T-cell bispecific antibodies (TCB) targeting BCMA or FcRH5 induce T cell–mediated myeloma cell death.

  • Major finding: T-cell bispecific antibodies (TCB) targeting BCMA or FcRH5 induce T cell–mediated myeloma cell death.

  • Concept: TCBs are well tolerated in animals and exhibit antitumor activity alone and with PD-L1 blockade.

  • Impact: TCBs exhibit promising activity animal models and may be effective in patients with multiple myeloma.

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Multiple myeloma is a hematologic malignancy characterized by abnormal plasma cell accumulation in the bone marrow. Although several therapies are available, the majority of patients eventually develop refractory disease or discontinue treatment due to toxicities. One potential immunotherapeutic strategy is the development of T-cell bispecific antibodies (TCB), which bind simultaneously to a surface tumor cell antigen and a T-cell receptor (TCR) to induce T cell–mediated killing of tumor cells harboring the target surface antigen. Seckinger, Delgado, and colleagues generated a TCB (EM801) targeting the B-cell maturation antigen (BCMA), a receptor required for the survival of long-lived bone marrow plasma cells. The constructed BCMA-CD3 TCB, EM801, promoted CD4+ and CD8+ T-cell activation and release of IFNγ, granzyme B, and perforin, resulting in T cell–mediated killing of myeloma cell lines. Further, EM801 induced autologous T cell–mediated cell death in 34 of 43 bone marrow aspirates from patients with myeloma, including those with relapse or refractory disease. In vivo, EM801 was well tolerated, induced tumor regression in 6 of 9 myeloma xenograft models, and depleted BCMA+ cells in cynomolgus monkeys. In a related study, Li and colleagues developed a TCB targeting FcRH5, a B-cell lineage marker that is broadly expressed in myeloma. TCBs induced T-cell receptor activation by clustering the tumor target and excluding inhibitory CD45 from the synapse. FcRH5-CD3 TCB killed human plasma cells and patient-derived myeloma cells. In vivo, FcRH5-CD3 TCB reduced the growth of multiple myeloma xenografts and eliminated FcRH5-expressing B cells and bone marrow plasma cells in cynomolgus monkeys at well-tolerated doses. PD-L1 blockade enhanced the activity of FcRH5-CD3 TCB, suggesting the possibility for combination therapy. Together, these studies show that TCBs targeting myeloma antigens can induce antitumor activity and warrant further clinical investigation in patients with multiple myeloma alone and in combination with other therapies.

Seckinger A, Delgado JA, Moser S, Moreno L, Neuber B, Grab A, et al. Target expression, generation, preclinical activity, and pharmacokinetics of the BCMA-T cell bispecific antibody EM801 for multiple myeloma treatment. Cancer Cell 2017;31:396–410.

Li J, Stagg NJ, Johnston J, Harris MJ, Menzies SA, DiCara D, et al. Membrane-proximal epitope facilitates efficient T cell synapse formation by anti-FcRH5/CD3 and is a requirement for myeloma cell killing. Cancer Cell 2017;31:383–95.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.

©2017 American Association for Cancer Research.
2017
American Association for Cancer Research.