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Chimeric antigen receptor (CAR)-T is one of the most promising modern cancer immunotherapies. In the recent years, impressive results have been obtained in the treatment of cancer which led to FDA approval for the treatment of liquid tumors. In this cell-based therapy, immune cells (e.g. T and NK cells) are engineered to express a synthetic receptor CAR to specifically recognize and eliminate cells expressing a target antigen. CAR has evolved through different generations aiming to boost its biological activity and overcome limitations such as low persistence, limited potency, life-threatening toxicity and inefficient activity against solid tumor. The present review provides an overview of the different CAR generations, starting from the 1 st generation with limited cytotoxic activity until the latest generation, the 5 th generation or new generation, developed to overcome various limitations of CAR T therapy. The current ongoing clinical trials in cancer and autoimmune diseases, and the limitation associated with CAR-T cells in cancer therapy, are also discussed., (© 2024 médecine/sciences – Inserm.)

Despite recent therapeutic advances, multiple myeloma remains an incurable disease and the therapeutic options currently available are insufficient in refractory patients. Chimeric antigen receptor (CAR)-expressing T cells are an innovative form of adoptive cell therapy in which T cells are reprogrammed to induce an anti-tumor response. Following the successful use of CAR-T cells in the treatment of other B-cell malignancies, CAR-T-based strategies which target the B cell maturation antigen (BCMA) on the surface of tumor plasma cell are now being used in MM patients. Idecabtagene vicleucel (ide-cel), an anti-BCMA CAR-T which has shown impressive efficacy in heavily pretreated patients, is now approved by both the FDA and EMA and is available in France through a temporary use authorization (ATU) status. However, relapses seem inevitable and strategies to delay the time to progression are being investigated. These include strategies to improve the functional persistence of CAR-T in vivo by enriching for a T memory profile and reducing their immunogenicity. In addition, since changes in BCMA expression may decrease the activity of CAR-T cells in tumor plasma cells, approaches to minimize this escape are also being studied. Finally, antigens other than BCMA on the surface of plasma cells could constitute new targets of interest for recognition by CAR-T cells. The development of CAR-T-based therapies in myeloma could lead to multiple therapeutic innovations and holds promise for eventual prolonged remissions or even cure., (Copyright © 2021 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

CAR-T cells originate from two different approaches, cellular immunotherapy based on tumor immunosurveillance by T lymphocytes, combined with molecular engineering of bispecific antibodies and antibody fragments. The latter makes it possible to retarget immune effector cytotoxic cells (such as NK cells and T lymphocytes) to tumor cells through the binding to tumor-associated antigens. We present herein the history of bispecific antibodies, highlighting how such antibodies played a major role in CAR-T cell development. We will first evoke how antibody engineering led to the construction of various bispecific formats, in particular using the single chain Fv fragment (scFv) which has been used as the initial building block to generate chimeric bi-, tri- or multifunctional molecules. We will also describe how bispecific antibodies, either full IgG or as scFv or F(ab') 2 format, directed against Fcγ receptors or CD3ɛ and against tumor-associated antigens, induce a potent anti-tumor cytotoxicity following the recruitment and activation of immune effector cells, including CD3 + T lymphocytes. These anti-tumor effects have been translated into the clinics, especially to treat malignant hemopathies. At last, recently generated bispecific CAR-T cells suggest that the embrace between cell therapy and bispecific antibodies is not over and that we are yet to witness further discoveries enabling these cells to be even more efficient., (Copyright © 2021. Published by Elsevier Masson SAS.)

CAR-T cells have recently made a stunning entry on the arena of immunotherapy of B-cell lymphomas. This new treatment approach represents the culmination of 30 years of efforts to understand the role of T cells in the antitumor response. However, this technology is still in its infancy and suffers from a number of limitations. Many areas for improvement, based in particular on the possibilities of additional genetic manipulations of CAR-T cells, aim at reducing their toxicity, increasing their persistence in vivo, preventing the risk of tumor escape, recruiting other immune effectors, or extending their application to other cancers. Further studies of the dynamic interaction between the patient and these live drugs will allow elucidating the mechanisms determining the antitumor response in this context and thus developing more efficiently the future CAR-T cells., (Copyright © 2021 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Ovarian cancers express highly immunogenic tissue-specific antigens. The resulting immune infiltration is a major prognostic factor. There is therefore a strong biological rationale for the development of immunotherapy in ovarian cancer. However, based on Phase I and II clinical trials data, the efficacy of anti-PD-1 and anti-PD-L1 immune checkpoint inhibitors (ICPIs) remains limited in monotherapy in heavily pre-treated patients. Currently, the identification of predictive biomarkers of response and resistance is one of the major areas of research. Identifying effective combination of anti-PD-1 or anti-PD-L1 with other anticancer agents is another clinical need. Several combinations were evaluated. The association of ICPIs with chemotherapy (anthracyclines or carboplatin+paclitaxel) is disappointing (JAVELIN studies). The association with PARP inhibitors, anti-angiogenic agents and CTLA-4 inhibitors seems promising. Other immune therapies such as cell therapies (adoptive transfer of intra-tumor lymphocytes, CAR T cells or vaccines from dendritic cells) could be the future of immunotherapy in ovarian cancer but only early phase studies clinical data is available at this time., (Copyright © 2020 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

FDA approval and French ATU for chimeric antigen receptor (CAR) T cells represent an advanced step in the challenge of immunotherapy to cure cancer. The field of adoptive cell therapy emerged with the discovery that tumor-infiltrating-lymphocytes (TIL) can be used to treat melanoma patients. CAR T cells are engineered by gene transfer to express both receptors that target tumor-associated molecules and killing T cell functions. We report here how several decades of technology combining the specific recognition of an antibody with T cell function have led to the potent activity of CD19-targeting CAR KYMRIAH™ and YESCARTA™ i.e, high remission rates in patients with chemorefractory lymphoma. However, potentially fatal toxicity including cytokine release syndrome and neurotoxicity need next generation developments. Affinity fine-tuning, combinational CARs and guidelines for toxicity management are enhancing the safety of more powerful CAR T. Such CARs are emerging for solid tumor targeting. Synthetic biology approaches leading to personalized cell therapy marks the beginning of a new area., (© 2019 médecine/sciences – Inserm.)

The offer of anti-cancer drugs has recently been disrupted by the introduction of checkpoint inhibitors on the market. Currently, one anti-CTLA-4, two anti-PD-1 and two anti-PD-L1 are authorized in the European Union, in seven different types of cancer. The clinical development of these therapies is still in full swing: in July 2017, more than 1 500 clinical trials were evaluating anti-PD-1, anti-PD-L1 and anti-CTLA-4 drugs in about twenty different locations and this number continues to increase. In the short term in France, other immunotherapies, the CAR-T cells, will complete this therapeutic arsenal. These immunotherapies appear as a real revolution in the treatment of some cancers. Nevertheless, many issues are associated with these therapies, particularly regarding the identification of good responders, the proper use of these drugs including the management of therapeutic strategies and safety profile, as well as the organization of care. In addition, the expenses associated with ipilimumab, nivolumab and pembrolizumab are substantial and almost tripled in one year, going from 120 million euros in 2015 to more than 340 million euros in 2016. This raises the question of the ability of the current healthcare system to maintain equitable access to innovation and best treatments for all patients. For all these reasons, the French National Cancer Institute decided to dedicate its thematic annual report on these innovative immunotherapies, targeting in particular checkpoint inhibitors and CAR-T cells, in order to produce an inventory of current data and an analysis regarding the different issues associated with these therapies., (Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Emerging Therapies Using Car-T Cells in Lymphoma: After the promising results obtained in North American academic centers suggesting the curative potential of these treatments, the development of T cells carrying a chimeric antigen receptor (CAR-T) directed against the CD19 antigen has experienced rapid developments in recent years. Three major trials (each involving about 100 patients with relapsed or refractory aggressive B-cell lymphoma) were conducted and evaluated the efficacy of these treatments (Zuma-1, Juliet and Transcend). Tumor responses are observed in 52% to 82% of patients, with a best complete response (CR) rate of 40% to 58%. Although some patients with early CR may relapse rapidly, the quality of the response appears to improve over time for other patients in partial response, all of which result in a proportion of patients with prolonged CR by approximately 30% to 40% (up to more than one year after treatment). Toxicities (mostly early and reversible) are mainly represented by the cytokine release syndrome (severe in 1% to 22% of patients) and neurological disorders sometimes severe (in 12% to 31% of patients), while other patients develop cytopenias or hypogammaglobulinemia. The updating of these studies over time and the new developments (in the improvement of their conception and in their use) of the CAR-T will allow to better defining the place of these innovative and promising treatments in the therapeutic strategy of patients with lymphoma. Cet article fait partie du numéro supplément Les cellules CAR-T : une révolution thérapeutique ? réalisé avec le soutien institutionnel des partenaires Gilead : Kite et Celgene., (© 2018 Société Française du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés.)

Mast cells are immune cells that mature within the host tissue. The acquired phenotype is dictated by the tissue microenvironment, giving rise to diverse tissue-dependent phenotypes and functions. The lack of cellular models reflecting phenotypes found in vivo and important differences between human and rodent mast cells are obstacles to the understanding of their exact role in several pathophysiological processes. Studies published over the past few years showed that mast cells' role lies far beyond their involvement in allergy and anaphylaxis. Studies demonstrating their participation in innate immune responses as well as tissue scaring and vascular pathologies allowed the understanding of their role in several diseases, but also gave contradictory results, especially concerning tissue response to ionizing radiations. Nevertheless, therapeutic tools exist to target mast cells, such as degranulation inhibitors, antihistamine, protease inhibitors or tyrosine kinase receptors antagonists, and may offer some interesting new therapeutic perspectives to manage acute and chronic after-effects of radiation therapy., (© 2018 médecine/sciences – Inserm.)

Introduction: Adoptive immunotherapy was first introduced in the 1980s. This new anticancer therapeutic approach has already demonstrated promising results in both animal models and humans affected by various tumors., Current Knowledge and Key Points: This review summarizes the requirements of such therapies involving either activated lymphocytes, tumor-infiltrating lymphocytes or activated macrophages. It focuses more particularly on the promising approaches that represent antigen presenting cells such as macrophages and antigen-loaded dendritic cells in the development of safe and effective cancer vaccines., Future Prospects and Projects: Standardized procedures for macrophages and dendritic cell generation, as well as preliminary results of clinical applications in patients with either prostate cancer or melanoma, are also discussed.