy and immunotherapy in LKB1 mutated NSCLC model. Methods: For isolation of cell lines with the genetic backgrounds, nodules from lungs of KRASG12D/LKB1wt and KRASG12D/LKB1mut transgenic mice were used. Stabilized cell lines were then inoculated intramuscularly in immunocompetent mice and treated with chemotherapy alone (cisplatin) or in combination with metformin and caloric restriction. Caloric restriction consisted of 36 hours of fasting every week for three weeks. Metformin was administered daily for the entire experiment while cisplatin was given once a week for three weeks. Results: We started our in vivo experiments comparing the response of the tumors characterized by the mutation in KRASG12D or the co-mutation KRASG12D/LKB1mut. The results indicate that the addition of metformin and caloric restriction improve the activity of cisplatin in both tumors but a stronger effect was detected in tumors presenting the deletion of LKB1. In fact, only in the latter group, the effect of the combination lasted beyond the end of the treatment slowing down the tumor growth. The different combinations were well tolerated. Molecular analysis on tumor samples run in parallel are in progress. Conclusion: Our in vivo preliminary studies confirm our hypothesis that the addition of the caloric restriction and metformin is able to improve the antitumor activity of the cisplatin without increasing the treatment toxicity in tumors characterized by the co-mutations of KRASG12D/LKB1mut. Further investigations are ongoing on the role of metabolic stress in addition to the immunotherapy (using anti PD-1 antibody as immunocheckpoint inhibitor). Citation Format: Gloriana Ndembe, Mirko Marabese, Ilenia Intini, Alessandra Fabbri, Massimo Moro, Mario Occhipinti, Elisa Sottotetti, Giuseppe Lo Russo, Monica Ganzinelli, Massimo Broggini. The effect of metabolic alterations on chemo-immunotherapy response in non-small-cell lung cancer model [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 2380.

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Li, Lincheng, Zhaoda Deng, Zhaohui Xiao, Wenbo Zou, and Rong Liu. "Analysis of Pyroptosis-Related Signature for Predicting Prognosis and Tumor Immune Microenvironment in Pancreatic Cancer." Frontiers in Oncology 12 (May 31, 2022). http://dx.doi.org/10.3389/fonc.2022.770005.

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Pancreatic cancer (PC) has a poor prognosis, which is attributable to its high aggressiveness and lack of effective therapies. Although immunotherapy has been used for the treatment of various tumor, its efficacy in pancreatic cancer is not satisfactory. As a caspase-1-dependent programmed cell death, pyroptosis s involved in the pathological process of many tumors. Nevertheless, the vital role of the pyroptosis-related gene (PRG) in PC remains unknown. In this study, univariate COX regression was performed for 33 pyroptosis-related genes. Based on these prognosis-related PRGs, all PC patients in the Cancer Genome Atlas (TCGA) database were divided into four subtypes. Then, pyroptosis score (PP-score) was established to quantify pyroptosis level for individual PC patients using principal component analysis (PCA) algorithms. Assessment of pyroptosis level within individual PC patients may predict tumor classification and patient prognosis. Finally, a signature was constructed in TCGA and verified in ICGC. In addition, immunocheckpoint analysis revealed the possibility that the low-risk group would benefit more from immunocheckpoint therapy. Taken together, pyroptosis-related genes play a significant role in tumor immunotherapy and can be utilized to predict the prognosis of PC patients.

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Hu, Meng, Weirong Yao, and Qinglin Shen. "Advances and challenges of immunocheckpoint inhibitors in the treatment of primary liver cancer." Frontiers in Genetics 13 (September 30, 2022). http://dx.doi.org/10.3389/fgene.2022.1005658.

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Primary liver cancer (PLC) is one of the most common malignant tumors, which clinically characterized by occult onset, rapid development, easy recurrence and poor prognosis. With the rapid development of tumor immunotherapy research, tumor immunotherapy has also achieved remarkable clinical efficacy, and jointly promoted the overall improvement of tumor immunology from mechanism research to clinical transformation, from single discipline to multi-disciplinary integration. Immunotherapy has obvious advantages in treatment-related toxicity and efficacy compared with traditional therapy. In hepatocellular carcinoma (HCC), immunotherapy alone or in combination with other therapies may help to control tumor progression, and there are many immune checkpoint inhibitors (ICIs) widely used in clinical or ongoing clinical trials. However, tumor immunology research is still facing many challenges. How to effectively evaluate the efficacy, whether there are related biomarkers, the generation of immune tolerance and the lack of clinical trials to objectively evaluate the efficacy are still urgent problems to be solved, but it also brings new research opportunities for basic and clinical immunology researchers. The study of treatment of ICIs of PLC has become a hot spot in clinical research field. This paper summarizes and prospects the research progress and challenges of ICIs for PLC.

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Zhang, Yu, Lifeng Wang, Rutian Li, and Baorui Liu. "The emerging development of tumor mutational burden in patients with NSCLC." Future Oncology, February 12, 2020. http://dx.doi.org/10.2217/fon-2019-0650.

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Immunocheckpoint inhibitors (ICIs) which target PD-1 and CTLA-4 have dramatically changed the history of non-small-cell lung cancer treatment. Multiple biomarkers especially tumor mutational burden (TMB) have been raised to be potential predictors of response to ICIs. However, great value of TMB has been observed in patients who receive ICIs monotherapy instead of ICIs combination therapy from latest exploratory studies. Thus, the innovative concept of TMB needs to be identified. This study uncovers specific aspects of TMB including signatures of TMB, factors related with variation, racial differences, heterogeneity between tissue TMB and blood-based TMB. Additionally, more and more factors are found valuable in clinical trials, suggesting that more markers should be further investigated as interesting candidates for response prediction beyond TMB.

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Boguszewska-Byczkiewicz, Katarzyna, and Agnieszka Kołacińska-Wow. "Liquid biopsy in targeting gene polymorphism related to the response within immunocheckpoint inhibitors therapeutic regimen." Medical Research Journal, May 10, 2021. http://dx.doi.org/10.5603/mrj.a2021.0022.

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Zhang, Jun, Yu Xia, Xiaomei Zhou, Honghao Yu, Yufang Tan, Yaying Du, Qi Zhang, and Yiping Wu. "Current landscape of personalized clinical treatments for triple-negative breast cancer." Frontiers in Pharmacology 13 (September 16, 2022). http://dx.doi.org/10.3389/fphar.2022.977660.

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Triple-negative breast cancer (TNBC) is a highly malignant subtype of breast cancer (BC) with vicious behaviors. TNBC is usually associated with relatively poor clinical outcomes, earlier recurrence, and high propensity for visceral metastases than other BC types. TNBC has been increasingly recognized to constitute a very molecular heterogeneous subtype, which may offer additional therapeutic opportunities due to newly discovered cancer-causing drivers and targets. At present, there are multiple novel targeted therapeutic drugs in preclinical researches, clinical trial designs, and clinical practices, such as platinum drugs, poly ADP-ribose polymerase (PARP) inhibitors, immunocheckpoint inhibitors, androgen receptor inhibitors as well as PI3K/AKT/mTOR targeted inhibitors. These personalized, single, or combinational therapies based on molecular heterogeneity are currently showing positive results. The scope of this review is to highlight the latest knowledge about these potential TNBC therapeutic drugs, which will provide comprehensive insights into the personalized therapeutic strategies and options for combating TNBC.

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Wang, Liguo, Song Han, Changxiang Yan, Yakun Yang, Zhiqiang Li, and Zuocheng Yang. "The role of clinical factors and immunocheckpoint molecules in the prognosis of patients with supratentorial extraventricular ependymoma: a single-center retrospective study." Journal of Cancer Research and Clinical Oncology, January 2, 2021. http://dx.doi.org/10.1007/s00432-020-03425-1.

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Abstract Purpose Supratentorial extraventricular ependymoma (SEE) is a rare subset of ependymomas located in the supratentorial parenchyma, and little is known regarding its management and prognosis. Our study aimed to reveal the prognostic factors in patients with SEE and the roles of programmed death ligand-1 (PD-L1), programmed cell death protein 1 (PD-1), Ki-67, and neural cell adhesion molecule L1 (L1CAM) in predicting these patients’ outcomes. Methods We retrospectively studied the clinical features and prognostic factors in 48 patients with SEE admitted to our center from April 2008 to October 2018. Tissue slides were constructed from patient samples, and PD-L1, PD-1, Ki-67, and L1CAM expression levels were evaluated by immunohistochemistry. Results Patients with gross total resection (GTR) had better progression-free survival than patients with subtotal resection (STR). Moreover, the recurrence hazard ratios in patients with STR at 3, 5, and 10 years were 8.746, 6.866 and 3.962 times those of patients with GTR, respectively. PD-L1 positivity predicted worse progression-free survival, while the recurrence hazard ratios for patients with PD-L1 positivity at 3, 5, and 10 years were 10.445, 5.539, and 3.949 times those of patients with PD-L1 negativity, respectively. Multivariate analysis revealed that PD-L1 expression and GTR could independently predict outcomes in patients with SEE. Conclusion PD-L1 expression was an independent and more readily obtained predictor of outcomes, representing a simple and reliable biological prognostic factor for patients with SEE. Further studies are needed to explore PD-L1 inhibitor treatment for patients with ependymoma. Clinical trial registration No clinical trials were performed in the study.

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Chen, Jierong, Lianghe Lu, Chunhua Qu, Gari A, Fangqi Deng, Muyan Cai, Wei Chen, Lie Zheng, and Jiewei Chen. "Body mass index, as a novel predictor of hepatocellular carcinoma patients treated with Anti-PD-1 immunotherapy." Frontiers in Medicine 9 (September 20, 2022). http://dx.doi.org/10.3389/fmed.2022.981001.

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Immunocheckpoint inhibitors have shown significant efficacy in the treatment of hepatocellular carcinoma (HCC), but there are individual differences. The aim of this study was to explore body mass index (BMI) as a predictor of anti-PD-1 efficacy in patients with HCC. We retrospectively analyzed 101 HCC patients who treated with anti-PD-1 at Sun Yat-sen University Cancer Center from July 2018 to November 2019 and divided them into overweight (BMI > 24.9) and non-overweight (BMI ≤ 24.9) groups based on baseline BMI levels. BMI > 24.9 accounted for 22 cases (21.8%) and BMI ≤ 24.9 accounted for 79 cases (78.2%) in the study cohort. Overweight patients had higher disease control rates than non-overweight patients (P = 0.019, respectively). The mean progression-free survival (PFS) in overweight patients (10.23 months) was significantly longer than that of non-overweight patients (6.85 months; P = 0.027). Among patients with immune-related adverse events (irAEs), the mean PFS was also significantly longer in overweight patients (7.72 months) than in non-overweight patients (5.31 months, P = 0.034). Multivariate analysis showed that BMI was an independent prognostic factor for PFS in HCC patients treated with anti-PD-1 (hazard ratio: 0.47, P = 0.044). Thus, higher BMI predicts a better prognosis among HCC patients treated with anti-PD-1. In clinical practice, patients' BMI can provide a useful tool for predicting the efficacy of anti-PD-1 therapy.

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Kawashima, Atsunari, Takayuki Kanazawa, Kumiko Goto, Mitsunobu Matsumoto, Yu Ishizuya, Cong Wang, Yoshiyuki Yamamoto, et al. "MP73-02 IMMUNOLOGICAL CLASSIFICATION IN RENAL CELL CARCINOMA BASED ON IMMUNOCHECKPOINT MOLECULES: THE RELATIONSHIP WITH TUMOR AGGRESSIVENESS AND THE PRESENCE OF INTRA-TUMOR DIVERSITY." Journal of Urology 197, no. 4S (April 2017). http://dx.doi.org/10.1016/j.juro.2017.02.3347.

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Takamori, Shinkichi, Takefumi Komiya, and Emily Powell. "Survival benefit from immunocheckpoint inhibitors in stage IV non‐small cell lung cancer patients with brain metastases: A National Cancer Database propensity‐matched analysis." Cancer Medicine, December 19, 2020. http://dx.doi.org/10.1002/cam4.3675.

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Merino, María, Teresa Lozano, Noelia Casares, Hugo Lana, Iñaki F. Troconiz, Timo L. M. ten Hagen, Grazyna Kochan, Pedro Berraondo, Sara Zalba, and María J. Garrido. "Dual activity of PD-L1 targeted Doxorubicin immunoliposomes promoted an enhanced efficacy of the antitumor immune response in melanoma murine model." Journal of Nanobiotechnology 19, no. 1 (April 13, 2021). http://dx.doi.org/10.1186/s12951-021-00846-z.

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Abstract Background The immunomodulation of the antitumor response driven by immunocheckpoint inhibitors (ICIs) such as PD-L1 (Programmed Death Ligand-1) monoclonal antibody (α-PD-L1) have shown relevant clinical outcomes in a subset of patients. This fact has led to the search for rational combinations with other therapeutic agents such as Doxorubicin (Dox), which cytotoxicity involves an immune activation that may enhance ICI response. Therefore, this study aims to evaluate the combination of chemotherapy and ICI by developing Dox Immunoliposomes functionalized with monovalent-variable fragments (Fab’) of α-PD-L1. Results Immunoliposomes were assayed in vitro and in vivo in a B16 OVA melanoma murine cell line over-expressing PD-L1. Here, immune system activation in tumor, spleen and lymph nodes, together with the antitumor efficacy were evaluated. Results showed that immunoliposomes bound specifically to PD-L1+ cells, yielding higher cell interaction and Dox internalization, and decreasing up to 30-fold the IC50, compared to conventional liposomes. This mechanism supported a higher in vivo response. Indeed, immunoliposomes promoted full tumor regression in 20% of mice and increased in 1 month the survival rate. This formulation was the only treatment able to induce significant (p < 0.01) increase of activated tumor specific cytotoxic T lymphocytes at the tumor site. Conclusion PD-L1 targeted liposomes encapsulating Dox have proved to be a rational combination able to enhance the modulation of the immune system by blocking PD-L1 and selectively internalizing Dox, thus successfully providing a dual activity offered by both, chemo and immune therapeutic strategies. Graphic Abstract

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Chiang, Zu-Chian, Shubin Fang, Yang-kun Shen, Dongya Cui, Huanjiao Weng, Dawei Wang, Yuxiang Zhao, Jizhen Lin, and Qi Chen. "Development of Novel CD47-Specific ADCs Possessing High Potency Against Non-Small Cell Lung Cancer in vitro and in vivo." Frontiers in Oncology 12 (May 12, 2022). http://dx.doi.org/10.3389/fonc.2022.857927.

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Targeted therapies hold promise for efficiently and accurately delivering cytotoxic drugs directly to tumor tissue to exert anticancer effects. CD47 is a membrane protein expressed in a variety of malignant tumors and hematopoietic cells, which plays a key role in immune escape and tumor progression. Although CD47 immunocheckpoint therapy has been developed in recent years, many patients cannot benefit from it because of its low efficiency. To strengthen and extend the therapeutic efficacy of anti-CD47 monoclonal antibody (mAb), we used the newly developed 7DC2 and 7DC4 mAbs as the targeting payload adaptor and VCMMAE as the toxin payload to construct novel CD47-specific immunotoxin (7DC-VCMMAE) by engineering cysteine residues. These CD47-specific ADCs have the better cell penetration, excellent DAR, similar payload distribution and good antigen-binding affinity. In vitro, 7DC-VCMMAE treatment induced death of non-small cell lung cancer (NSCLC) cell lines 95D and SPC-A1, but not A549 that express low levels of CD47 on the cell membrane. This finding suggests that 7DC-VCMMAE may possess greater therapeutic effect on NSCLC tumors expressing a high level of CD47 antigen; however, 7DC-VCMMAE treatment also promoted phagocytosis of A549 cells by macrophages. In vivo, 7DC-VCMMAE treatment had remarkable antitumor effects in a NSCLC cell line-derived xenograft (CDX) mouse model based on nonobese diabetic/severe combined immunodeficient (NOD/SCID). In summary, this study combined VCMMAE with anti-CD47 mAbs, emphasizing a novel and promising immunotherapy method for direct killing of NSCLC, which provides a valuable new way to meet the needs of the cancer therapy field.

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Kawashima, Atsunari, Yoshiyuki Yamamoto, Mototaka Sato, Wataru Nakata, Yoichi Kakuta, Yu Ishizuya, Yuichiro Yamaguchi, et al. "FAN score comprising fibrosis-4 index, albumin–bilirubin score and neutrophil–lymphocyte ratio is a prognostic marker of urothelial carcinoma patients treated with pembrolizumab." Scientific Reports 11, no. 1 (October 27, 2021). http://dx.doi.org/10.1038/s41598-021-00509-x.

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AbstractIt is important to identify prognostic and predictive markers of metastatic urothelial carcinoma (mUC) treated with immunocheckpoint inhibitors. We sought to establish a prognostic marker for patients with mUC treated with pembrolizumab based on only blood test results. We included 165 patients with mUC in the discovery cohort and 103 with mUC who were treated with pembrolizumab in the validation cohort. Multivariate and Cox regression analyses were used to analyse the data. In the discovery cohort, the fibrosis-4 index (hazard ratio [HR]: 2.13, 95% confidence interval [CI] 1.20–3.76, p = 0.010), albumin–bilirubin score (HR 1.91, 95% CI 1.27–2.88, p = 0.002), and neutrophil–lymphocyte ratio (HR: 1.84, 95% CI 1.22–2.79, p = 0.004) were independent significant prognostic factors. We established a ‘FAN score’ that included these three aforementioned items, which were assigned one point each. We divided patients into the 0–1 point (n = 116) and 2–3 points (n = 49) groups. The FAN score was a significant prognostic marker for cancer-specific survival (CSS) (HR 1.48, 95% CI 1.19–1.83, p < 0.001) along with the Eastern Cooperative Oncology Group Performance Status. The FAN score was also a prognostic factor of progression-free survival (PFS) (HR: 1.25, 95% CI 1.01–1.54, p = 0.036) along with the presence of liver metastasis. In the validation cohort, the FAN score was a significant prognostic factor for CSS (HR: 1.48, 95% CI 1.19–1.85, p = 0.001) and PFS (HR: 1.29, 95% CI 1.02–1.62, p = 0.034). We established the FAN score as a prognostic marker for patients with mUC treated with pembrolizumab.

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Roberta, P., U. Isola, M. Marchetti, M. Giusti, F. Manca, and R. Montisci. "P144 PEMBROLIZUMAB–INDUCED MYOCARDITIS." European Heart Journal Supplements 24, Supplement_C (May 1, 2022). http://dx.doi.org/10.1093/eurheartj/suac012.139.

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Abstract Introduction Patients treated with Immunocheckpoint Inhibitors (ICI) can develop adverse cardiovascular events, most frequently myocarditis, but also arrhythmias, conduction abnormalities, pericarditis, Takotsubo syndrome, ACS, heart failure, cardiac arrest. Myocarditis occurs early, within the first 3–4 administrations of therapy, and is fraught with a high mortality rate. Case Presentation 80–year–old patient with renal pelvic carcinoma who underwent nephroureterectomy and subsequent adrenalectomy. Twenty days after the first cycle of Pembrolizumab, the patient is admitted to cardiology for syncope and ECG finding of Left Posterior Fascicular Block (LPFB) and right bundle branch block (RBBB) with significant increase in troponin without any alterations in regional kinetics and normal ventricular function (EF). The patient also complains of widespread muscle pain and severe hyponatremia on blood tests. On ECG monitoring, alternation of RBBB with associated LPFB and Left Posterior Fascicular Block, left bundle branch block, first and second degree atrio–ventricular block (AV block) and on day II appearance of complete paroxysmal AV block controlled with temporary pacemaker implantation. On the 4th day, we documented changes in the segmental motion of the left ventricle (LV) and progressive gradual worsening of the EF. During the hospitalization the patient manifested episodes of general malaise with profuse sweating and marked hypotension with possible SIADH picture. In suspicion of acute myocarditis, peripheral myositis and possible Pembrolizumab SIADH, the patient was treated with high dose methylprednisolone (1000 mg / day) with little benefit. On the 6th day the patient was found in critical condition, severely suffering, hypotensive and oliguric, resigned herself. Conclusions Our case highlights how even a single dose of Pembrolizumab can trigger an acute inflammatory pattern affecting the myocardium with prevalent involvement of the conduction tissue even before the appearance of alterations in the kinetics and ventricular dysfunction. During ICI therapy cycles it is therefore important to monitor the ECG and troponin levels in order to be able to diagnose myocardial involvement early. In fact, although this complication is rare, it is burdened by a high mortality rate. The only treatment currently available involves the suspension of immunotherapy and the administration of high–dose methylprednisolone.

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Annibali, Ombretta, Antonella Bianchi, Alba Grifoni, Valeria Tomarchio, Mariantonietta Tafuri, Martina Verri, Giuseppe Avvisati, and Anna Crescenzi. "A novel scoring system for TIGIT expression in classic Hodgkin lymphoma." Scientific Reports 11, no. 1 (March 29, 2021). http://dx.doi.org/10.1038/s41598-021-86655-8.

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AbstractClinical use of immune-checkpoints inhibitors (anti PD-1/PD-L1) resulted very effective for the treatment of relapsed/refractory classic Hodgkin Lymphoma (CHL). Recently, T cell Ig and ITIM domains (TIGIT) has been recognized as an immune checkpoint receptor able to negatively regulate T cell functions. Herein, we investigated the expression of TIGIT in CHL microenvironment in order to find a potential new target for inhibitor therapy. TIGIT, PD-1 and PD-L1 expression was evaluated in 34 consecutive patients with CHL. TIGIT expression in T lymphocytes surrounding Hodgkin Reed-Sternberg (HRS) cells was observed in 19/34 patients (56%), of which 11 (58%) had advanced stages. In 16/19 (84%) cases, TIGIT+ peritumoral T lymphocytes showed also PD-1 expression. All 15 TIGIT− patients had PD-L1 expression in HRS cells (100%) while among 19 TIGIT+ patients, 11 (58%) were PD-L1+ and 8 (42%) were PD-L1−. Using a new scoring system for TIGIT immunoreactivity, all TIGIT+ cases with higher score (4/19) were PD-L1−. Our results confirm co-expression of TIGIT and PD-1 in peritumoral T lymphocytes. Of relevance, we demonstrated a mutually exclusive expression of TIGIT and PD-L1 using new TIGIT scoring system able to identify this immunocheckpoints’ modulation. These results pave the way to new therapeutic strategies for relapsed/refractory CHL.

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Journal articles on the topic 'Immunocheckpoint'

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