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T cells engineered to express HIV-specific chimeric antigen receptors (CARs) represent a promising strategy to clear HIV-infected cells, but to date have not achieved clinical benefits. A likely hurdle is the limited T cell activation and persistence when HIV antigenemia is low, particularly during antiretroviral therapy (ART). To overcome this issue, we propose to use a cytomegalovirus (CMV) vaccine to stimulate CMV-specific T cells that express CARs directed against the HIV-1 envelope protein gp120. In this study, we use a GMP-compliant platform to engineer CMV-specific T cells to express a second-generation CAR derived from the N6 broadly neutralizing antibody, one of the broadest anti-gp120 neutralizing antibodies. These CMV-HIV CAR T cells exhibit dual effector functions upon in vitro stimulation through their endogenous CMV-specific T cell receptors or the introduced CARs. Using a humanized HIV mouse model, we show that CMV vaccination during ART accelerates CMV-HIV CAR T cell expansion in the peripheral blood and that higher numbers of CMV-HIV CAR T cells were associated with a better control of HIV viral load and fewer HIV antigen p24+ cells in the bone marrow upon ART interruption. Collectively, these data support the clinical development of CMV-HIV CAR T cells in combination with a CMV vaccine in HIV-infected individuals.

Chimeric Antigen-Receptor (CAR) T-cell therapies have shown dramatic efficacy in treating relapsed and refractory cancers, especially B cell malignancies. However, these innovative therapies cause adverse toxicities that limit the broad application in clinical settings. Hematologic cytopenias, one frequently reported adverse event following CAR T cell treatment, are manifested as a disorder of hematopoiesis with decreased number of mature blood cells and subdivided into anemia, thrombocytopenia, leukopenia, and neutropenia, which increase the risk of infections, fatigue, bleeding, fever, and even fatality. Herein, we initially summarized the symptoms, etiology, risk factors and management of cytopenias. Further, we elaborated the cellular and molecular mechanisms underlying the initiation and progression of cytopenias following CAR T cell therapy based on previous studies about acquired cytopenias. Overall, this review will facilitate our understanding of the etiology of cytopenias and shed lights into developing new therapies against CAR T cell-induced cytopenias. [ABSTRACT FROM AUTHOR]

Introduction : B cell maturation antigen (BCMA) contributes to MM pathophysiology and is a target antigen for novel MM immunotherapy. Complete responses have been observed in heavily pretreated MM patients after treatment with BCMA antibody-drug conjugates (ADC), chimeric antigen receptor T, and bi-specific T cell engagers (BiTE®). These and other innovative BCMA-targeted therapies transform the treatment landscape and patient outcome in MM. Areas covered : The immunobiological rationale for targeting BCMA in MM is followed by key preclinical studies and available clinical data on efficacy and safety of therapies targeting BCMA from recent phase I/II studies. Expert opinion : BCMA is the most selective MM target antigen, and BCMA-targeted approaches have achieved high responses even in relapse and refractory MM as a monotherapy. Long-term follow-up and correlative studies using immuno-phenotyping and -sequencing will delineate mechanisms of overcoming the immunosuppressive MM bone marrow microenvironment to mediate additive or synergistic anti-MM cytotoxicity. Moreover, they will delineate cellular and molecular events underlying the development of resistance underlying relapse of disease. Most importantly, targeted BCMA-based immunotherapies used earlier in the disease course and in combination (adoptive T cell therapy, mAbs/ADCs, checkpoint and cytokine blockade, and vaccines) have great promise to achieve long-term disease control and potential cure.