Abstract
Simple SummaryIn relapsed, refractory B cell malignancies and multiple myeloma, chimeric antigen receptor (CAR) T cell therapy has represented a major scientific advancement with high response rates and durable responses for many. Nonetheless, target antigen downregulation in tumor cells can lead to poor responses and relapsed disease. Current FDA approved CAR T cell therapies only target a single B-cell specific cell marker. While effective, single targeted CAR T cell therapy can lead selective pressure against the target antigen leading to loss of expression and tumor cell escape. Simultaneous dual antigen targeting CAR therapy has been evaluated in multiple early phase clinical trials in response to these clinical challenges in hopes of improving response rates and preventing relapse. This article discusses the limitations of single targeted CAR T cell therapy, approaches to dual antigen targeting, and the results of early phase trials utilizing dual antigen targeting CAR T cell therapy.Chimeric antigen receptor (CAR) modified T cell therapy offers a targeted immunotherapeutic approach to patients with refractory hematological malignancies. This technology is most advanced in B cell malignancies and multiple myeloma and is rapidly evolving as more data become available regarding clinical efficacy and response durability. Despite excellent initial response rates with single antigen targeting CARs, failure to respond to therapy and relapse due to target antigen downregulation remain clinical challenges. To mitigate immunophenotypic selective pressures, simultaneous dual antigen targeting with bispecific CAR T cells or multiple administration of different populations of CAR T cells may prevent relapse by addressing one resistance mechanism attributed to antigenic loss. This article will review recently published data on the use of dual targeting with CAR T cells from early phase clinical trials aimed at treating B cell malignancies and multiple myeloma.
Highlights
In an era of rapidly expanding adaptive cellular immuno-therapies, chimeric antigen receptor (CAR) T cells have shown unprecedented results in the treatment of relapsed, refractory (R/R)hematologic malignancies
CAR T cell therapy can be complicated by a cytokine mediated inflammatory storm that can present with high fevers, confusion, hypotension, confusion, seizures, and in rare cases death
Limited data exist evaluating the effect of third generation CAR T products with incorporation of multiple co-stimulatory domains [6,7], though early phase data in CD19 targeting for B cell malignancies show excellent safety data and persistence of the CAR T cells beyond three months following infusion [8]
Summary
In an era of rapidly expanding adaptive cellular immuno-therapies, chimeric antigen receptor (CAR) T cells have shown unprecedented results in the treatment of relapsed, refractory (R/R). Autologous T cells are collected via leukapheresis, activated and expanded after being exposed to a viral vector that encodes for costimulatory domains attached to a monoclonal antibody-derived single-chain variable fragment (scFv) capable of targeting specific tumor-associated antigens [1,2]. Following lymphodepletion, these genetically modified CAR T cells are reinfused into the patient through autologous adoptive T cell transfer, exerting their effects independently of human leukocyte antigen (HLA) signaling. Limited data exist evaluating the effect of third generation CAR T products with incorporation of multiple co-stimulatory domains [6,7], though early phase data in CD19 targeting for B cell malignancies show excellent safety data and persistence of the CAR T cells beyond three months following infusion [8]
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