Cancer Patient T Cells Genetically Targeted to Prostate-Specific Membrane Antigen Specifically Lyse Prostate Cancer Cells and Release Cytokines in Response to Prostate-Specific Membrane Antigen

AbstractThe expression of immunoglobulin-based artificial receptors in normal T lymphocytes provides a means to target lymphocytes to cell surface antigens independently of major histocompatibility complex restriction. Such artificial receptors have been previously shown to confer antigen-specific tumoricidal properties in murine T cells. We constructed a novel ζ chain fusion receptor specific for prostate-specific membrane antigen (PSMA) termed Pz-1. PSMA is a cell-surface glycoprotein expressed on prostate cancer cells and the neovascular endothelium of multiple carcinomas. We show that primary T cells harvested from five of five patients with different stages of prostate cancer and transduced with the Pz-1 receptor readily lyse prostate cancer cells. Having established a culture system using fibroblasts that express PSMA, we next show that T cells expressing the Pz-1 receptor release cytokines in response to cell-bound PSMA. Furthermore, we show that the cytokine release is greatly augmented by B7.1-mediated costimulation. Thus, our findings support the feasibility of adoptive cell therapy by using genetically engineered T cells in prostate cancer patients and suggest that both CD4+ and CD8+ T lymphocyte functions can be synergistically targeted against tumor cells

HLA-Class II Artificial Antigen Presenting Cells in CD4+ T Cell-Based Immunotherapy

CD4+ T cells differentiate into various T helper subsets characterized by distinct cytokine secreting profiles that confer them effector functions adapted to a variety of infectious or endogenous threats. Regulatory CD4+ T cells are another specialized subset that plays a fundamental role in the maintenance of immune tolerance to self-antigens. Manipulating effector or regulatory CD4+ T cells responses is a promising immunotherapy strategy for, respectively, chronical viral infections and cancer, or severe autoimmune diseases and transplantation. Adoptive cell therapy (ACT) is an emerging approach that necessitates defining robust and efficient methods for the in vitro expansion of antigen-specific T cells then infused into patients. To address this challenge, artificial antigen presenting cells (AAPCs) have been developed. They constitute a reliable and easily usable platform to stimulate and amplify antigen-specific CD4+ T cells. Here, we review the recent advances in understanding the functions of CD4+ T cells in immunity and in immune tolerance, and their use for ACT. We also describe the characteristics of different AAPC models and the way to improve their stimulating functions. Finally, we discuss the potential interest of these AAPCs, both as fundamental tools to decipher CD4+ T cell responses and as reagents to generate clinical grade antigen-specific CD4+ T cells for immunotherapy

Case report: CAR-T cell therapy-induced cardiac tamponade

CD19-specific chimeric antigen receptor T (CAR-T) cell therapy has recently been shown to improve the prognosis of refractory diffuse large B-cell lymphoma (DLBCL). However, CAR-T cells may induce numerous adverse events, in particular cytokine release syndrome (CRS) which is frequently associated with cardiovascular manifestations. Among the latter, acute pericardial effusion represents less than 1% of cases and cardiac tamponade has only been reported once. The management and outcome of these severe complications are not well established. We report here, a case of cardiac tamponade associated with CRS in a context of CAR-T cell therapy, which required urgent pericardiocentesis.Case summaryA 65-year-old man with refractory DLBCL was treated with CAR-T cell therapy. He had a history of dilated cardiomyopathy with preserved ejection fraction and transient atrial fibrillation. A pericardial localization of the lymphoma was observed on the second relapse. One day after CAR-T cell infusion the patient was diagnosed with grade 1 CRS. Due to hypotension, he was treated with tocilizumab and dexamethasone, and then transferred to intensive care unit (ICU). Echocardiography performed at ICU admission showed acute pericardial effusion with signs of right ventricular heart failure due to cardiac tamponade. It was decided to perform pericardiocentesis despite grade IV thrombocytopenia in a context of aplasia. Analysis of pericardial fluid showed a large number of lymphoma cells and 73% of CAR-T cells amongst lymphocytes, a level that was similar in blood. Hemodynamic status improved after pericardiocentesis, and no recurrence of pericardial effusion was observed. The presence of a high count of activated CAR-T cells in the pericardial fluid as well as the short interval between CAR-T cells injection and the symptoms appear as potential arguments for a direct action of CAR-T cells in the mechanism of this adverse event. The patient was discharged from ICU after two days and initially exhibited a good response to DLBCL treatment. Unfortunately, he died fifty days after starting CAR-T cell therapy due to a new DLBCL relapse.ConclusionPatients with a pericardial localization of DLBCL should be assessed for a risk of cardiac tamponade if receiving CAR-T cell therapy and presenting CRS. In this case, cardiac tamponade seems directly related to CAR-T cell expansion. Pericardiocentesis should be considered as a feasible and effective treatment if the risk of bleeding is well controlled, in association with anti-IL6 and corticosteroids

Heterogeneous epigenetic regulation of HACE1 in Burkitt- Lymphoma-derived cells

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Cancer Patient T Cells Genetically Targeted to Prostate-Specific Membrane Antigen Specifically Lyse Prostate Cancer Cells and Release Cytokines in Response to Prostate-Specific Membrane Antigen

The expression of immunoglobulin-based artificial receptors in normal T lymphocytes provides a means to target lymphocytes to cell surface antigens independently of major histocompatibility complex restriction. Such artificial receptors have been previously shown to confer antigen-specific tumoricidal properties in murine T cells. We constructed a novel ζ chain fusion receptor specific for prostate-specific membrane antigen (PSMA) termed Pz-1. PSMA is a cell-surface glycoprotein expressed on prostate cancer cells and the neovascular endothelium of multiple carcinomas. We show that primary T cells harvested from five of five patients with different stages of prostate cancer and transduced with the Pz-1 receptor readily lyse prostate cancer cells. Having established a culture system using fibroblasts that express PSMA, we next show that T cells expressing the Pz-1 receptor release cytokines in response to cell-bound PSMA. Furthermore, we show that the cytokine release is greatly augmented by B7.1-mediated costimulation. Thus, our findings support the feasibility of adoptive cell therapy by using genetically engineered T cells in prostate cancer patients and suggest that both CD4(+) and CD8(+) T lymphocyte functions can be synergistically targeted against tumor cells

Direct Toll-Like Receptor 8 signaling increases the functional avidity of human CD8+ T lymphocytes generated for adoptive T cell therapy strategies

International audienceAdoptive transfer of in vitro activated and expanded antigen-specific cytotoxic T lymphocytes (CTLs) is a promising therapeutic strategy for infectious diseases and cancers. Obtaining in vitro a sufficient amount of highly specific cytotoxic cells and capable of retaining cytotoxic activity in vivo remains problematic. We studied the role of Toll-Like Receptor-8 (TLR8) engagement on peripheral CTLs activated with melanoma antigen MART-1-expressing artificial antigen-presenting cells (AAPCs). After a 3-week co-culture, 3–27% of specific CTLs were consistently obtained. CTLs expressed TLR8 in the intracellular compartment and at the cell surface. Specific CTLs activated with a TLR8 agonist (CL075) 24 h before the end of the culture displayed neither any change in their production levels of molecules involved in cytotoxicity (IFN-γ, Granzyme B, and TNF-α) nor major significant change in their cell surface phenotype. However, these TLR8-stimulated lymphocytes displayed increased cytotoxic activity against specific peptide-pulsed target cells related to an increase in specific anti-melanoma CTL functional avidity. TLR8 engagement on CTLs could, therefore, be useful in different immunotherapy strategies

HLA-Class II Artificial Antigen Presenting Cells in CD4+ T Cell-Based Immunotherapy

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