Multispecific CAR T Cells Deprive Lymphomas of Escape via Antigen Loss

Abstract

Chimeric antigen receptor (CAR) modified T cell therapy has transformed the management of relapsed/refractory B cell malignancies. Despite high overall response rates, relapse post CAR T treatment remains a clinical challenge. Loss of target antigen, specifically CD19, is one well-defined mechanism of disease relapse. The mechanism of CD19 loss and which patients are at higher risk of CD19 loss remain poorly understood. To overcome CD19 loss, CARs targeting multiple antigens are being tested in clinical trials. CD19/20 and CD19/22 bispecific CARs demonstrate cytotoxicity against CD19-negative cells in preclinical studies. These CARs have also shown efficacy, safety, and a relatively low rate of CD19-negative relapse in phase I trials. These small studies suggest that multispecific CAR T cells can deprive lymphomas of escape via antigen loss. However, the selection of an ideal target, the right CAR construct, and whether these multispecific CARs can induce long-term remissions are still under investigation. Expected final online publication date for the Annual Review of Medicine, Volume 74 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The role of chimeric antigen receptor T cells targeting more than one antigen in the treatment of B‐cell malignancies

“…If we focus on antigen escape, this mechanism could be theoretically overcome by the administration of CART cells targeting more than one antigen. [11][12][13]27 Indeed, there currently are many initiatives in this regard, and the aim of this manuscript is to review the pros and cons of such combinatorial approaches for the treatment of patients with NHL and ALL.…”

Are we ready for personalized CAR‐T therapy?

“…32 For patients with B-ALL and relapse after initial CAR-T therapy, CAR-T cells targeting CD19 and CD22 simultaneously may be applicable. 32 Yan et al 33 used that construct in 23 patients with B-ALL and relapse after allo-HSCT. Only two patients developed CD19-negative relapse.…”

“…The above‐mentioned difficulties and limitations can be overcome by bispecific or even trispecific CARs. Potential, other than CD19, markers for B‐cell malignancies include CD22, CD123, CD79b, CD38, B‐cell activating factor receptor (BAFF‐R), receptor tyrosine kinase like orphan receptor 1 (ROR1), CD70, and CD37 32 . For patients with B‐ALL and relapse after initial CAR‐T therapy, CAR‐T cells targeting CD19 and CD22 simultaneously may be applicable 32 .…”

“…Potential, other than CD19, markers for B‐cell malignancies include CD22, CD123, CD79b, CD38, B‐cell activating factor receptor (BAFF‐R), receptor tyrosine kinase like orphan receptor 1 (ROR1), CD70, and CD37 32 . For patients with B‐ALL and relapse after initial CAR‐T therapy, CAR‐T cells targeting CD19 and CD22 simultaneously may be applicable 32 . Yan et al 33 used that construct in 23 patients with B‐ALL and relapse after allo‐HSCT.…”

Best Practices and Considerations for Clinical Pharmacology and Pharmacometric Aspects for Optimal Development of CAR‐T and TCR‐T Cell Therapies: An Industry Perspective

“…However, transient T-cell proliferation and limited cytokine secretion led to the development of second-and third-generation CARs, which included co-stimulatory endo domains, such as CD28 or/and 4-1BB to improve in vivo proliferative capacity, persistence, and overall activity of CAR-Ts. [10][11][12][13] Next generation CAR-Ts are further modified to include bispecific or multispecific scFvs to target different tumor antigens for improving selectivity and specificity, 14 suicidal genes to trigger CAR-T depletion in case of toxicity, additional armoring to improve T-cell function, and/or to overcome immunosuppressive tumor microenvironment, such as IL-12 expression, along with other modifications. 15 However, such next generation engineering also comes with its own set of challenges (e.g., safety risk due to a new mode of action) and hence should be thoroughly investigated during the early development stage.…”