Elsevier

Blood Reviews

Volume 54, July 2022, 100929
Blood Reviews

Review
Current state and next-generation CAR-T cells in multiple myeloma

https://doi.org/10.1016/j.blre.2022.100929Get rights and content

Abstract

Chimeric antigen receptor T cells (CAR-T cells) have emerged as a potentially transformative new approach to treating hematological malignancies. Ide-cel, an autologous B cell maturation antigen (BCMA) targeting CAR-T cells, has recently been approved to treat multiple myeloma (MM). Here, we review the main clinical trials of CAR-T cells in MM with the most advanced autologous BCMA-directed ide-cel and cilta-cel, the human CARs orva-cel and CT053, the alternative manufacturing process with P-BCMA-101 and bb21217, the dual CAR GC012F and the allogenic BCMA-directed CAR-T cells ALLO-715. In light of those clinical data, we provide an overview of CAR-T cells' main potential resistance mechanisms, including antigen loss, antigen spreading, anti-CAR antibodies, CAR-T cell exhaustion, and the emergence of a non-permissive microenvironment. Finally, we describe the principal area of research to build the next generation of CAR-T cells, with armored-, gated- or commuting-CARs, CARs associated with knock out of specific genes, and CAR-T cells made from γδT cells or NK cells.

Introduction

Multiple myeloma (MM) is the second most frequent hematological malignancy with an incidence of 6.5 per 100,000 persons per year. Despite considerable advances in treatment options, including new generations of proteasome inhibitors, immunomodulatory drugs, and immunotherapies with anti-CD38 antibodies, MM remains an incurable disease with a 5 years relative survival of 55.6% in 2011–2017 [1]. A substantial proportion of patients either do not respond to current therapies or acquire resistance to treatment highlighting an unmet need for improved therapeutic options for MM. Typically, patients with triple-class or penta-class refractory MM have an overall survival (OS) of 9.2 and 5.6 months, respectively [2]. The new treatment approaches have focused on immunotherapies to address this unmet need, including development of antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor (CAR) T cells. Their evaluation in phase 1 dose escalation studies have demonstrated high response rates in late-stage refractory MM.

CAR-T cells are T cells modified ex vivo to express a chimeric receptor with an antigen receptor containing a single chain variable fragment (scFv) and an intracellular T-cell receptor (TCR) signaling domain. The scFv is the recognition domain directed to target tumor cells. The intracellular domain of CAR contains various components with CD3-zeta (first generation), in addition to a costimulatory domain such as CD28 or 41bb (second generation) or both (third generation). A fourth-generation CAR-T cells is known as armored CAR-T cells and co-express key cytokines or suicide genes to enhance the efficacy and safety of CAR-T therapy. Notably, CAR-T target cell recognition does not require HLA presentation of antigens. To this end, the patient's own T cells are isolated and genetically modified to express the CAR, redirecting T cell specificity to the tumor-associated antigen. Adoptively transferred CAR-T cells are therefore equipped to induce and sustain remissions through a synergy of antibody-based target cell recognition and the memory and effector function of T cells. These results represent a substantial improvement compared to conventional therapies yielding complete and durable response rate.

B cell maturation antigen (BCMA) is currently the main target for CAR-T cells in MM as it is predominantly expressed on differentiated B cells including malignant plasma cells. BCMA, also known as TNF receptor superfamily 17 (TNFRSF17), delivers pro-survival signaling upon binding to its ligands - B cell activator of the TNF family (BAFF) and a proliferation inducing ligand (APRIL) - participating in the survival and proliferation of MM cells. BCMA is shed from the surface of MM cells by γ-secretase, releasing a soluble form BCMA (sBCMA), which serves as a biomarker of MM tumor burden. Additionally, soluble BCMA can limit therapeutic efficacy of membrane-bound BCMA-targeted therapies.

This review discusses the primary clinical data on anti-BCMA CAR-T cells in MM and known mechanisms of resistance and next generations CAR-T cells that are currently under research.

Section snippets

Clinical trials of CAR-T cells in myeloma

Since the development of CAR-T cells in MM, several clinical trials have been reported for this indication. So far, all CAR-T cells used in MM target BCMA. Most of them are autologous, but some allogenic products are emerging, they bear human or chimeric scFv and have various manufacturing processes. The main clinical trials data are reported here (Table 1).

Mechanisms of resistance to CAR-T cells

The main mechanism of resistance to CAR-T cells are either antigen dependent (antigen escape, antigen shedding or anti-CAR antibodies) or T cell driven (CAR-T cell exhaustion and a non-permissive microenvironment), (Fig. 1). Their precise knowledge will help guide medical decisions [13] and improve the next generation of CAR-T cells.

Next generation CARs

A major limiting factor of adoptive CAR-T therapy is poor in vivo persistence, lineage stability of infused CAR-T cells, properties that are known to be critical for generating robust and durable Treg-mediated functional responses. Additionally, current methods of CAR-T cell therapy are limited for broader use by the risk of severe adverse events, including CRS and neurotoxicity. Hence, the next-generation CAR-T cell-based therapies are focused on designing CAR-T with improving efficacy while

Conclusion

The rapid development of BCMA-targeting CAR-T cells in MM since their first administration in 2014 to the FDA and EMA approvals of ide-cel in 2021 holds great expectation for the future of myeloma treatments. BCMA-targeting CAR-T cells have demonstrated remarkable efficacy in the context of relapsed and refractory MM. Current studies are evaluating CAR-T cells in earlier lines of treatment, including frontline, with the hope of achieving long-lasting remission in MM. Many different approaches

Practice points

  • Autologous BCMA-directed CAR-T cells used in multiple myeloma induce an overall response rate above 80% and median progression free-survivals from 12 to 22 months, in late stage refractory setting of the disease.

  • New generation CAR-T cells with humanized scFv, alternative manufacturing or generated from allogenic T cells are effective.

  • Loss of BCMA is observed in about 4% of the cases at relapse, with some bi-allelic deletions of BCMA on chromosome 16p13.13.

Research agenda

  • Understanding the impact of the immune microenvironment in response and resistance to CAR-T cells.

  • Determining the nature of resistant myeloma cells to CAR-T cells, despite high rates of MRD negativity.

  • Improving CAR-T cells efficacy with newer approaches such as commuting CARs or knock-out of immune checkpoints.

Future considerations

  • Future clinical trials will evaluate the efficacy of CAR-T cells in early line of treatments, including frontline and in combination with other treatment.

  • Learning how to sequence anti-BCMA therapies will be important in clinical practice with future approvals of bispecific antibodies and antibody-drug conjugate.

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    These authors contributed equally.

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