How to Train Your T Cells: Overcoming Immune Dysfunction in Multiple Myeloma

Abstract

The progression of multiple myeloma, a hematologic malignancy characterized by unregulated plasma cell growth, is associated with increasing innate and adaptive immune system dysfunction, notably in the T-cell repertoire. Although treatment advances in multiple myeloma have led to deeper and more durable clinical responses, the disease remains incurable for most patients. Therapeutic strategies aimed at overcoming the immunosuppressive tumor microenvironment and activating the host immune system have recently shown promise in multiple myeloma, particularly in the relapsed and/or refractory disease setting. As the efficacy of T-cell-dependent immuno-oncology therapy is likely affected by the health of the endogenous T-cell repertoire, these therapies may also provide benefit in alternate treatment settings (e.g., precursor disease; after stem cell transplantation). This review describes T-cell-associated changes during the evolution of multiple myeloma and provides an overview of T-cell-dependent immuno-oncology approaches under investigation. Vaccine and checkpoint inhibitor interventions are being explored across the multiple myeloma disease continuum; treatment modalities that redirect patient T cells to elicit an anti-multiple myeloma response, namely, chimeric antigen receptor (CAR) T cells and bispecific antibodies [including BiTE (bispecific T-cell engager) molecules], have been primarily evaluated to date in the relapsed and/or refractory disease setting. CAR T cells and bispecific antibodies/antibody constructs directed against B-cell maturation antigen have generated excitement, with clinical data demonstrating deep responses. An increased understanding of the complex interplay between the immune system and multiple myeloma throughout the disease course will aid in maximizing the potential for T-cell-dependent immuno-oncology strategies in multiple myeloma.

Figure 1.

Changes in the T-cell repertoire during multiple myeloma disease progression. Bars with gradients denote changes in T cell populations (, , –17, 21, 85, 86); darker shades correspond to increased levels, whereas lighter shades correspond to reduced levels. BM, bone marrow; MGUS, monoclonal gammopathy of undetermined significance; NKT, natural killer T cell; PB, peripheral blood; SMM, smoldering multiple myeloma; Th, T helper cell. ^aReferenced studies do not include BM and PB of age-matched healthy donors (16, 21). ^bReferenced studies do not include PB of patients with precursor disease or direct comparisons of BM Th17 frequency between age-matched healthy donors and patients with precursor disease (14, 15).

Figure 2.

Select T cell-dependent immuno-oncology studies across the MM disease continuum. Studies include early stages of disease (MGUS, SMM, NDMM), patients with MM and low tumor burden (transplant setting), and patients in the relapsed and/or refractory MM setting. BCMA, B cell maturation antigen; bsAb, bispecific antibody; CAR T, chimeric antigen receptor T cell; CPI, checkpoint inhibitor; DC, dendritic cell; GPS, galinpepimut-S; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; NDMM, newly diagnosed multiple myeloma; RRMM, relapsed and/or refractory multiple myeloma; SCT, stem cell transplantation; SMM, smoldering multiple myeloma. Based on www.clinicaltrials.gov search conducted on February 20, 2019. ^aSCT studies may include NDMM or RRMM patients (i.e., not mutually exclusive). ^bStudies in RRMM are not shown, as the focus of more recent vaccine therapy trials has been for disease stages with lower tumor burden/immunosuppression. ^cAutologous DC vaccine. ^dStudy also includes SMM and MM patients. ^eStudies evaluating pembrolizumab/immunomodulatory drug combinations in RRMM are not included due to clinical holds placed on some of these studies. ^fStudy also includes patients at first relapse. ^gIn conjunction with DC/MM vaccine. ^hFollowing the completion of our clinicaltrials.gov search, a phase 1/2 study of CT053, a BCMA-targeting CAR T-cell therapy, has opened (NCT03975907). ⁱFollowing the completion of our clinicaltrials.gov search, a phase 1 study of TNB-383B, a BCMA-targeting bsAb/antibody construct, has entered clinical trials (NCT03933735).

Figure 3.

Comparison of CAR T cell and bsAb/antibody construct immuno-oncology approaches in MM. Similarities and differences in structure and manufacturing (43, 49, 68), as well as challenges and current strategies for improvement (, , –92). BCMA, B cell maturation antigen; BiTE®, bispecific T-cell engager; bsAb, bispecific antibody; CAR, chimeric antigen receptor; CM, central memory; CRS, cytokine release syndrome; HAMA, human antimouse antibody; mAb, monoclonal antibody; MIL, marrow-infiltrating lymphocyte; scFV, single-chain variable fragment; SCM, stem cell memory; TAA, tumor-associated antigen; TCR, T-cell receptor.