Determinants of Response and Mechanisms of Resistance of CAR T-cell Therapy in Multiple Myeloma

Abstract

B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T cells have substantial therapeutic potential in multiple myeloma (MM), but most patients eventually relapse. Determinants of response and mechanisms of resistance are most likely multifactorial and include MM-related factors, premanufacturing T-cell characteristics, CAR T-cell-related features, and several components of the immunosuppressive microenvironment. Efforts to improve the potency and safety of CAR T-cell therapy include optimizing CAR design, combinatorial approaches to enhance persistence and activity, treatment of less heavily pretreated patients, and dual-antigen targeting to prevent antigen escape. We expect that these rationally designed strategies will contribute to further improvement in the clinical outcome of patients with MM.Significance: Although BCMA-specific CAR T-cell therapies are highly effective in heavily pretreated patients with MM, there has been, until now, no indication of a plateau in the survival curves. In this review, we provide an overview of the determinants of response and the mechanisms that contribute to the development of treatment failure after initial remission (acquired resistance). A better understanding of these mechanisms, underlying lack of disease response, and acquired resistance may lead to further improvements in the effectiveness of CAR T-cell therapy. iNtRODUctiONAlthough the introduction of new anti-multiple myeloma (MM) agents has markedly improved the survival of patients with MM, there is an unmet need for new drugs for patients who develop resistance to immunomodulatory drugs (IMiD), proteasome inhibitors (PI), and CD38-targeting antibodies (triple-class refractory disease), which carries a poor prognosis (1). Also, newly diagnosed patients with high-risk disease [e.g., presence of del(17p), t(4;14), or t(14;16)] or suboptimal response have an impaired outcome, and these patients may benefit from the incorporation of new drugs with novel mechanisms of action in first-line regimens.A promising new strategy is the reprogramming of T cells to target MM cells by introducing genes encoding chimeric antigen receptors (CAR). CARs are fusion proteins, combining an antigen-recognition moiety [commonly a monoclonal antibody-derived single-chain variable fragment (scFv), but other formats such as natural ligands are also possible; ref.2] with a T-cell activation domain, typically CD3ζ. These two parts are connected via an extracellular spacer region (hinge) and a transmembrane-spanning element. Second-generation CARs incorporating a costimulatory domain, such as CD28, 4-1BB, OX40, or ICOS, into the CAR endodomain result in enhanced antitumor activity of the modified T cells compared with first-generation CARs without such domain (Fig. 1; ref. 3). Importantly, CAR T cells eliminate tumor cells in a non-major histocompatibility complex (MHC)restricted manner.Most CAR T-cell products, currently evaluated in clinical trials for patients with MM, target B-cell maturation antigen (BCMA), which is...

Patient selection for CAR T or BiTE therapy in multiple myeloma: Which treatment for each patient?

“…Van de Donk et al reviewed hypotheses regarding this controversy. Possible determinants could be differences in assays (flow cytometry versus immunohistochemistry) used to quantify BCMA expression or the effects of soluble BCMA (sBCMA) formed by shedding of MM cell membranes [ 48 ]. Furthermore, some authors relate that sBCMA plasma levels could be a valid biomarker in response assessment in the future [ 49 ].…”

Gaps and opportunities in the treatment of relapsed-refractory multiple myeloma: Consensus recommendations of the NCI Multiple Myeloma Steering Committee

“…Questions remain regarding immunotherapies, including the optimal timing for specific therapeutic platforms with respect to disease burden at therapy initiation, specific combinations that can enhance efficacy, post-therapy interventions that can extend the durability of response with one-time treatment therapies like CAR T cells and understanding the role of the immune micro-environment. In particular, sequencing of therapies that target B cell maturation agent (BCMA) merits exploration, as do the mechanisms that lead to therapeutic failure, including deletion of the BCMA gene [ 82 , 83 ], increased levels of soluble BCMA and whether treatment with a different BCMA directed therapy after failure of the first attempt produces meaningful responses [ 84 ].…”

Relapsed/Refractory Multiple Myeloma in 2020/2021 and Beyond

“…Moreover, we need to better understand mechanisms of resistance against CAR T cell therapy; contributing factors include CAR T cell-and tumor cell-intrinsic features (i.e., poor T cell expansion and persistence; impaired T cell function via exhaustion resistance, high tumor burden or tonic signaling; tumor cell heterogeneity with changes in target antigen expression via clonal selective pressure, trogocytosis, splice variants, and lineage switch), features mediated via the microenvironment (e.g., immune suppression), as well as impaired T cell trafficking [61,62]. Specifically, recently discovered mechanisms-of-actions include biallelic BCMA-loss [63,64] or the inhibitory effect of T regs [65], which induce resistance against BCMA-targeting agents [66]. Counteracting therapeutic strategies to overcome resistance against BCMA-targeting CAR T cells may include the use of non-BCMA CD38-, SLAMF7-, GPRC5D-, CD138-, ikappa light chain-targeting CAR T cells; as well as dual-targeted, triple CAR T cells such as BCMA/CD38/CD3-or CD19/BCMA/CD3-CAR T cells [67][68][69]; or also off-the-shelf AlloCAR T cells.…”