1. Academic Validation
  2. Tumor burden limits bispecific antibody efficacy through T cell exhaustion averted by concurrent cytotoxic therapy

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.
Erin W Meermeier 1 Seth J Welsh 1 Meaghen E Sharik 1 Megan T Du 1 Victoria M Garbitt 1 Daniel L Riggs 1 Chang-Xin Shi 1 Caleb K Stein 1 Marco Bergsagel 1 Bryant Chau 2 Matthew L Wheeler 3 Natalie Bezman 3 Feng Wang 2 Pavel Strop 2 P Leif Bergsagel 1 Marta Chesi 4
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Hematology/Oncology, Mayo Clinic Arizona, Scottsdale, Arizona.
  • 2 Discovery Biotherapeutics, Bristol Myers Squibb, Redwood City, California.
  • 3 Tumor Microenvironment Thematic Research Center, Bristol Myers Squibb, Redwood City, California.
  • 4 Department of Medicine, Division of Hematology/Oncology, Mayo Clinic Arizona, Scottsdale, Arizona. chesi.marta@mayo.edu.
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.

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