Tumor burden limits bispecific antibody efficacy through T cell exhaustion averted by concurrent cytotoxic therapy

Blood Cancer Discov. 2021 Jul;2(4):354-369. doi: 10.1158/2643-3230.BCD-21-0038.

Abstract

BCMA-CD3-targeting bispecific antibodies (BsAb) are a recently developed immunotherapy class which shows potent tumor killing activity in multiple myeloma (MM). Here, we investigated a murine BCMA-CD3-targeting BsAb in the immunocompetent Vk*MYC and its IMiD-sensitive derivative Vk*MYChCRBN models of MM. The BCMA-CD3 BsAb was safe and efficacious in a subset of mice, but failed in those with high-tumor burden, consistent with clinical reports of BsAb in leukemia. The combination of BCMA-CD3 BsAb with pomalidomide expanded lytic T cells and improved activity even in IMiD resistant high-tumor burden cases. Yet, survival was only marginally extended due to acute toxicity and T cell exhaustion, which impaired T cell persistence. In contrast, the combination with cyclophosphamide was safe and allowed for a tempered pro-inflammatory response associated with long-lasting complete remission. Concurrent cytotoxic therapy with BsAb actually improved T cell persistence and function, offering a promising approach to patients with a large tumor burden.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Bispecific* / pharmacology
  • Humans
  • Immunotherapy
  • Mice
  • Multiple Myeloma* / drug therapy
  • T-Lymphocytes
  • Tumor Burden

Substances

  • Antibodies, Bispecific