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Sandri, Sara, Sara Bobisse, Kelly Moxley, Alessia Lamolinara, Francesco De Sanctis, Federico Boschi, Andrea Sbarbati et al. « Feasibility of Telomerase-Specific Adoptive T-cell Therapy for B-cell Chronic Lymphocytic Leukemia and Solid Malignancies ». Cancer Research 76, no 9 (1 mai 2016) : 2540–51. http://dx.doi.org/10.1158/0008-5472.can-15-2318.
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Janelle, Valérie, Mathieu Neault, Marie-Eve Lebel, Dave De Sousa, Salix Boulet, Ludovic Durrieu, Cedric Carli et al. « 516 Caspase-8 regulated senescence as an immune checkpoint in T lymphocytes for adoptive cell therapy ». Journal for ImmunoTherapy of Cancer 8, Suppl 3 (novembre 2020) : A552. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0516.
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BackgroundThe development of immunotherapies holds great promise for the treatment of refractory infections and cancer. Current approaches, although effective in many settings, have limitations that prevent their widespread use. Hence, several aspects require improvements, including the re-wiring of T-cell fates and function. T-cell dysfunction is central to the persistence of several chronic viral infections and the progression of malignancies. Upon activation, T cells can follow several paths of differentiation, leading to terminal effector differentiation and/or exhaustion which are widely recognized as dysfunctional features limiting human immune competence. Furthermore, dysfunctional features induced during laboratory-based manipulations of T-cell products prior to adoptive cell transfer has a determining effect on outcomes. Similarly, repeated antigen encounters after transfer in vivo favors the development of T-cell dysfunction. However, the nature and underlying mechanisms of T-cell dysfunction are still incompletely understood.MethodsCombining genomics, phenotypic and functional analyses in various physiologically and clinically relevant settings, we investigated the key factors leading to T-cell dysfunction. Specifically, we evaluated the impact of repeated stimulations using CD3/CD28-coated beads or antigen-loaded dendritic cells in human T-cell long term cultures, and BCMA-expressing cells for anti-BCMA CAR T cells. We also examined mouse antigen-specific T cells during chronic lymphocytic choriomeningitis virus (LCMV) infection as well as datasets obtained from circulating T cells from acute myeloid leukemia (AML) patients.ResultsWe identified telomere-independent cellular senescence as a central aspect of exhausted PD-1-expressing T cells following repeated stimulations. Mechanistically, it is associated the induction of p16INK4a. Additionally, we found that cellular senescence features are partly regulated by the activation of caspase-8, through a non-apoptotic function of this molecule not previously described in T cells.ConclusionsWe thus conclude that caspase-8 may regulate the balance between apoptosis and proliferation by protecting T cells from cellular senescence. Senescence-associated mechanisms may be seen as key players in T-cell dysfunction occurring following repeated stimulations and as such should be considered as novel immune checkpoints impeding the success of T-cell adoptive immunotherapy in humans.Ethics ApprovalThis study was approved by the local Maisonneuve-Rosemont Hospital research ethics authorities and participants’ informed consent was obtained (CÉR2020-2141 and CÉR13030).
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Tanimoto, Kazushi, Hiroshi Fujiwara, Hiroki Tanaka, Fumihiro Ochi, Hiroaki Asai, Sachiko Okamoto, Junichi Mineno et al. « Concomitant Administration of Gene-Modified T Cells Expressing a Chimeric CD16-CD3ζ Receptor with Mogamulizmab Synergistically Suppresses Adult T Cell Leukemia Cells in Vivo ». Blood 124, no 21 (6 décembre 2014) : 307. http://dx.doi.org/10.1182/blood.v124.21.307.307.
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Abstract [Background and purpose] Mogamulizumab, a newly developed monoclonal antibody (mAb) targeting the receptor for C-C chemokine 4 (CCR4) has initially demonstrated a promising clinical outcome for the treatment of therapy-resistant Adult T cell leukemia (ATL) of which tumor cells broadly express CCR4. However, in practice, we sometimes encounter unsuccessful cases of ATL treated with mogmulizumab, especially in the setting of combination therapy with multiple anticancer agents. In those cases, ATL tumor cells were still positive for CCR4, but the chemotherapy-induced lymphocytopenia was reproducibly noticeable. Considering the pharmacologic action of mogamulizumab, the defucosylation-enhanced antibody-dependent cellular cytotoxicity (ADCC) exerted by FcγRIIIa (CD16) expressing effector cells in vivo, as observed for Natural Killer (NK) cells, we hypothesized that adoptive transfer of ADCC effector cells might be able to regain the anti-ATL efficacy of mogamulizumab. Accordingly, we examined in vivo the feasibility of T cells gene-modified to express a newly generated chimeric CD16-CD3ζ receptor as a transferable alternative effector cell for mogamulizumab. [Methods] A novel affinity-matured chimeric CD16 with a 158V/V-CD3ζ (cCD16ζ ) gene construct was lentivirally introduced into CD3+ T cells from both healthy individuals (n=4) and patients with adult T cell leukemia (ATL) (n=3) (cCD16ζ-T cells). Using ATL or HTLV-1 infected cell lines variably expressing CCR4 on the cell surface (n=7), and primary ATL tumor cells (n=3), in the context of ADCC activity, functional properties of cCD16ζ-T cells were extensively examined both in vitro and in vivo, compared with those of NK cells from healthy donors (n=3). Next, we examined the in vivo therapeutic efficacy of concomitantly infused cCD16ζ-T cells with mogamulizumab via tail vein using a xenografted mouse model. Finally, we examined the feasibility of double gene-modified T cells to express human telomerase reverse transcriptase (hTERT)-specific TCR and cCD16ζ receptor, because we recently demonstrated that HLA-A*24:02-restricted and hTERT461-469 (VYGFVRACL)-specific TCR gene-modified CD8+ T cells displayed the cytocidal activity against ATL tumor cells (Blood, 2014). [Results] cCD16ζ-T cells were readily expandable in ex vivo culture using anti-CD2/CD3/CD28 beads and recombinant human (rh)IL-2, and they successfully displayed ADCC-mediated tumoricidal activity against CCR4+ MT-4 and ATN-1 (ATL cell lines) cells, but not CCR4- K562 cells with mogamulizumab, in a effector cell number and an antibody dose dependent manner. Pharmacological dose of 0.1μg/ml mogamulizumab could bind to ATL cell line cells expressing variable extent of CCR4 ranging from MFI 1.01 for HUT102 cell line to 12.3 for MT-2 (0.57 for K562 as a negative control), and could mediate the similar degree of ADCC activity exerted by cCD16ζ-T cells. The magnitude of ADCC activity mediated by cCD16ζ-T cells against opsonized ATN-1 with mogamulizumab was almost similar to that by activated NK cells using rhIL-2. This cytotoxicity was inhibited by anti-CD16 mAb. During ADCC, ligation of opsonized cancer cells with mogamulizumab to cCD16ζ receptor stimulated cCD16ζ-T cells to release toxic granules shown by CD107a expression. cCD16ζ-T cells generated from patients with ATL (n=3) successfully displayed ADCC activity against autologous tumor cells in vitro. Human cCD16ζ-T cells infused concomitantly with mogamulizumab synergistically inhibited the growth of disseminated luciferase gene-modified ATN-1 cells in immunodeficient mice, demonstrated using an in vivo bioluminescence assay. Additionally, this tumor suppressive effect contributed to the longer survival of treated mice. Finally, the double-gene modified CD3+ T cells could successfully recognize ATN-1 through both the mogamulizumab-opsonized CCR4 and hTERT epitope/HLA-A24*02 complex on the cell surface. Disclosures Okamoto: CDM Center, Takara Bio Inc.: Employment. Mineno:Takara Bio Inc.: Employment. Shiku:Takara Bio Inc.: Research Funding.
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Bankoti, Rashmi, Hazal Pektas Akbal, Maddalena Adorno et Benedetta Di Robilant. « 830 Targeting cellular senescence to increase CAR-T cell fitness ». Journal for ImmunoTherapy of Cancer 8, Suppl 3 (novembre 2020) : A882. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0830.
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BackgroundImmunosenescence refers to the age-associated decline of the adaptive immune system, which results in increased incidence and severity of infections, cancers, and autoimmunity. The elderly show reduced numbers of naïve T cells, skewed CD4:CD8 ratio, reduced proliferative and functional capabilities, and increased expression of senescence markers. These phenomena have strong repercussion in adoptive immunotherapy.Notably, the ex vivo manufacturing process of CAR-T cells per se induces senescence extremely quickly; 15 days of T cell expansion age cells 30 years, as measured by telomere length, T cells differentiation and CDKN2a mRNA levels.To circumvent this problem, we here propose the modulation of USP16, an epigenetic regulator of stem cells and senescence in multiple tissues. Downregulation of USP16 rejuvenates T cells, offering a powerful tool to dramatically improve the efficacy of CAR-T treatments.MethodsDuring ex vivo CAR-T cell manufacture, cells age very rapidly, strongly decreasing T cell fitness. Importantly, we observed that cellular senescence is an early event that precedes T cell exhaustion upon CD3/CD28 T cell stimulation, making it a very interesting pathway to target. In line with this hypothesis, we demonstrated that reducing cellular senescence increases CAR-T cell functions both in vitro and in vivo.ResultsWe identified an epigenetic regulator, USP16, whose mRNA levels increase during T cell expansion and correlate with the expression of the aging marker par excellence, CDKN2a. Genetic modulation of USP16 in CD19 and GD2 CAR-expressing T cells not only reduces senescence markers but also expands the naive (CD45RA+CD62L+) population and enhances cell self-renewal, without negative effects on T cell expansion. USP16 modulation also results in increased killing, polyfunctionality, and expansion upon in vitro stimulation with tumor cells. Notably, the delay of cellular senescence induces long-lasting cellular fitness (figure 1) as T cells are less exhausted upon multiple tumor challenges. In vivo, T cells rejuvenated by USP16 modulation, are 60% more efficient in controlling tumor growth in a mouse model of leukemia (NALM-6) and neuroblastoma (CHLA-255).Abstract 830 Figure 1Effect of USP16 modulation in T cell agingThe schematic shows the relation between cell functionality, exhaustion and cellular senescence in normal T cell aging (top) and when USP16 is inhibited (bottom). USP16 modulation reduces T cell aging, increasing cell functionality and delaying exhaustion and cellular senescence.ConclusionsWe demonstrated that modulation of USP16 prevents cellular senescence and increases self-renewal in T cells. This approach can significantly improve CAR-T therapy in multiple diseases, including leukemias and solid tumors. Development of small molecules against USP16 could offer a viable solution to improve T cell fitness during manufacturing.Ethics ApprovalThe study was approved by Institutional Animal Care and Use Committees (IACUC), approval number CR-0104.
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Garber, Haven R., Asma Mirza, Elizabeth A. Mittendorf et Gheath Alatrash. « Adoptive T-cell therapy for Leukemia ». Molecular and Cellular Therapies 2, no 1 (2014) : 25. http://dx.doi.org/10.1186/2052-8426-2-25.
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Calado, Rodrigo T. « Targeting telomerase : T-cell friendly fire ». Blood 115, no 7 (18 février 2010) : 1316. http://dx.doi.org/10.1182/blood-2009-12-254961.
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Abstract In this issue of Blood, Ugel and colleagues provide evidence that, in murine models, telomerase is an efficient target for adoptive cell therapy against a variety of cancer cells, but also can elicit an autoimmune response against B cells.1
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Ma, Hongbing, Swaminathan Padmanabhan Iyer, Simrit Parmar et Yuping Gong. « Adoptive cell therapy for acute myeloid leukemia ». Leukemia & ; Lymphoma 60, no 6 (10 janvier 2019) : 1370–80. http://dx.doi.org/10.1080/10428194.2018.1553300.
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Ugel, Stefano, Elisa Scarselli, Manuela Iezzi, Carmela Mennuni, Tania Pannellini, Francesco Calvaruso, Barbara Cipriani et al. « Autoimmune B-cell lymphopenia after successful adoptive therapy with telomerase-specific T lymphocytes ». Blood 115, no 7 (18 février 2010) : 1374–84. http://dx.doi.org/10.1182/blood-2009-07-233270.
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Abstract Telomerase reverse transcriptase (TERT) is a good candidate for cancer immunotherapy because it is overexpressed in 85% of all human tumors and implicated in maintenance of the transformed phenotype. TERT-based cancer vaccines have been shown to be safe, not inducing any immune-related pathology, but their impact on tumor progression is modest. Here we show that adoptive cell therapy with the use of high-avidity T lymphocytes reactive against telomerase can control the growth of different established tumors. Moreover, in transgenic adenocarcinoma mouse prostate mice, which develop prostate cancer, TERT-based adoptive cell therapy halted the progression to more aggressive and poorly differentiated tumors, significantly prolonging mouse survival. We also demonstrated that human tumors, including Burkitt lymphoma, and human cancer stem cells, are targeted in vivo by TERT-specific cytotoxic T lymphocytes. Effective therapy with T cells against telomerase, different from active vaccination, however, led to autoimmunity marked by a consistent, although transient, B-cell depletion in primary and secondary lymphoid organs, associated with alteration of the spleen cytoarchitecture. These results indicate B cells as an in vivo target of TERT-specific cytotoxic T lymphocytes during successful immunotherapy.
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Lulla, Premal D., Maksim Mamonkin et Malcolm K. Brenner. « Adoptive Cell Therapy for Acute Myeloid Leukemia and T-Cell Acute Lymphoblastic Leukemia ». Cancer Journal 25, no 3 (2019) : 199–207. http://dx.doi.org/10.1097/ppo.0000000000000376.
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Miyazaki, Yukihiro, Hiroshi Fujiwara, Hiroaki Asai, Fumihiro Ochi, Toshiki Ochi, Taichi Azuma, Takashi Ishida et al. « Development of a novel redirected T-cell–based adoptive immunotherapy targeting human telomerase reverse transcriptase for adult T-cell leukemia ». Blood 121, no 24 (13 juin 2013) : 4894–901. http://dx.doi.org/10.1182/blood-2012-11-465971.
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Key Points The efficacy and safety of a novel redirected T-cell–based adoptive immunotherapy targeting hTERT for patients with adult T-cell leukemia. hTERT-specific T-cell receptor gene-transduced CD8+ T cells lyse ATL cells, but not normal cells, both in vitro and in vivo.
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Cardoso, Angelo A., J. Pedro Veiga, Paolo Ghia, Hernani M. Afonso, W. Nicholas Haining, Stephen E. Sallan et Lee M. Nadler. « Adoptive T-Cell Therapy for B-Cell Acute Lymphoblastic Leukemia : Preclinical Studies ». Blood 94, no 10 (15 novembre 1999) : 3531–40. http://dx.doi.org/10.1182/blood.v94.10.3531.422k14_3531_3540.
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We have previously shown that leukemia-specific cytotoxic T cells (CTL) can be generated from the bone marrow of most patients with B-cell precursor acute leukemias. If these antileukemia CTL are to be used for adoptive immunotherapy, they must have the capability to circulate, migrate through endothelium, home to the bone marrow, and, most importantly, lyse the leukemic cells in a leukemia-permissive bone marrow microenvironment. We demonstrate here that such antileukemia T-cell lines are overwhelmingly CD8+ and exhibit an activated phenotype. Using a transendothelial chemotaxis assay with human endothelial cells, we observed that these T cells can be recruited and transmigrate through vascular and bone marrow endothelium and that these transmigrated cells preserve their capacity to lyse leukemic cells. Additionally, these antileukemia T-cell lines are capable of adhering to autologous stromal cell layers. Finally, autologous antileukemia CTL specifically lyse leukemic cells even in the presence of autologous marrow stroma. Importantly, these antileukemia T-cell lines do not lyse autologous stromal cells. Thus, the capacity to generate anti–leukemia-specific T-cell lines coupled with the present findings that such cells can migrate, adhere, and function in the presence of the marrow microenvironment enable the development of clinical studies of adoptive transfer of antileukemia CTL for the treatment of ALL.
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Yeku, Oladapo, Xinghuo Li et Renier J. Brentjens. « Adoptive T-Cell Therapy for Solid Tumors ». American Society of Clinical Oncology Educational Book, no 37 (mai 2017) : 193–204. http://dx.doi.org/10.1200/edbk_180328.
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Chimeric antigen receptor (CAR) T-cell therapy is an innovative form of immunotherapy wherein autologous T cells are genetically modified to express chimeric receptors encoding an antigen-specific single-chain variable fragment and various costimulatory molecules. Upon administration, these modified T cells traffic to, and recognize, cancer cells in an HLA-independent manner. CAR T-cell therapy has shown remarkable success in the treatment of CD-19–expressing B-cell acute lymphocytic leukemia. However, clinical gains to the same magnitude have not been reported in solid tumors. Several known obstacles to CAR T-cell therapy for solid tumors include target antigen identification, effective trafficking to the tumor, robust activation, proliferation, and in vivo cytotoxicity. Beyond these T-cell intrinsic properties, a complex and dynamic immunosuppressive tumor microenvironment in solid tumors hinders T-cell efficacy. Notable advancements in CAR design to include multiple costimulatory molecules, ligands, and soluble cytokines have shown promise in preclinical models, and some of these are currently in early-phase clinical trials. In this review, we discuss selected solid tumor malignancies and relevant preclinical data and highlight clinical trial results that are available. Furthermore, we outline some obstacles to CAR T-cell therapy for each tumor and propose strategies to overcome some of these limitations.
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Fry, Terry J., et Crystal L. Mackall. « T-cell adoptive immunotherapy for acute lymphoblastic leukemia ». Hematology 2013, no 1 (6 décembre 2013) : 348–53. http://dx.doi.org/10.1182/asheducation-2013.1.348.
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Abstract Substantial progress has been made in the treatment of precursor B-cell acute lymphoblastic leukemia (B-ALL), but recurrent disease remains a leading cause of death in children due to cancer and outcomes for adults with B-ALL remain poor. Recently, complete clinical responses have been observed in small numbers of patients with B-ALL treated with adoptive immunotherapy using T cells genetically engineered to express chimeric antigen receptors (CARs) targeting CD19, a cell surface molecule present in essentially all cases of B-ALL. Preclinical data suggest that CARs targeting CD22, another antigen present in the majority of B-ALL cases, are similarly potent. Several clinical studies already under way will soon more clearly define the rate of response to this novel therapy in B-ALL. Further work is needed to identify optimal platforms for CAR-based adoptive immunotherapy for leukemia, to establish guidelines for managing toxicity, and to determine whether the remissions induced by this approach can be rendered durable.
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Barwe, Sonali P., Fei Huang, Edward Anders Kolb et Anilkumar Gopalakrishnapillai. « Imetelstat Induces Leukemia Stem Cell Death in Pediatric Acute Myeloid Leukemia Patient-Derived Xenografts ». Journal of Clinical Medicine 11, no 7 (30 mars 2022) : 1923. http://dx.doi.org/10.3390/jcm11071923.
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Acute myeloid leukemia (AML) in children remains deadly, despite the use of maximally intensive therapy. Because leukemia stem cells (LSCs) significantly contribute to chemoresistance and relapse, therapies that specifically target the LSCs are likely to be more beneficial in improving outcome. LSCs are known to have high telomerase activity and telomerase activity is negatively correlated with survival in pediatric AML. We evaluated the preclinical efficacy of imetelstat, an oligonucleotide inhibitor of telomerase activity in patient-derived xenograft (PDX) lines of pediatric AML. Imetelstat treatment significantly increased apoptosis/death of the LSC population in a dose-dependent manner in six pediatric AML PDX lines ex vivo, while it had limited activity on the stem cell population in normal bone marrow specimens. These results were validated in vivo in two distinct PDX models wherein imetelstat as single agent or in combination with chemotherapy greatly reduced the LSC percentage and prolonged median survival. Imetelstat combination with DNA hypomethylating agent azacitidine was also beneficial in extending survival. Secondary transplantation experiments showed delayed engraftment and improved survival of mice receiving imetelstat-treated cells, confirming the diminished LSC population. Thus, our data suggest that imetelstat represents an effective therapeutic strategy for pediatric AML.
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Ragnarsson, Gunnar, Hieu Nguyen, Colette Chaney, Bill Ho et Phil Greenberg. « Adoptive T Cell Therapy Targeting WT1 in Leukemia and MDS patients (41.34) ». Journal of Immunology 182, no 1_Supplement (1 avril 2009) : 41.34. http://dx.doi.org/10.4049/jimmunol.182.supp.41.34.
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Abstract Objectives: A clinical trial is being performed to primarily determine the safety in leukemia patients of targeting WT1, a transcription factor over-expressed in leukemia cells that promotes the malignant phenotype, by adoptive transfer of WT1-specific CD8+ clones (CTL). The secondary objectives are to assess in vivo persistence of transferred CTL, localization of transferred cells to bone marrow (BM), and potential antileukemic activity. Methods: HLA-A0201+ patients with relapsed Acute Leukemia, Chronic Myeloid Leukemia or Myelodysplastic Syndrome after allogeneic hematopoietic cell transplant receive 5 infusions, with the last two followed by IL2, of CTL (3.3x10 8-1.0x1010 cells/m2) derived from their matched donor. Results: Four patients have now completed and a fifth patient started therapy. No significant treatment related toxicities were observed in patients who completed therapy. WT1 was elevated in PBMC in 1 patient prior to therapy (a marker of minimal residual disease), and became undetectable after therapy. A second patient exhibited reduction in leukemic blasts after CTL infusion (11.8% to 1.8% of PBMC). The infused CTL persisted for up to 2 weeks in PBMC and were detected in the BM after CTL infusions. Conclusion: The preliminary results suggest infusion of WT1-specific CD8+ clones is safe; and that CTL can localize to the BM and may have anti-leukemic activity. Support: NCI CA18029 & LLS 4442-09
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Mo, Feiyan, Madhuwanti Srinivasan, Royce Ma, Tyler S. Smith, Mary K. McKenna, Erden Atilla, Pinar Ataca Atilla, Helen E. Heslop, Malcolm K. Brenner et Maksim Mamonkin. « Rejection-resistant off-the-shelf T cells for adoptive cell therapy ». Journal of Immunology 202, no 1_Supplement (1 mai 2019) : 71.8. http://dx.doi.org/10.4049/jimmunol.202.supp.71.8.
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Abstract ‘Off-the-shelf’ (OTS) chimeric antigen receptor (CAR) T cells pre-manufactured from healthy donors are a readily available and less expensive alternative to autologous products. However, immune rejection of OTS cells by host T- and NK-cells may limit their persistence and reduce therapeutic effect. Here, we engineered rejection-resistant OTS T cells that recognize and eliminate alloreactive lymphocytes while retaining desired anti-tumor activity. As T- and NK-cells transiently upregulate 4-1BB after activation, T cells expressing a 4-1BB-specific alloimmune defense receptor (ADR) selectively eliminated activated T- and NK-cells while sparing resting lymphocytes. Using this mechanism, ADR-expressing T cells suppressed alloimmune activation and resisted rejection in a mixed lymphocyte reaction (MLR) model in vitro. Further, T cells co-expressing the ADR and a CD19 CAR retained undiminished activity through both receptors in vitro and in vivo. We established a mouse model of allogeneic cell therapy in which NSG mice were engrafted with systemic CD19+ leukemia and normal human T cells. In this model, adoptively transferred unmodified CD19 CAR T cells from an HLA mismatched donor produced only transient anti-tumor activity and were rapidly rejected by pre-engrafted alloreactive T cells within 7 days, leading to fatal leukemia relapse. In contrast, T cells co-expressing both CAR and ADR were protected from immune rejection, resulting in long-term persistence (>9 weeks) and durable leukemia eradication in most animals. These data support the feasibility of using ADR to generate highly potent OTS CAR T cell products that suppress immune rejection to produce long-term therapeutic benefit even in immunocompetent patients.
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Bruedigam, Claudia, Frederik Otzen Bagger, Florian H. Heidel, Catherine Kuhn, Solene Guignes, Axia Song, Rebecca Austin et al. « Inhibition of Telomerase with Imetelstat Is Detrimental to Leukemia Stem Cells in Acute Myeloid Leukemia (AML) ». Blood 124, no 21 (6 décembre 2014) : 2322. http://dx.doi.org/10.1182/blood.v124.21.2322.2322.
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Abstract Telomerase is essential to maintain the long-term replicative potential in many cancers including AML. We have recently shown that genetic deletion of telomerase eradicates long-term LSC function in murine AML, mediated by p53-dependent cell cycle arrest and LSC apoptosis. Novel inhibitors of telomerase have recently entered clinical trials for a variety of malignancies including imetelstat (GRN163L), a competitive inhibitor that binds to the RNA template (TERC) of the telomerase holoenzyme. Here we investigated the therapeutic potential of pharmacologic telomerase inhibition in vivo using primary AML patient sample xenograft transplantation models. Xenografts were established using the NSGS model as recipient and donor patient samples of various AML subtypes including MLL-AF9 translocations (AML-X, AML-18), normal cytogenetics with FLT3-ITD mutation (AML-16), or complex cytogenetics (AML-5). AML engraftment was confirmed by flow cytometry prior to the commencement of GRN163L therapy and found to be similar between groups. Administration of imetelstat prevented the in vivo expansion of AML cells from all subtypes tested as measured by human-specific CD45 flow cytometry in the peripheral blood and spleen. Prolonged treatment with imetelstat (AML-X) prevented AML expansion in vivo and remained cytostatic after imetelstat treatment, until disease progression 5 weeks after the completion of treatment. Imetelstat treatment was associated with prolonged overall survival compared to vehicle control (p < 0.0001). In order to identify the cellular mechanism of imetelstat-mediated inhibition of AML expansion, we performed cell cycle flow cytometry of LSCs from AML xenografts at least three weeks after start of treatment. LSCs from imetelstat-treated xenografts showed marked reduction in G0 (p < 0.0002) but unchanged G1 and S/G2/M percentages demonstrating enforced cell cycle entry or impaired re-entry into quiescence. Gamma-H2AX staining demonstrated significantly increased DNA damage (p < 0.0001) in all AML subtypes analyzed. Next, to determine the effect of imetelstat on bone marrow LSCs, we examined LSCs by immunophenotype. There was depletion of immunophenotypic LSCs and expansion of the differentiated AML population in AML-16 (normal cytogenetic, Flt3 ITD+ve) xenografts. Concordantly, the engraftment and proliferation of AML-16 cells in secondary recipients was significantly delayed, impairing the in vivo expansion of this sample. In contrast, imetelstat prevented AML expansion without depletion in immunophenotypic LSCs or delay in disease relapse after transplantation in the AML-5 xenografts (containing complex cytogenetics, predicting resistance to chemotherapy and dismal clinical outcome). Interestingly, telomerase activity was ten fold higher in this sample than AML-16. We therefore investigated whether imetelstat could impair disease relapse after chemotherapy, a highly clinically relevant model of LSC function. AML-5 transplanted recipient mice were treated with chemotherapy, imetelstat, a combination of imetelstat and chemotherapy, or vehicle control. Chemotherapy alone caused a striking depletion in AML cells, however there was rapid relapse and expansion of the residual hCD45+ AML cells. In contrast, chemotherapy combined with imetelstat prevented hCD45+ cell expansion in recipient mice, an effect that was more pronounced than treatment with imetelstat alone. These data demonstrate the efficacy of pharmacologic inhibition of telomerase using imetelstat in human AML and propose a novel paradigm of AML therapy that is to delay or prevent relapse by targeting AML stem cells in vivo. Together, these data demonstrate a requirement for telomerase in human LSC function from a wide range of AML subtypes and identify telomerase as a tractable therapeutic target in human AML. Disclosures No relevant conflicts of interest to declare.
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Fraietta, Joseph A., Kyle A. Beckwith, Prachi R. Patel, Marco Ruella, Zhaohui Zheng, David M. Barrett, Simon F. Lacey et al. « Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia ». Blood 127, no 9 (3 mars 2016) : 1117–27. http://dx.doi.org/10.1182/blood-2015-11-679134.
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Key Points Ibrutinib treatment of CLL enhances the generation of CAR T cells for adoptive immunotherapy. Concurrent ibrutinib therapy improves the engraftment and therapeutic efficacy of anti-CD19 CAR T cells in mouse models.
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James, Scott E., Nural N. Orgun, Thomas F. Tedder, Mark J. Shlomchik, Michael C. Jensen, Yukang Lin, Philip D. Greenberg et Oliver W. Press. « Antibody-mediated B-cell depletion before adoptive immunotherapy with T cells expressing CD20-specific chimeric T-cell receptors facilitates eradication of leukemia in immunocompetent mice ». Blood 114, no 27 (24 décembre 2009) : 5454–63. http://dx.doi.org/10.1182/blood-2009-08-232967.
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Abstract We have established a model of leukemia immunotherapy using T cells expressing chimeric T-cell receptors (cTCRs) targeting the CD20 molecule expressed on normal and neoplastic B cells. After transfer into human CD20 (hCD20) transgenic mice, cTCR+ T cells showed antigen-specific delayed egress from the lungs, concomitant with T-cell deletion. Few cTCR+ T cells reached the bone marrow (BM) in hCD20 transgenic mice, precluding effectiveness against leukemia. Anti-hCD20 antibody-mediated B-cell depletion before adoptive T-cell therapy permitted egress of mouse CD20-specific cTCR+ T cells from the lungs, enhanced T-cell survival, and promoted cTCR+ T cell–dependent elimination of established mouse CD20+ leukemia. Furthermore, CD20-specific cTCR+ T cells eliminated residual B cells refractory to depletion with monoclonal antibodies. These findings suggest that combination of antibody therapy that depletes antigen-expressing normal tissues with adoptive T-cell immunotherapy enhances the ability of cTCR+ T cells to survive and control tumors.
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Bruedigam, Claudia, Frederik Otzen Bagger, Catherine Paine Kuhn, Therese Vu, Rebecca Austin, Florian H. Heidel, Lars Bullinger et al. « Inhibition Of Telomerase Is a Novel and Effective Therapy In MLL-Rearranged Acute Myeloid Leukemia (AML) ». Blood 122, no 21 (15 novembre 2013) : 2887. http://dx.doi.org/10.1182/blood.v122.21.2887.2887.
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Abstract Telomerase is activated to maintain the long-term replicative potential in many human cancers including AML and novel inhibitors of telomerase have recently entered clinical trials for a variety of malignancies. We investigated the therapeutic potential of telomerase inhibition on MLL-rearranged AML using genetic and pharmacological approaches in murine and humanized models. Telomerase-deficient AML was generated by retroviral transduction of G3 Terc-/- LKS+ (Lin-Kit+Sca1+, enriched for hematopoietic stem cells) with pMIG-MLL-AF9 and compared to wild type (WT) controls. Transformed Terc-/- LKS+ colony-forming units (CFU) were mildly reduced at early passage (week 1 Terc-/- 13.1 ± 1 vs. WT 32.7 ± 4 per 1000 cells input, p < 0.01) but became progressively extinguished with serial replating (week 6 Terc-/- 3.8 ± 0.4 vs. WT 27.0 ± 2.7 per 1000 input, p < 0.01). Loss of CFU correlated with enforced differentiation (reduced Kit, increased Gr1), cell cycle arrest and preferential apoptosis of Kit+ cells. In vivo, AML developed with delayed latency, but was fully penetrant in recipients of G3 Terc-/- and WT cells (Terc-/- 64 days vs. WT 45 days, p < 0.01). Leukemic burden and leukemia stem cell (LSC, GFP+Lin-Sca1-Kit+FcgR+CD34-) frequency were similar between Terc-/- and WT AML. To determine the consequences of telomerase loss on AML LSCs, we performed gene expression profiling of purified LSCs. MLL-AF9-Terc-/- LSCs revealed enrichment of pathways controlling DNA damage/repair, cell cycle and apoptosis. Upstream analysis predicted activation of p53, Rbl1 and Cdkn2a, and inhibition of E2f1 in Terc-/- LSCs. Functionally, shRNA-mediated knockdown of p53 in Terc-/- LSCs partially rescued in vitro CFU, differentiation, cell cycle arrest and apoptosis. The phenotypic changes in Terc-/- AML were amplified by serial passage, suggesting that replicative stress may exacerbate the deleterious effects of telomerase loss on LSC function. To enforce replicative stress in vivo, we performed serial transplantation of Terc-/- AML vs. WT AML. Terc-/- LSCs were unable to generate secondary AML (survival Terc-/- not reached vs. WT 28 days, p < 0.01) and this was confirmed by limiting dilution analysis (Terc-/- LSC frequency 1:224,000 vs. WT 1:184 p < 0.001). Initial engraftment was similar between Terc-/- and WT LSCs. In vivo leukemogenesis was prevented by cell cycle arrest, DNA damage and massive apoptosis (Terc-/- 76.8% ± 3.6% vs. WT 22.49% ± 2.3%, p < 0.0001). Together, these findings demonstrate that in this murine model, telomerase loss eradicates LSC in vivo. To validate these findings in human AML we performed lentiviral shRNA knockdown of hTERT in the MLL-AF9-containing AML cell line Monomac6, followed by transplantation into NSGS (NOD/SCID/IL2Rgamma-/- transgenic for hSCF/hIL3/hGMCSF) xenograft recipients. Two independent shTERT constructs revealed significantly increased survival compared to non-transduced and non-targeting controls (sh-hTERT 149.5 days and 146 days vs. non-transduced 47 days, non-targeting 53.5 days, p< 0.01 for both sh-hTERT). hTERT knockdown correlated with reduced hCD45 engraftment, induction of DNA damage, cell cycle arrest and apoptosis compared to non-transduced or non-targeting shRNA controls. Pharmacological inhibition of telomerase (Telomerase Inhibitor IX, T-IX, Sigma) reduced growth of multiple human AML cell lines in vitro. Treatment with T-IX followed by transplantation of equal numbers of Monomac6 cells prolonged NSGS xenograft survival (T-IX 96.5 days vs. DMSO 59 days, p < 0.05). Finally, we examined the prognostic impact of telomerase-regulated genes in a large cohort of patients with AML. The top 140 differentially expressed genes (p < 0.001) between murine Terc-/- and WT LSCs predicted survival in 2 independent AML clinical trial cohorts. Computational modelling using a random forest approach was able to identify 10 key telomerase-regulated human homologues that could cluster AML patients into prognostically relevant groups and was reproducible in multiple independent datasets. These findings provide new mechanistic understanding into the effects of telomerase inhibition on MLL-rearranged AML and identify the telomerase complex as a novel therapeutic target for AML. Disclosures: No relevant conflicts of interest to declare.
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Kyte, Jon Amund, Gustav Gaudernack, Anne Faane, Kari Lislerud, Else Marit Inderberg, Paal Brunsvig, Steinar Aamdal, Gunnar Kvalheim, Sébastien Wälchli et Martin Pule. « T-helper cell receptors from long-term survivors after telomerase cancer vaccination for use in adoptive cell therapy ». OncoImmunology 5, no 12 (24 octobre 2016) : e1249090. http://dx.doi.org/10.1080/2162402x.2016.1249090.
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Greenberg, P. D. « Therapy of murine leukemia with cyclophosphamide and immune Lyt-2+ cells : cytolytic T cells can mediate eradication of disseminated leukemia. » Journal of Immunology 136, no 5 (1 mars 1986) : 1917–22. http://dx.doi.org/10.4049/jimmunol.136.5.1917.
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Abstract Several animal models have been developed in which the adoptive transfer of specifically immune syngeneic T cells has been shown to mediate the eradication of established tumors. In adoptive chemoimmunotherapy (ACIT) of disseminated FBL leukemia with cyclophosphamide and immune T cells, the major effector T cell has been shown to be a noncytolytic Lyt-1+2- T cell that mediates its therapeutic effect without the participation of CTL. Because studies in other models have suggested that CTL can mediate an anti-tumor effect, the efficacy of Lyt-2+ T cells rendered highly cytolytic before adoptive transfer in ACIT of disseminated FBL was examined. The results demonstrated that such CTL had a detectable but limited therapeutic effect in the treatment of FBL. Because this limited activity of transferred purified CTL might have reflected a requirement for helper T cells to produce IL 2 for promotion of the in vivo survival and proliferation of the CTL, the effect of administering IL 2 to tumor-bearing hosts after transfer of CTL was examined. A dose of IL 2 previously shown to induce in vivo proliferation of transferred T cells rendered CTL that were minimally effective alone curative in ACIT of FBL leukemia. Thus, either lymphokine-producing T cells or the lymphokines produced by these cells are necessary for the full expression of the in vivo therapeutic potential of CTL.
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Boyiadzis, Michael, Chang Sook Hong et Theresa L. Whiteside. « Circulating Exosomes Carrying an Immunosuppressive Cargo Interfere with Adoptive Cell Therapy in Acute Myeloid Leukemia ». Blood 128, no 22 (2 décembre 2016) : 1609. http://dx.doi.org/10.1182/blood.v128.22.1609.1609.
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Abstract Introduction: Adoptive immunotherapy, including transfer of activated NK cells (aNK), is currently under active investigation for patients with refractory/relapsed acute myeloid leukemia (AML). However, the highly immunosuppressive microenvironment in patients with AML may create a major barrier for adoptive immunotherapy. Exosomes, virus-size (30-100 nm) membrane-bound vesicles found in all body fluids, are produced in abundance by leukemic blasts and are strongly immunosuppressive. The presence of exosomes in the plasma of relapsed/refractory AML patients could impair anti-leukemia activity of adoptively transferred aNK cells. To test this hypothesis, we evaluated ex vivo effects of exosomes isolated from plasma of AML patients on the activity of aNK cells which were used for adoptive immunotherapy in a Phase 1 clinical trial (NCT00900809) for patients with relapsed/refractory AML performed at our institution. Methods: Venous blood (20-50 mL) was obtained from patients with refractory/relapsed AML (n=7) prior to and after therapy with adoptively-transferred aNK cells. Exosomes were isolated from the patients' plasma as well as normal controls' (NC) plasma by size exclusion chromatography on Sepharose 2B. Exosome numbers and size (qNano), morphology (TEM) and protein levels were determined. The presence of exosome-related markers (Tsg101, CD81), myeloid cell-surface markers associated with AML (CD123, CLL-1, CD44, CD96) and of immunosuppressive proteins (CD39, CD73, PD-1/ PDL-1, Fas/FasL, TGF-β1) in exosomes was studied by Western blots. The AML plasma-derived exosomes were co-incubated with normal human NK cells or aNK cells used for therapy. Up-take of PKH26-labeled exosomes by recipient aNK cells was monitored by confocal microscopy and changes in NKG2D expression levels on aNK cells or in NK-cell cytotoxicity by multiparameter flow cytometry. Exosome-induced signaling via receptors (A2AR, TGFβR, CD95 or PD-1) on aNK cells was studied by Western blots ± inhibitors of each relevant pathway. Results: The protein levels of exosome fractions in plasma of refractory/relapsed AML patients prior to adoptive therapy with aNK cells were significantly higher (70 ± 15 μg protein/mL) than those isolated from plasma of NCs (35±2.7 μg protein/mL) (P<0.05). Exosome protein levels remained persistently elevated after therapy with the aNK cells. The molecular profile of exosomes in AML patients' plasma was distinct from that of exosomes in plasma of NCs; in addition to leukemia-associated antigens (LAA), AML exosomes were enriched in TGF-β1 (LAP), CD39 and CD73 ectoenzymes, PD-L1 and FasL. Co-incubation of these AML exosomes with the aNK cells that express cognate surface receptors for the above listed ligands or ectoenzymes down-regulated survival and lytic functions of aNK cells. Pharmacologic inhibitors or blocking anti-PD1 mAbs and anti-TGF-β1 mAbs prevented apoptosis and partly abrogated dysfunction of aNK cells. Inhibitory in vivo effects of the high plasma exosome levels in plasma of AML patients was demonstrated by the absence of evidence for up-regulation of NK cytotoxicity in the peripheral blood of the patients receiving adoptive therapy with aNK cells. Conclusions: Persistently elevated levels of biologically-active immunosuppressive exosomes carrying leukemia-associated antigens and various immunosuppressive proteins in plasma of patients with relapsed/refractory AML interfere with anti-leukemia activity of adoptively transferred aNK cells. Blast-derived exosomes emerge as a significant deterrent to a success of adoptive immunotherapies with activated immune cells. Disclosures No relevant conflicts of interest to declare.
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Naik, Swati, Premal Lulla, Ifigeneia Tzannou, Robert A. Krance, George Carrum, Rammurti Kamble, Carlos A. Ramos et al. « Adoptive T-Cell Therapy for Acute Lymphoblastic Leukemia Targeting Multiple Tumor Associated Antigens ». Blood 132, Supplement 1 (29 novembre 2018) : 2693. http://dx.doi.org/10.1182/blood-2018-99-115465.
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Abstract Background: Leukemic relapse remains the major cause of treatment failure in hematopoietic stem cell transplant (HSCT) recipients. While the infusion of donor lymphocytes to prevent and treat relapse has been clinically implemented this strategy does not provide durable remissions and carries the risk of life-threatening graft-versus-host disease (GVHD). More recently the adoptive transfer of T cells that have been engineered to express CD19-targeted chimeric antigen receptors (CARs), has shown potent anti-leukemic activity in HSCT recipients with recurrent disease. However, disease relapse with the emergence of CD19 negative tumors is an emerging clinical issue post-administration of these mono-targeted T cells. To overcome these limitations, we developed a protocol for the generation of donor-derived T cell lines that simultaneously targeted a range of tumor associated antigens (multiTAAs) that are frequently expressed by B- and T-cell ALL including PRAME, WT1 and Survivin for adoptive transfer to high risk recipients transplanted for ALL. Methods/Results: We were consistently able to generate donor-derived multiTAA-specific T cells by culturing PBMCs in the presence of a Th1-polarizing/pro-proliferative cytokine cocktail, using autologous DCs as APCs and loading them with pepmixes (15 mer peptides overlapping by 11 amino acids) spanning all 3 target antigens. The use of whole antigen increases the range of patient HLA polymorphisms that can be exploited beyond those matched to single peptides, while targeting multiple antigens simultaneously reduces the risk of tumor immune evasion. To date, we have generated 14 clinical grade multiTAA-specific T cell lines comprising CD3+ T cells (mean 94±9%) with a mixture of CD4+ (mean 21±28%) and CD8+ (mean 52±24 %) cells, which expressed central [CD45RO+/CD62L+: 14±9%] and effector memory markers [CD45RO+/CD62L-: 80±11%] associated with long term in vivo persistence. The expanded lines recognized the targeted antigens WT1, PRAME and Survivin by IFNg ELIspot with activity against >1 targeted antigens in all cases. None of the lines reacted against non-malignant patient-derived cells (4±3% specific lysis; E: T 20:1) - a study release criterion. Thus far we have treated 8 high risk ALL patients with donor derived TAA T cells post-transplant to prevent disease relapse (Table 1). Infusions were well tolerated with no dose-limiting toxicity, GVHD, CRS or other adverse events. Two patients were not evaluable per study criteria as they received >0.5mg/kg of steroids within 4 weeks of infusion and were replaced. Five of the 6 remaining patients infused remain in CR a median of 11.2 months post-infusion (range 9-22 months). We detected the expansion of tumor-reactive T cells in patient peripheral blood post-infusion against both targeted (WT1, Survivin, PRAME) and non-targeted antigens (SSX2, MAGE-A4, -A1, -A2B, -C1, MART1, AFP and NYESO1) reflecting epitope and antigen spreading. The single patient who relapsed showed no evidence of tumor-directed T cell expansion despite receiving 3 additional infusions at 4 week intervals. Conclusion: In summary, infusion of donor multi-TAA-specific T cells to patients with ALL post allogeneic HSCT is feasible, safe and as evidenced by expansion and antigen spreading in patients, may contribute to disease control. This strategy may present a promising addition to current immunotherapeutic approaches for prophylaxis for leukemic relapse in HSCT recipients. Table 1. Table 1. Disclosures Vera: Marker: Equity Ownership. Heslop:Marker: Equity Ownership; Cytosen: Membership on an entity's Board of Directors or advisory committees; Cell Medica: Research Funding; Gilead Biosciences: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Viracyte: Equity Ownership. Leen:Marker: Equity Ownership.
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Naik, Swati, Premal Lulla, Ifigeneia Tzannou, Juan F. Vera, Adrian P. Gee, Robert A. Krance, Malcolm K. Brenner, Cliona M. Rooney, Stephen Gottschalk et Ann M. Leen. « Adoptive T-Cell Therapy for Acute Lymphoblastic Leukemia Targeting Multiple Tumor-Associated Antigens ». Biology of Blood and Marrow Transplantation 25, no 3 (mars 2019) : S62—S63. http://dx.doi.org/10.1016/j.bbmt.2018.12.144.
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Cantilena, Caroline R., Xin Zhao, Sachiko Kajigaya, Neil Dunavin, Xin Tian, Stephen A. Strickland, Bipin N. Savani et al. « Activity of the Telomerase Inhibitor GRN163L (Imetelstat) on Acute Myeloblastic Leukemia Blasts Is Enhanced By DNA Methyltransferase Inhibitors Irrespective of TERT Promoter Methylation Status ». Blood 126, no 23 (3 décembre 2015) : 1267. http://dx.doi.org/10.1182/blood.v126.23.1267.1267.
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Abstract Introduction. The high telomerase activity in leukemia cells protects them from proliferation arrest, senescence, and apoptosis and may be driven by mutation or epigenetic alteration in the telomerase promoter. However, the mechanism of telomerase regulation and potential therapeutic application of telomerase inhibition in leukemia are not fully understood. We evaluated epigenetic methylation patterns in the telomerase promoter region in myeloid cell lines and primary acute myeloid leukemia (AML) blasts. These epigenetic patterns may serve as a biomarker for sensitivity to DNA methyltransferase (DNMT) inhibitors and have prognostic significance. We also studied whether the telomerase inhibitor GRN163L (imetelstat)can favorably combine with the DNMT inhibitor 5-Azacytidine (5-Aza) to target poor prognosis leukemias. Methods. We developed a pyrosequencing-based methylation assay to screen methylation profiles of the proximal promoter and partial exon 1 of the human telomerase reverse transcriptase (hTERT pro/Ex1) region in primary leukemic cells and various cell lines.We used a chemosensitivity assay to determine specific killing of primary leukemia and cell lines by imetelstat. An inert mismatched oligonucleotide (Geron Corporation, Menlo Park, CA, USA) was used to control for specific inhibition of the telomerase active site. Cells were cultured for 48 hours with either active imetelstat or the inert control at varying concentrations, stained with annexin-V and propidium iodide, and then analyzed by flow cytometry to measure cell viability, apoptosis, and necrosis. Results. The hTERT pro/Ex1 region was highly methylated in cell lines, relative to de novo primary leukemic cells. Primary leukemic cells showed significantly different methylation profiles and hypermethylation status correlated to poor survival of AML patients. Three commercially available leukemia cell lines (K562, Ramos, THP-1), two primary leukemia-derived cell lines (AML1, CML1), and CD34+ blasts isolated from primary leukemia in six different AML patients with varying degrees of hTERT pro/Ex1 region methylation were tested. Imetelstat showed dose dependent cytotoxicity to both myeloid leukemia cell lines and primary leukemic blasts. Cell toxicity was telomerase specific since the inert control had no or minimal toxicity at the half inhibitory concentration (IC50) of imetelstat between 10-40 µM. Higher methylation status of the hTERT pro/Ex1 region was significantly associated with increased resistance to imetelstat in leukemia cell lines (Figure 1A). However, no correlation was found in primary leukemic blasts. Pretreatment of leukemia cell lines with 5-Aza for 24 hours prior to imetelstat exposure was associated with a decrease in viability from 0.78±0.01 to 0.54±0.01 at a concentration of 10µM of imetelstat (Figure 1B). 5-Aza alone had no effect on the leukemic cell lines' viability. Conclusion. High risk primary leukemias are susceptible to killing by the telomerase inhibitor irrespective of the degree of methylation of the hTERT pro/Ex1 region. Furthermore, demethylating agents can enhance the activity of the telomerase inhibitor, imetelstat. These findings suggest that combination therapy of imetelstat and DNMT inhibitors may have synergistic anti-leukemic efficacy in high risk AML patients. Disclosures Strickland: Amgen: Other: Advisory Board Particpation; Boehringer-Ingelheim: Other: Advisory Board Particpation; Daiichi-Sankyo: Other: Advisory Board Particpation; Sunesis Pharmaceuticals: Other: Steering Committee and Advisory Board Participation; Alexion Pharmaceuticals: Other: Advisory Board Particpation. Rezvani:Pharmacyclics: Research Funding. Townsley:Novartis: Research Funding; GSK: Research Funding.
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Rezvani, Katayoun. « Aurora : a new direction for a new dawn ». Blood 119, no 2 (12 janvier 2012) : 322–23. http://dx.doi.org/10.1182/blood-2011-11-389452.
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The use of gene transfer techniques to introduce TCR α/β genes that confer specificity for a target antigen offers the opportunity to produce large numbers of cancer-specific T cells for adoptive therapy.1 In this issue of Blood, Nagai and colleagues examine the feasibility of adoptive therapy using lymphocytes genetically engineered to express the T-cell receptor (TCR) for the leukemia-associated antigen Aurora kinase A (AURKA).2
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Tarkanyi, I., C. Dudognon, J. Hillion, F. Pendino, M. Lanotte, J. Aradi et E. Ségal-Bendirdjian. « Retinoid/arsenic combination therapy of promyelocytic leukemia : induction of telomerase-dependent cell death ». Leukemia 19, no 10 (18 août 2005) : 1806–11. http://dx.doi.org/10.1038/sj.leu.2403923.
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Mardiana, Sherly, Benjamin J. Solomon, Phillip K. Darcy et Paul A. Beavis. « Supercharging adoptive T cell therapy to overcome solid tumor–induced immunosuppression ». Science Translational Medicine 11, no 495 (5 juin 2019) : eaaw2293. http://dx.doi.org/10.1126/scitranslmed.aaw2293.
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The development of new cancer immunotherapies including checkpoint blockade and chimeric antigen receptor (CAR) T cell therapy has revolutionized cancer treatment. CAR T cells have shown tremendous success in certain B cell malignancies, resulting in U.S. Food and Drug Administration (FDA) approval of this approach for certain types of leukemia and lymphoma. However, response rates against solid cancer have been less successful to date. Approaches to modulate the immunosuppressive tumor microenvironment including targeting checkpoint pathways, modulating metabolic pathways, and generating cytokine-producing T cells have led to considerable enhancement of adoptive T cell immunotherapy, first in preclinical models and now in patients. This review provides a discussion of the most recent strategies to enhance the efficacy of CAR T cell antitumor responses in solid cancers.
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Stromnes, Ingunn, Carla Fowler, Joseph Blattman, Xiaoxia Tan et Philip Greenberg. « Abrogation of SHP-1 in tumor-specific effector T cells during adoptive immunotherapy of disseminated leukemia (131.15) ». Journal of Immunology 184, no 1_Supplement (1 avril 2010) : 131.15. http://dx.doi.org/10.4049/jimmunol.184.supp.131.15.
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Abstract Adoptive therapy is a promising modality for treating patients with cancer. Currently, there are many obstacles to success, such as the low avidity of self/tumor-reactive T cells and the failure of transferred T cells to persist and to function in a tolerizing tumor environment. To overcome some of these obstacles, we asked if abrogating the Src homology region 2 domain-containing tyrosine phosphatase -1 (SHP-1), a negative regulator of lymphocyte activation, in tumor-reactive effector T cells would influence efficacy of adoptive therapy. A conditional knockout of SHP-1 in mature, tumor-specific transgenic T cells (TCRgag) was developed to analyze cell intrinsic effects of complete or partial ablation of SHP-1 on effector CD8 T cell function, persistence and efficacy in adoptive therapy of disseminated leukemia. In vitro-expanded TCRgag SHP-1-/- cells exhibited greater therapeutic efficacy than TCRgag SHP-1+/+ or SHP-1+/- cells, due to enhanced T cell expansion and survival in vivo, independent of providing exogenous IL-2. The increased expansion and cytokine production of SHP-1-/- effector cells was most pronounced in settings of lymphopenia. The role of SHP-1 in regulating signals received during lymphopenia-induced expansion and on the activation threshold of effector T cells will be discussed. Targeting SHP-1 in human T cells may provide a means to increase in vivo expansion following transfer and avidity for tumor targets during adoptive therapy of cancer.
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Roex, Gils, Tom Feys, Yves Beguin, Tessa Kerre, Xavier Poiré, Philippe Lewalle, Peter Vandenberghe, Dominique Bron et Sébastien Anguille. « Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies : An Update of the Pivotal Clinical Trial Data ». Pharmaceutics 12, no 2 (24 février 2020) : 194. http://dx.doi.org/10.3390/pharmaceutics12020194.
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Chimeric antigen receptor (CAR)-T-cell therapy is an innovative form of adoptive cell therapy that has revolutionized the treatment of certain hematological malignancies, including B-cell non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL). The treatment is currently also being studied in other B-cell neoplasms, including multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). CD19 and B-cell maturation antigen (BCMA) have been the most popular target antigens for CAR-T-cell immunotherapy of these malignancies. This review will discuss the efficacy and toxicity data from the pivotal clinical studies of CD19- and BCMA-targeted CAR-T-cell therapies in relapsed/refractory B-cell malignancies (NHL, ALL, CLL) and MM, respectively.
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Obrocea, Mihail, Jerry Shay, Sergei Gryaznov, Ilgen Mender, Silvia Siteni et Vlad Vitoc. « 697 Telomerase-driven telomeric DNA modification in cancer cells leads to efficient induction of cGAS-mediated innate and adoptive immune responses ». Journal for ImmunoTherapy of Cancer 9, Suppl 2 (novembre 2021) : A725. http://dx.doi.org/10.1136/jitc-2021-sitc2021.697.
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BackgroundTelomeres and telomerase in cancer cells are highly attractive targets for specific anti-tumor therapy, since telomerase is almost universally expressed in cancer cells, but not in the majority of normal counterparts.MethodsIn this presentation we summarize an unexpected, yet promising functional property of a modified nucleoside - 6-thio-2'-deoxyguanosine (6-thio-dG; THIO), as a potential anticancer agent with a unique mechanism of action. In vitro and in vivo, THIO is readily converted into the corresponding 5'-triphosphate, which is a substrate for mammalian telomerase. Incorporation of THIO into de novo synthesized cancer cell telomeres by telomerase leads to a fast induction of DNA damage responses and cancer cell senescence and apoptosis. Importantly, cancer cell death occurs in a telomere length-independent manner. THIO treatment leads to the generation of chromosomal bridges and, eventually, to the formation of cytosolic micronuclei structures, containing de novo modified telomeric DNA fragments. In addition to activation of innate immunity (i.e., cGAS pathway and NK cells), these in situ produced neo-adjuvants are exported extracellularly and then sensed by host-derived naïve dendritic cells, resulting in an enhanced cross-priming and tumor-specific T- cell (both CD4+ and CD8+) activation.ResultsTreatment with THIO overcomes resistance to checkpoint blockade (by aPD-1 or aPD-L1 agents) in advanced in vivo cancer models, leading to profound and persistent tumor regression with induction of cancer type specific long-term immune memory. Thus, in vivo cancer curative activity was observed in murine syngeneic models of colorectal (MC-38) and lung (LLC) cancers, when THIO administration was followed sequentially by atezolizumab. Combinations with other immune checkpoint inhibitors (cemiplimab; pembrolizumab) were also highly effectiveConclusionsIn summary, our findings demonstrate the importance of cancer cell telomeric DNA structural and functional integrity, as well as a therapeutically attractive opportunity to induce telomerase-mediated telomere replication stress. THIO modified telomeres increase innate sensing and adaptive antitumor immunity via “cancer cell self-produced” chemical modification of telomeres.AcknowledgementsSupported in part by CA070907 to JWS
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Bachanova, Veronika, Sarah Cooley, Todd E. Defor, Michael R. Verneris, Bin Zhang, David H. McKenna, Julie Curtsinger et al. « Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein ». Blood 123, no 25 (19 juin 2014) : 3855–63. http://dx.doi.org/10.1182/blood-2013-10-532531.
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Key Points Depletion of host regulatory T cells with IL2DT improves efficacy of haploidentical NK cell therapy for refractory acute myeloid leukemia. Depletion of Treg and persistence of NK cells for ≥7 days after NK cell adoptive transfer predicts beneficial clinical responses.
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Weng, Jinsheng, Kelsey Moriarty, Yong Pan, Man Chun John MA, Rohit Mathur, Zheng Zhang, Hiroki Torikai et al. « Adoptive T-Cell Therapy with TCL1-Specific TCR for B-Cell Lymphomas ». Blood 132, Supplement 1 (29 novembre 2018) : 3488. http://dx.doi.org/10.1182/blood-2018-99-115424.
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Abstract Chimeric antigen receptor (CAR)-modified T-cell therapy targeting CD19 induces high response rates in patients with relapsed or refractory B-cell lymphomas. However, about 60% of patients experience primary or secondary resistance after CD19-targeted CAR T-cell therapy and a major of cause of failure appears to be due to loss of CD19 expression on the tumor. Therefore, novel targets for adoptive T-cell therapeutic approaches are needed to further improve clinical outcome in these patients. T-cell leukemia/lymphoma antigen1 (TCL1) is an oncoprotein that is overexpressed in multiple B-cell malignancies including follicular lymphoma (FL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). Importantly, it has restricted expression in only a subset of B cells among normal tissues. We previously identified a TCL1-derived HLA-A2-binding epitope (TCL170-79 SLLPIMWQLY) that can be used to generate TCL1-specific CD8+ T cells from peripheral blood mononuclear cells of both HLA-A2+ normal donors and lymphoma patients. More importantly, we showed that the TCL1-specific CD8+ T cells lysed autologous primary lymphoma cells but not normal B cells (Weng et al. Blood 2012). To translate the above discovery into clinic, we cloned the T-cell receptor (TCR) alpha and beta chains from a TCL1-specific CD8+ T-cell clone and showed that this TCL1-TCR could be transduced into polyclonal donor T cells using a lentiviral system with a transduction efficiency of >40% as determined by TCL170-79 tetramer positive T cells. Furthermore, we demonstrated that the TCL1-TCR-transduced T cells recognized T2 cells pulsed with TCL170-79 peptide producing IFN- γ >8 ng/ml and IL-2 >350 ng/ml but were not reactive to control HIV-Gag peptide (IFN- γ <0.1 ng/ml and IL-2 <0.2 ng/ml). The TCL1-TCR-transduced T cells recognized TCL170-79 peptide pulsed onto T2 cells at a concentration of 1-10 nM (IL-2 >10 ng/ml) suggesting it has moderate to high avidity. Importantly, TCL1-TCR-transduced T cells lysed HLA-A2+ (up to 43% lysis of Mino and 25% lysis of Jeko-1 at 40:1 Effector:Target ratio) but not HLA-A2- lymphoma cell lines (5.5% lysis of HLA A2- Raji and 2.3% lysis of Daudi at 40:1 Effector:Target ratio). TCL1-TCR-transduced T cells were also cytotoxic to HLA-A2+ primary lymphoma tumor cells (up to 48% lysis of CLL, 43% lysis of FL, 41% lysis of DLBCL, 46% lysis of splenic marginal zone lymphoma, and 11% lysis of MCL at 40:1 Effector:Target ratio) but not normal B cells derived from the same patients. Lastly, TCL1-TCR transduced T cells showed high efficacy in in vivo models. Adoptive transfer of the TCL1-TCR-tranduced T cells significantly reduced lymphoma tumor growth and extended survival in Mino mantle cell lymphoma cell line xenograft model (48% survival in TCL1-TCR-T treated group vs. 12.5% survival in control group at 10 weeks n=7-8 mice/group; P=0.02). Collectively, our data suggest that the high expression in B-cell tumors, restricted expression in normal tissues, and presence of an immunogenic CD8 T-cell epitope, make TCL1 a target for T cell-based therapeutic approaches in multiple B-cell malignancies. Our results also demonstrate that the TCL1-specific TCR-transduced T cells may serve as a novel adoptive immunotherapy approach for the treatment of patients with various B-cell malignancies (including FL, MCL, DLBCL, CLL). Acknowledgments: This study is supported by MD Anderson Moon Shot Program and CPRIT and the National Natural Science Foundation of China Grant (No. 81570189) Disclosures Neelapu: Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Karus: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Membership on an entity's Board of Directors or advisory committees.
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Castro, Januario E., et Thomas J. Kipps. « Adoptive cellular therapy for chronic lymphocytic leukemia and B cell malignancies. CARs and more ». Best Practice & ; Research Clinical Haematology 29, no 1 (mars 2016) : 15–29. http://dx.doi.org/10.1016/j.beha.2016.08.011.
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Stromnes, Ingunn M., Joseph N. Blattman, Xiaoxia Tan et Philip D. Greenberg. « Cbl-b-deficiency in tumor-reactive CD8+ T cells improves efficacy and bypasses the requirement for IL-2 administration during adoptive therapy of progressive leukemia (40.38) ». Journal of Immunology 182, no 1_Supplement (1 avril 2009) : 40.38. http://dx.doi.org/10.4049/jimmunol.182.supp.40.38.
Texte intégralRésumé :
Abstract OBJECTIVE: We have examined if decreasing Cbl-b expression in tumor-reactive CD8 T cells used for adoptive immunotherapy of progressive leukemia can enhance efficacy and bypass the requirement for IL-2 administration. METHODS: Mice expressing a transgenic receptor, TCRgag, which renders CD8 T cells reactive with FBL leukemia, were crossed with Cbl-b-deficient and CD28-deficient mice. TCRgag Cbl-b+/+ and Cbl-b-/- cells were tested for function and expanded in vitro prior to use in adoptive therapy. RESULTS: Cbl-b-/- TCRgag cells exhibited a lower threshold for T cell activation, greater IL-2 production and enhanced proliferation, expansion and survival. The enhanced response of Cbl-b-/- TCRgag cells compared to Cbl-b+/+ cells in vitro revealed both IL-2-dependent and IL-2-independent effects. In vivo, adoptively transferred Cbl-b+/+ TCRgag CD8 T cells can only prevent lethal disease in mice bearing disseminated leukemia if low dose IL-2 is subsequently administered to promote proliferation and maintain cell survival. By contrast, Cbl-b-/- TCRgag cells cured mice independent of a requirement for IL-2 administration. CONCLUSIONS: These results suggest that targeting Cbl-b in antigen-specific T cells may provide a strategy to enhance efficacy of CD8 T cell adoptive immunotherapy in humans with cancer.
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Klobuch, Sebastian, Kathrin Hammon, Sarah Vatter-Leising, Elisabeth Neidlinger, Michael Zwerger, Annika Wandel, Laura Maria Neuber et al. « HLA-DPB1 Reactive T Cell Receptors for Adoptive Immunotherapy in Allogeneic Stem Cell Transplantation ». Cells 9, no 5 (20 mai 2020) : 1264. http://dx.doi.org/10.3390/cells9051264.
Texte intégralRésumé :
HLA-DPB1 antigens are mismatched in about 80% of allogeneic hematopoietic stem cell transplantations from HLA 10/10 matched unrelated donors and were shown to be associated with a decreased risk of leukemia relapse. We recently developed a reliable in vitro method to generate HLA-DPB1 mismatch-reactive CD4 T-cell clones from allogeneic donors. Here, we isolated HLA-DPB1 specific T cell receptors (TCR DP) and used them either as wild-type or genetically optimized receptors to analyze in detail the reactivity of transduced CD4 and CD8 T cells toward primary AML blasts. While both CD4 and CD8 T cells showed strong AML reactivity in vitro, only CD4 T cells were able to effectively eliminate leukemia blasts in AML engrafted NOD/SCID/IL2Rγc−/− (NSG) mice. Further analysis showed that optimized TCR DP and under some conditions wild-type TCR DP also mediated reactivity to non-hematopoietic cells like fibroblasts or tumor cell lines after HLA-DP upregulation. In conclusion, T cells engineered with selected allo-HLA-DPB1 specific TCRs might be powerful off-the-shelf reagents in allogeneic T-cell therapy of leukemia. However, because of frequent (common) cross-reactivity to non-hematopoietic cells with optimized TCR DP T cells, safety mechanisms are mandatory.
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Fujisaki, Hiroyuki, Harumi Kakuda, Chihaya Imai et Dario Campana. « Sustained Expansion of Human Natural Killer Cells for Leukemia Therapy. » Blood 108, no 11 (16 novembre 2006) : 3719. http://dx.doi.org/10.1182/blood.v108.11.3719.3719.
Texte intégralRésumé :
Natural killer (NK) cells are a promising tool for cell therapy of hematologic malignancies. They have potential for enhancing graft-versus-leukemia responses in recipients of hematopoietic stem cell transplant, and can also be used in a non-transplant setting, where haploidentical donor NK cells have been shown to expand in vivo. NK cells represent a small subset of peripheral blood cells. Hence, it can be problematic to obtain them in quantities sufficient to exert significant anti-leukemic activity in patients. We sought to identify culture conditions that would stimulate vigorous, sustained and specific expansion of CD56+ CD3− NK cells. NK cell proliferation was stimulated by contact with the K562 leukemia cell line transfected with two NK stimulatory molecules: membrane-bound interleukin 15 and 4-1BB ligand. Exposure of peripheral blood cells from 23 donors to irradiated K562-mb15-41BBL cells in the presence of 10 IU/mL interleukin-2 resulted in a median expansion of CD56+ CD3− cells of 22-fold (range, 9- to 87-fold) after only 7 days of culture; expansion of CD3+ T cells was negligible. After 14 days of culture, K562-mb15-41BBL cells were completely lysed by the NK cells and no further expansion occurred. However, further NK cell expansion could be achieved by addition of fresh K562-mb15-41BBL cells to the cultures. Using this method, NK cell expansions ranged from 2,000- to 98,000-fold (n = 4) after 65 days of culture. We noted that NK cells eventually became unresponsive to stimulation and underwent senescence after 2–5 months of culture. To determine whether NK cell senescence could be overcome by enforced expression of human telomerase reverse transcriptase (hTERT), we stimulated NK cells for 1 week with K562-mb15-41BBL cells and then transfected them using an MSCV retroviral vector and the hTERT gene (gift of Dr. J. Dome, St. Jude). hTERT expression and telomerase activity was demonstrated by reverse transcriptase-polymerase chain reaction and telomerase repeat amplification protocol assay. The cultures were then stimulated with periodic pulses of K562-mb15-41BBL cells. In 2 donors, enforced expression of hTERT overcame senescence: NK cells transfected with an empty vector died after 85 and 170 days of culture, whereas hTERT-NK cells continue to grow after more than 350 days of culture, while retaining a normal karyotype. hTERT-NK cells maintained their cytotoxicity against the NK-sensitive leukemic cell lines K562, KG1, U937, HL60 and Jurkat. They could be also be genetically modified to express anti-CD19 chimeric signaling receptors, thus becoming cytotoxic against NK-resistant CD19+ B-lineage acute lymphoblastic leukemia cells. Cytotoxicity against CD19+ targets was similar to that of NK cells transfected with the signaling receptor after only one week of culture. In conclusion, coculture of human peripheral blood mononuclear cells with pulses of irradiated K562-mb15-41BBL cells allows the generation of a large numbers of NK cells which have powerful anti-leukemic capacity and can be redirected to lyse NK-resistant target cells. Although senescence eventually ensues, this can be overcome by hTERT expression. The culture system described here has now been adapted to large scale expansion for clinical use.
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Thiel, Eckhard, Igor W. Blau, Martin Neumann, Carola Tietze-Buerger, Armin Gerbitz et Lutz Uharek. « Treatment of Leukemic Meningeosis by CD 14 Depleted Adoptive Intrathecal Cell Therapy. » Blood 112, no 11 (16 novembre 2008) : 3261. http://dx.doi.org/10.1182/blood.v112.11.3261.3261.
Texte intégralRésumé :
Abstract Background: Leukemic relapse within the central nervous system (CNS) is generally difficult to treat and results in poor outcome. Limiting factors for effective treatment are mainly extended neurotoxicity and availability of only few agents that will effectively act across the blood brain barrier (BBB). Although graft versus leukemia effects after allogeneic stem cell transplantation are well documented, its application is not recommended in patients with CNS disease. Since the CNS represents an immunologically privileged organ, conventional donor lymphocyte infusion (DLI) has not proven to be effective in CNS relapse situation after stem cell transplantation. Here we present results from three patients suffering from isolated CNS relapse of CML or AML after allogeneic stem cell transplantation receiving for the first time intrathecal cell therapy using CD14 depleted peripheral blood mononuclear cells from their allogeneic donor. Besides leukemic blast cell counts of the CSF molecular genetic analyses for chimerism as well as for translocations were applied for monitoring in addition to MRI and to neuroclinical symptoms. Results: Up to eight consecutive CD14 depleted intrathecal infusions were applied in escalating doses starting at 1x106 CD3+ cells. In all cases we did not observe any immediate or delayed side effects post application. In the case of the CML patient we observed disappearance of the leukemic blasts and of bcr-abl translocations and reversal to full donor chimerism of the CSF. In one AML patient we observed a transient disappearance of leukemic blasts, followed by a delayed increase. No clear and sustained response was recorded in the other AML patient. All patients are still under observation (9–14 months) and remained full chimeras in peripheral blood and bone marrow; however, the AML patients meanwhile developed chloroma lesions. Conclusion: Intrathecal DLI for CNS relapse of leukemia after allogeneic stem cell transplantation is a new still experimental approach. The first applications indicate no side effects e.g. cerebral or meningeal GVHD and a possible efficacy in CNS relapse of CML. This new approach merits further investigation in the setting of a clinical trial.
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Dahmani, Amina, Cédric Carli, Louis-Philippe Caron, Catherine Jean, Martin Giroux et Jean-Sebastien Delisle. « The Immune “Combination Therapy” of Leukemia Using Adoptive Transfer and TGF-β Blockade. » Blood 120, no 21 (16 novembre 2012) : 3017. http://dx.doi.org/10.1182/blood.v120.21.3017.3017.
Texte intégralRésumé :
Abstract Abstract 3017 The immunosuppressive cytokine Transforming Growth factor-beta (TGF-β), either tumor or T cell-derived, can significantly alter T-dependent immune responses to tumors in mouse models. However, the role of TGF-β neutralization on other cell types of the tumor microenvironment and the ensuing impact on immunotherapies is still unclear. Moreover, pre-clinical models aimed at harnessing the likely synergy between TGF- β signaling blockade and immunotherapy are lacking. Using the TGF- β producing, acute lymphoblastic leukemia/lymphoma cell line EL4, we undertook to characterize how TGF-β affects the leukemic microenvironment and the outcome of adoptive immunotherapy. After inoculation, EL4 cells form large tumor masses that attract a wide variety of leukocytes, including mono-myeloid cells and T lymphocytes (5–10% of tumor cellularity). In order to assess whether TGF-β contributed to shape the leukemic microenvironment, we administered the pan anti-TGF-β antibody 1D11 or isotype control to EL4 bearing mice. Antibodies were administered after leukemic cell inoculation for a period of three weeks (300 μg three times a week). The systemic administration of 1D11 altered the EL-4 leukemia microenvironment. Notably, the concentration of inflammatory cytokines IL-2, GM-CSF and MIP-1α increased along with a trend in the abundance of CD44 positive CD4 T cells and myeloid cells infiltrating the tumors. However, the administration of anti-TGF-β antibody failed to alter tumor growth kinetics or vasculogenesis. These results 1) imply that the mobilization of immune effectors cells following TGF-β neutralization is insufficient and 2) correlate with our in vitro data which showed that TGF-β blockade have no impact on EL4 cells growth and apoptosis. Although insufficient by itself, could the use of TGF-β neutralizing strategies nonetheless improve the outcome of cancer immunotherapies? In order to investigate how inhibition of TGF-β signaling in the microenvironment can alter the outcome of adoptive immunotherapy, we designed an autologous adoptive immunotherapy model of leukemia. We have generated specific anti-EL4 responses using a vaccination and an in vitro restimulation system. Following in vitro stimulation with EL4 cells vs. splenocyte lysate, T cell effectors induced 34.42 % and 4.3% specific lysis respectively against EL4 targets. The injection of these effectors in sub-lethally irradiated leukemia bearing syngeneic hosts led to 50% survival at 120 days post adoptive transfer (n=6) compared to 0% survival in unprimed host. In order to assess whether concomitant TGF-β blockade improves this response, we are currently testing the in vivo efficacy of our strategy in the context of TGF-β neutralization in terms of survival and leukemia infiltration by T cells. The possibility to harness the combined effects of TGF- β signaling blockade and current immunotherapeutic approaches has immediate translational relevance given the numerous anti-TGF modalities currently being developed. Disclosures: No relevant conflicts of interest to declare.
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Handgretinger, Rupert, Peter Lang et Maya C. André. « Exploitation of natural killer cells for the treatment of acute leukemia ». Blood 127, no 26 (30 juin 2016) : 3341–49. http://dx.doi.org/10.1182/blood-2015-12-629055.
Texte intégralRésumé :
Abstract Natural killer (NK) cells play an important role in surveillance and elimination of malignant cells. Their spontaneous cytotoxicity was first demonstrated in vitro against leukemia cell lines, and NK cells might play a crucial role in the therapy of leukemia. NK cell activity is controlled by an array of germ line–encoded activating and inhibitory receptors, as well as modulating coreceptors. This biologic feature can be exploited in allogeneic cell therapy, and the recognition of “missing-self” on target cells is crucial for promoting NK cell–mediated graft-versus-leukemia effects. In this regard, NK cells that express an inhibitory killer immunoglobulin-like receptor (iKIR) for which the respective major histocompatibility complex class I ligand is absent on leukemic target cells can exert alloreactivity in vitro and in vivo. Several models regarding potential donor–patient constellations have been described that have demonstrated the clinical benefit of such alloreactivity of the donor-derived NK cell system in patients with adult acute myeloid leukemia and pediatric B-cell precursor acute lymphoblastic leukemia after allogeneic stem cell transplantation. Moreover, adoptive transfer of mature allogeneic NK cells in the nontransplant or transplant setting has been shown to be safe and feasible, whereas its effectivity needs further evaluation. NK cell therapy can be further improved by optimal donor selection based on phenotypic and genotypic properties, by adoptive transfer of NK cells with ex vivo or in vivo cytokine stimulation, by the use of antibodies to induce antibody-dependent cellular cytotoxicity or to block iKIRs, or by transduction of chimeric antigen receptors.
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Campillo-Davo, Diana, Sébastien Anguille et Eva Lion. « Trial Watch : Adoptive TCR-Engineered T-Cell Immunotherapy for Acute Myeloid Leukemia ». Cancers 13, no 18 (8 septembre 2021) : 4519. http://dx.doi.org/10.3390/cancers13184519.
Texte intégralRésumé :
Despite the advent of novel therapies, acute myeloid leukemia (AML) remains associated with a grim prognosis. This is exemplified by 5-year overall survival rates not exceeding 30%. Even with frontline high-intensity chemotherapy regimens and allogeneic hematopoietic stem cell transplantation, the majority of patients with AML will relapse. For these patients, treatment options are few, and novel therapies are urgently needed. Adoptive T-cell therapies represent an attractive therapeutic avenue due to the intrinsic ability of T lymphocytes to recognize tumor cells with high specificity and efficiency. In particular, T-cell therapies focused on introducing T-cell receptors (TCRs) against tumor antigens have achieved objective clinical responses in solid tumors such as synovial sarcoma and melanoma. However, contrary to chimeric antigen receptor (CAR)-T cells with groundbreaking results in B-cell malignancies, the use of TCR-T cells for hematological malignancies is still in its infancy. In this review, we provide an overview of the status and clinical advances in adoptive TCR-T-cell therapy for the treatment of AML.
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Sandri, Sara, Francesco De Sanctis, Alessia Lamolinara, Federico Boschi, Ornella Poffe, Rosalinda Trovato, Alessandra Fiore et al. « Effective control of acute myeloid leukaemia and acute lymphoblastic leukaemia progression by telomerase specific adoptive T-cell therapy ». Oncotarget 8, no 50 (23 mai 2017) : 86987–7001. http://dx.doi.org/10.18632/oncotarget.18115.
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Kolb, Hans-Jochem, Christoph Schmid, A. John Barrett et Dolores J. Schendel. « Graft-versus-leukemia reactions in allogeneic chimeras ». Blood 103, no 3 (1 février 2004) : 767–76. http://dx.doi.org/10.1182/blood-2003-02-0342.
Texte intégralRésumé :
AbstractThere is a strong graft-versus-leukemia (GVL) effect of allogeneic stem cell transplantation (SCT) due to elimination of tumor cells by alloimmune effector lymphocytes. When leukemia relapses after allogeneic SCT, donor lymphocyte transfusions (DLTs) can induce sustained remissions in some patients. This review summarizes the current status on clinical use of DLT, the basis of GVL reactions, problems associated with this therapy, and new strategies to improve DLT. Several multicenter surveys demonstrated that the GVL effect of DLT is most effective in chronic myelogenous leukemia (CML), whereas it is less pronounced in acute leukemia and myeloma. Cytokine stimulation to induce differentiation of myeloid progenitor cells or to up-regulate costimulatory molecules on tumor cells may improve the efficacy of DLT. Infections and graft-versus-host disease (GVHD) are major complications of DLT. Control of GVHD may be improved using suicide gene–modified T cells for DLT, allowing T-cell elimination if severe GVHD develops. Hopefully, in the future, GVL effect can be separated from GVHD through adoptive transfer of selected T cells that recognize leukemia-specific antigens or minor histocompatibility antigens, which are expressed predominantly on hematopoietic cells, thereby precluding attack of normal tissues. In patients with leukemia and lymphomas with fast progression, tumor growth may outpace development of effector T cells. Here it may be preferable to select stem cell transplant donors with HLA-mismatches that allow alloreactive natural killer cells, which appear early after transplantation, to retain their cytolytic function. New approaches for adoptive immune therapy of leukemia, which promise a better prognosis for these patients, are being developed.
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Öztürk, Selcen, Verena Kalter, Philipp M. Roessner, Murat Sunbul et Martina Seiffert. « IDO1-Targeted Therapy Does Not Control Disease Development in the Eµ-TCL1 Mouse Model of Chronic Lymphocytic Leukemia ». Cancers 13, no 8 (15 avril 2021) : 1899. http://dx.doi.org/10.3390/cancers13081899.
Texte intégralRésumé :
Indoleamine-2,3-dioxygenase 1 (IDO1), a tryptophan (Trp)-catabolizing enzyme producing metabolites such as kynurenine (Kyn), is expressed by myeloid-derived suppressor cells (MDSCs) and associated with cancer immune escape. IDO1-expressing monocytic MDSCs were shown to accumulate in patients with chronic lymphocytic leukemia (CLL) and to suppress T cell activity and induce suppressive regulatory T cells (Tregs) in vitro. In the Eµ-TCL1 mouse model of CLL, we observed a strong upregulation of IDO1 in monocytic and granulocytic MDSCs, and a significantly increased Kyn to Trp serum ratio. To explore the potential of IDO1 as a therapeutic target for CLL, we treated mice after adoptive transfer of Eµ-TCL1 leukemia cells with the IDO1 modulator 1-methyl-D-tryptophan (1-MT) which resulted in a minor reduction in leukemia development which disappeared over time. 1-MT treatment further led to a partial rescue of the immune cell changes that are induced with CLL development. Similarly, treatment of leukemic mice with the clinically investigated IDO1 inhibitor epacadostat reduced the frequency of Tregs and initially delayed CLL development slightly, an effect that was, however, lost at later time points. In sum, despite the observed upregulation of IDO1 in CLL, its inhibition is not sufficient to control leukemia development in the Eµ-TCL1 adoptive transfer model.
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Ochi, Toshiki, Hiroshi Fujiwara et Masaki Yasukawa. « Application of Adoptive T-Cell Therapy Using Tumor Antigen-Specific T-Cell Receptor Gene Transfer for the Treatment of Human Leukemia ». Journal of Biomedicine and Biotechnology 2010 (2010) : 1–10. http://dx.doi.org/10.1155/2010/521248.
Texte intégralRésumé :
The last decade has seen great strides in the field of cancer immunotherapy, especially the treatment of melanoma. Beginning with the identification of cancer antigens, followed by the clinical application of anti-cancer peptide vaccination, it has now been proven that adoptive T-cell therapy (ACT) using cancer antigen-specific T cells is the most effective option. Despite the apparent clinical efficacy of ACT, the timely preparation of a sufficient number of cancer antigen-specific T cells for each patient has been recognized as its biggest limitation. Currently, therefore, attention is being focused on ACT with engineered T cells produced using cancer antigen-specific T-cell receptor (TCR) gene transfer. With regard to human leukemia, ACT using engineered T cells bearing the leukemia antigen-specific TCR gene still remains in its infancy. However, several reports have provided preclinical data on TCR gene transfer using Wilms' tumor gene product 1 (WT1), and also preclinical and clinical data on TCR gene transfer involving minor histocompatibility antigen, both of which have been suggested to provide additional clinical benefit. In this review, we examine the current status of anti-leukemia ACT with engineered T cells carrying the leukemia antigen-specific TCR gene, and discuss the existing barriers to progress in this area.
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Warren, Edus H., Nobuharu Fujii, Yoshiki Akatsuka, Colette N. Chaney, Jeffrey K. Mito, Keith R. Loeb, Ted A. Gooley et al. « Therapy of relapsed leukemia after allogeneic hematopoietic cell transplantation with T cells specific for minor histocompatibility antigens ». Blood 115, no 19 (13 mai 2010) : 3869–78. http://dx.doi.org/10.1182/blood-2009-10-248997.
Texte intégralRésumé :
Abstract The adoptive transfer of donor T cells that recognize recipient minor histocompatibility antigens (mHAgs) is a potential strategy for preventing or treating leukemic relapse after allogeneic hematopoietic cell transplantation (HCT). A total of 7 patients with recurrent leukemia after major histocompatibility complex (MHC)–matched allogeneic HCT were treated with infusions of donor-derived, ex vivo–expanded CD8+ cytotoxic T lymphocyte (CTL) clones specific for tissue-restricted recipient mHAgs. The safety of T-cell therapy, in vivo persistence of transferred CTLs, and disease response were assessed. Molecular characterization of the mHAgs recognized by CTL clones administered to 3 patients was performed to provide insight into the antileukemic activity and safety of T-cell therapy. Pulmonary toxicity of CTL infusion was seen in 3 patients, was severe in 1 patient, and correlated with the level of expression of the mHAg-encoding genes in lung tissue. Adoptively transferred CTLs persisted in the blood up to 21 days after infusion, and 5 patients achieved complete but transient remissions after therapy. The results of these studies illustrate the potential to selectively enhance graft-versus-leukemia activity by the adoptive transfer of mHAg-specific T-cell clones and the challenges for the broad application of this approach in allogeneic HCT. This study has been registered at http://clinicaltrials.gov as NCT00107354.
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Maude, Shannon L., David T. Teachey, David L. Porter et Stephan A. Grupp. « CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia ». Blood 125, no 26 (25 juin 2015) : 4017–23. http://dx.doi.org/10.1182/blood-2014-12-580068.
Texte intégralRésumé :
Abstract Relapsed and refractory acute lymphoblastic leukemia (ALL) remains difficult to treat, with minimal improvement in outcomes seen in more than 2 decades despite advances in upfront therapy and improved survival for de novo ALL. Adoptive transfer of T cells engineered to express a chimeric antigen receptor (CAR) has emerged as a powerful targeted immunotherapy, showing striking responses in highly refractory populations. Complete remission (CR) rates as high as 90% have been reported in children and adults with relapsed and refractory ALL treated with CAR-modified T cells targeting the B-cell–specific antigen CD19. Distinct CAR designs across several studies have produced similar promising CR rates, an encouraging finding. Even more encouraging are durable remissions observed in some patients without additional therapy. Duration of remission and CAR-modified T-cell persistence require further study and more mature follow-up, but emerging data suggest these factors may distinguish CAR designs. Supraphysiologic T-cell proliferation, a hallmark of this therapy, contributes to both efficacy and the most notable toxicity, cytokine release syndrome (CRS), posing a unique challenge for toxicity management. This review will discuss the current landscape of CD19 CAR clinical trials, CRS pathophysiology and management, and remaining challenges.
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Heyman, Benjamin M., Dimitrios Tzachanis et Thomas J. Kipps. « Recent Advances in CAR T-Cell Therapy for Patients with Chronic Lymphocytic Leukemia ». Cancers 14, no 7 (28 mars 2022) : 1715. http://dx.doi.org/10.3390/cancers14071715.
Texte intégralRésumé :
Chimeric antigen receptor T cells (CAR T cells) have resulted in dramatic treatment responses for patients with hematologic malignancies, resulting in improved survival for patients with intractable disease. The first patient treated with CD19 directed CAR T cell therapy had chronic lymphocytic leukemia (CLL) and achieved a complete remission. Subsequent clinical trials have focused largely on patients with other B-cell hematologic malignancies, owing to the fact that CAR T cell therapy for patients with CLL has met with challenges. More recent clinical trials have demonstrated CAR T cell therapy can be well tolerated and effective for patients with CLL, making it a potential treatment option for patients with this disease. In this article we review the background on CAR T cells for the treatment of patients with CLL, focusing on the unique obstacles that patients with CLL present for the development of adoptive T cell therapy, and the novel approaches currently under development to overcome these hurdles.
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Allison, Michaela, Joel Mathews, Taylor Gilliland et Stephen O. Mathew. « Natural Killer Cell-Mediated Immunotherapy for Leukemia ». Cancers 14, no 3 (8 février 2022) : 843. http://dx.doi.org/10.3390/cancers14030843.
Texte intégralRésumé :
Leukemia is a malignancy of the bone marrow and blood resulting from the abnormal differentiation of hematopoietic stem cells (HSCs). There are four main types of leukemia including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL). While chemotherapy and radiation have been conventional forms of treatment for leukemia, these therapies increase infection susceptibility, adverse side effects and immune cell inactivation. Immunotherapies are becoming promising treatment options for leukemia, with natural killer (NK) cell-mediated therapy providing a specific direction of interest. The role of NK cells is critical for cancer cell elimination as these immune cells are the first line of defense against cancer proliferation and are involved in both recognition and cytolysis of rapidly dividing and abnormal cell populations. NK cells possess various activating and inhibitory receptors, which regulate NK cell function, signaling either inhibition and continued surveillance, or activation and subsequent cytotoxic activity. In this review, we describe NK cells and NK cell receptors, functional impairment of NK cells in leukemia, NK cell immunotherapies currently under investigation, including monoclonal antibodies (mAbs), adoptive transfer, chimeric antigen receptor-NKs (CAR-NKs), bi-specific/tri-specific killer engagers (BiKEs/TriKEs) and future potential targets of NK cell-based immunotherapy for leukemia.