Elsevier

Cellular Immunology

Volume 345, November 2019, 103964
Cellular Immunology

The promise of chimeric antigen receptor (CAR) T cell therapy in multiple myeloma

https://doi.org/10.1016/j.cellimm.2019.103964Get rights and content

Highlights

  • •

    Multiple myeloma remains an incurable disease.

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    BCMA CAR T therapy shows promise in trials of relapsed and/or refractory myeloma.

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    Timing, targets, toxicities, and resistance mechanisms of CAR T need further studies.

Abstract

A cure for multiple myeloma (MM), a malignancy of plasma cells, remains elusive. Nearly all myeloma patients will eventually relapse and develop resistance to currently available treatments. There is an unmet medical need to develop novel and effective therapies that can induce sustained responses. Early phase clinical trials using chimeric antigen receptor (CAR) T cell therapy have shown great promise in the treatment of relapsed and/or refractory MM. In this review article, we provide an overview of the CAR constructs, the gene transfer vector systems, and approaches for T cell activation and expansion. We then summarize the outcomes of several early phase clinical trials of CAR T cell therapy in MM and the novel CAR T targets that are under development. Finally, we explore the potential mechanisms that result in disease relapse after CAR T therapy and propose future directions in CAR T therapy in MM.

Section snippets

Multiple myeloma

Multiple Myeloma (MM) is a malignancy of terminally differentiated plasma cells typically characterized by clonal proliferation of these plasma cells in the bone marrow. MM represents 1% of all malignancies and 18% of hematologic malignancies in the United States; accounting for an estimated 32,110 new diagnoses and 12,960 deaths in 2019 alone [1]. The diagnosis of MM is made based on the presence of ≥10% clonal plasma cells in the bone marrow, and evidence of end organ damage (typically

Chimeric antigen receptor constructs

Cancer patients have profound defects in anti-tumor immunity, resulting in the failure to suppress tumor growth [22], [23]. The objective of CAR T therapy is to activate the anti-tumor immunity by adoptive infusion of a sufficient number of immune effector cells. Most of the immune effector cells used for the adoptive transfer are T cells, although NK cells have also been used. Autologous immune effector cells are typically used but allogeneic immune effector cells have been reported [24], [25]

Early phase multiple myeloma CAR T clinical trials targeting BCMA

B-cell maturation antigen (BCMA), also referred to as tumor necrosis factor receptor superfamily member 17 (TNFRSF17) or CD269, is the receptor for BAFF and APRIL and is expressed consistently on myeloma cells and normal plasma cells at varying intensities [54], [55], [56]. BCMA has been shown to promote multiple myeloma pathogenesis, and targeting BCMA has been shown to have potent anti-myeloma activity [56], [57], [58], [59]. BCMA antigen can be cleaved by gamma-secretase and released into

Phase I clinical trial with CAR T therapy targeting the κ light chain

Ramos et al. at the Baylor College of Medicine and Houston Methodist Hospital conducted a phase 1 clinical trial in patients with κ+ non-Hodgkin lymphoma/chronic lymphocytic leukemia or MM (ClinicalTrials.gov: NCT00881920) (Table 3) [74]. Autologous T cells were genetically engineered by retroviral vector to express a murine scFv fragment targeting the κ light chain of human immunoglobulin, a CD28 costimulatory domain and a CD3ζ domain. A spacer region derived from the human IgG1-CH2CH3 domains

CAR T therapy targeting SLAMF7

SLAMF7 (CD319, CS-1) is a member of the signaling lymphocytic activation molecule family of trans-membrane receptors. SLAMF7 is expressed on NK cells and a proportion of CD8+ T cells. SLAMF7 is uniformly expressed on malignant plasma cells in newly diagnosed multiple myeloma and in relapsed myeloma after intensive chemotherapy [86], [87], [88]. Furthermore, SLAMF7-CAR T cells were effective against myeloma cells in vitro and in vivo in a murine xenograft model [89]. Importantly, SLAMF7-CAR T

Mechanisms of resistance/relapse after CAR T therapy

Despite the promise of CAR T therapy in the treatment of MM, patients still relapse with CAR T therapy even after achieving MRD negativity. The progression-free survival in bb2121 and LCAR-B38M trial was 17.7 and 15 months, respectively. The mechanisms for the relapse remain to be characterized but may include the following.

Second CAR T therapy

At the 2019 ASCO annual meeting, Li et al. presented 4 cases who received human BCMA-targeting CAR T therapy (CT103A) after the patients’ myeloma relapsed from a murine BCMA-targeting CAR T therapy. The CT103A CAR construct is a lentiviral vector encoding a fully human scFV, CD8a hinger and transmembrane, 4-1BB costimulatory and CD3ζ activation domain. Patients received 1–6 × 106 CAR T cells/kg. All 4 patients had objective responses: 3 patients achieved a CR and 1 patient had a VGPR. More

Summary and future direction

CAR T therapy has shown promising results and safety profiles. It is highly likely that in the near future CAR T therapy will become an important modality of treatment especially for relapsed/refractory MM. It remains to be determined when will be the best time to incorporate CAR T therapy in MM: as part of induction therapy, in the relapsed setting, as an alternative to ASCT, or as an adjunctive to ASCT? Finally, the mechanisms of resistance/relapse with CAR T therapy remain to be

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgement

Funding: This work is supported by Duke Cancer Institute Fund, NIH R44CA199767, NIH 5T32 HL007057-42, NCI R21CA234701, and NIH R01CA197792.

Authors’ contributions

All authors wrote, read, and approved the final manuscript.

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