Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data

Roex, Gils; Feys, Tom; Béguin, Yves; Kerre, Tessa; Poiré, Xavier; Lewalle, Philippe; Vandenberghe, Peter; Bron, Dominique; Anguille, Sébastien

doi:10.3390/pharmaceutics12020194

Cited by 45 publications

(42 citation statements)

References 83 publications

(167 reference statements)

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“…Since our in vivo studies were conducted in immunedeficient NSG-SGM3 mice, we do not know whether the in vitro safety or the in vivo toxicity is more likely to predict treatment outcomes in humans. 35 If clinical studies demonstrate that the benefits we observed treating human AML with CLL-1-CAR-IL15 T cells in mice are similar in patients, then TNFα antibody may need to be added to the repertoire of cytokine-neutralizing agents [54][55][56] required to ensure both safe and effective CAR T cell treatments. Combination of such antibodies with regulation of T cell expansion and survival with a clinically validated safety system such as described here using iC9 56 may be optimal.…”

Section: Discussionmentioning

confidence: 99%

Modulating TNFα activity allows transgenic IL15-Expressing CLL-1 CAR T cells to safely eliminate acute myeloid leukemia

Atilla

McKenna

Tashiro

et al. 2020

J Immunother Cancer

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BackgroundC-type lectin-like molecule 1 (CLL-1) is highly expressed in acute myeloid leukemia (AML) but is absent in primitive hematopoietic progenitors, making it an attractive target for a chimeric antigen receptor (CAR) T-cell therapy. Here, we optimized our CLL-1 CAR for anti-leukemic activity in mouse xenograft models of aggressive AML.MethodsFirst, we optimized the CLL-1 CAR using different spacer, transmembrane and costimulatory sequences. We used a second retroviral vector to coexpress transgenic IL15. We measured the effects of each construct on T cell phenotype and sequential (recursive) co culture assays with tumor cell targets to determine the durability of the anti tumor activity by flow cytometry. We administered CAR T cells to mice engrafted with patient derived xenografts (PDX) and AML cell line and determined anti tumor activity by bioluminescence imaging and weekly bleeding, measured serum cytokines by multiplex analysis. After euthanasia, we examined formalin-fixed/paraffin embedded sections. Unpaired two-tailed Student’s t-tests were used and values of p<0.05 were considered significant. Survival was calculated using Mantel-Cox log-rank test.ResultsIn vitro, CLL-1 CAR T cells with interleukin-15 (IL15) were less terminally differentiated (p<0.0001) and had superior expansion compared with CD28z-CD8 CAR T cells without IL15 (p<0.001). In both AML PDX and AML cell line animal models, CLL-1 CAR T coexpressing transgenic IL15 initially expanded better than CD28z-CD8 CAR T without IL15 (p<0.0001), but produced severe acute toxicity associated with high level production of human tumor necrosis factor α (TNFα), IL15 and IL2. Histopathology showed marked inflammatory changes with tissue damage in lung and liver. This acute toxicity could be managed by two strategies, individually or in combination. The excessive TNF alpha secretion could be blocked with anti-TNF alpha antibody, while excessive T cell expansion could be arrested by activation of an inducible caspase nine safety switch by administration of dimerizing drug. Both strategies successfully prolonged tumor-free survival.ConclusionCombinatorial treatment with a TNFα blocking antibody and subsequent activation of the caspase-9 control switch increased the expansion, survival and antileukemic potency of CLL-1 CAR T-cells expressing transgenic IL15 while avoiding the toxicities associated with excessive cytokine production and long-term accumulation of activated T-cells.

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Section: Discussionmentioning

confidence: 99%

Modulating TNFα activity allows transgenic IL15-Expressing CLL-1 CAR T cells to safely eliminate acute myeloid leukemia

Atilla

McKenna

Tashiro

et al. 2020

J Immunother Cancer

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“…CAR T-cell therapy is an innovative form of adoptive cell therapy that has revolutionized the treatment of certain hematological malignancies. 8 B-cell maturation antigen (BCMA), a highly plasma cell-selective protein expressed on malignant plasma cells of patients with multiple myeloma (MM), has appeared as a promising antigen to target, using a variety of immunotherapy treatments including CAR T-cells, for MM patients. 9 It will likely result in increased acquired deficiencies in humoral immunity and subsequent infections in persons with cancer.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 infection in immunocompromised patients: humoral versus cell-mediated immunity

Wei

Zhao

Han

et al. 2020

J Immunother Cancer

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BackgroundThe coronavirus disease 2019 (COVID-19) pandemic placed unprecedented pressure on various healthcare systems, including departments that use immunotherapies such as chimeric antigen receptor (CAR) T-cell therapy and immunosuppression therapy in organ transplantation units. The true impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on immunocompromised CAR T-cell therapy recipients and kidney transplant recipients (KTRs) has not yet been established.Case presentationIn this report, we compare two patients with severe COVID-19 pneumonia in either the humoral or cell-mediated immunodeficient states. The first patient was a man in his early 30s who was diagnosed with refractory multiple myeloma. He received fully humanized, anti-B-cell maturation antigen, CAR T-cell therapy before 4 months and achieved strict complete remission. He was infected with SARS-CoV-2 starting on January 26, 2019 and gradually progressed to severe pneumonia. Throughout the clinical progression of the disease, SARS-CoV-2 could not be cleared due to his humoral immunodeficient state. During this period of his severe COVID-19 pneumonia, elevated cytotoxic T-cells were observed in this patient’s peripheral blood while elevated plasma levels of interleukin (IL)-2R, IL-6, tumor necrosis factor α, and ferritin were observed in his cytokine profiles. This patient eventually progressed into acute respiratory distress syndrome and recieved non-invasive ventilatory support. He failed to generate specific SARS-CoV-2 antibodies and died of respiratory failure on day 33 (d33). The second patient was a 52-year-old kidney transplant recipient (KTR) who took ciclosporin after renal transplantation for more than 7 years. He confirmed SARS-CoV-2 infection on January 20, 2019 and gradually progressed into severe pneumonia on d16 with a slightly elevated B-cell percentage and normal T-lymphocyte subsets. Viral clearance occurred together with the generation of specific anti-immunoglobulin G-SARS-CoV-2 antibodies after 2 weeks of treatment. He was symptom-free and discharged from the hospital on d42.ConclusionWe report a CAR T-cell therapy recipient diagnosed with COVID-19 for the first time. His virus clearance failure and life-threating cytokine storm during SARS-CoV-2 infection suggested that any decision to proceed CAR T-cell therapy during COVID-19 pandemics will require extensive discussion of potential risks and benefits. Immunosuppressant treatment based on ciclosporin could be relatively safe for KTRs diagnosed with COVID-19.Trial registration numberChiCTR-OPN-1800018137.

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“…Finally, chimeric antigen receptor modified T cells (CAR-T cells) have appeared in recent years as a successful immunotherapy for certain hematological malignancies [ 84 ]. However, some patients treated with CAR-T cells relapse, which is partially caused by a lack of functional persistence following treatment administration [ 221 ]. As the effectiveness of CAR-T cell therapy is dependent on the fitness of the patients’ T cells from which they are derived [ 222 ], the lack of sustained functional capacity of CAR-T cells could be due to the inflated levels of T cell senescence observed in cancer patients [ 107 ].…”

Section: Clinical Relevance Of Senescence In Immunotherapy: a Balamentioning

confidence: 99%

Senescence in the Development and Response to Cancer with Immunotherapy: A Double-Edged Sword

Battram

Bachiller

Martín-Antonio

2020

IJMS

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Cellular senescence was first described as a physiological tumor cell suppressor mechanism that leads to cell growth arrest with production of the senescence-associated secretory phenotype known as SASP. The main role of SASP in physiological conditions is to attract immune cells to clear senescent cells avoiding tumor development. However, senescence can be damage-associated and, depending on the nature of these stimuli, additional types of senescence have been described. In the context of cancer, damage-associated senescence has been described as a consequence of chemotherapy treatments that were initially thought of as a tumor suppressor mechanism. However, in certain contexts, senescence after chemotherapy can promote cancer progression, especially when immune cells become senescent and cannot clear senescent tumor cells. Moreover, aging itself leads to continuous inflammaging and immunosenescence which are responsible for rewiring immune cells to become defective in their functionality. Here, we define different types of senescence, pathways that activate them, and functions of SASP in these events. Additionally, we describe the role of senescence in cancer and its treatments, including how aging and chemotherapy contribute to senescence in tumor cells, before focusing on immune cell senescence and its role in cancer. Finally, we discuss potential therapeutic interventions to reverse cell senescence.

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Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data

Cited by 45 publications

References 83 publications

Modulating TNFα activity allows transgenic IL15-Expressing CLL-1 CAR T cells to safely eliminate acute myeloid leukemia

Modulating TNFα activity allows transgenic IL15-Expressing CLL-1 CAR T cells to safely eliminate acute myeloid leukemia

SARS-CoV-2 infection in immunocompromised patients: humoral versus cell-mediated immunity

Senescence in the Development and Response to Cancer with Immunotherapy: A Double-Edged Sword

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