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

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.

• Authors: Erin W Meermeier, Seth J Welsh, Meaghen E Sharik, Megan T Du, Victoria M Garbitt, Daniel L Riggs, Chang-Xin Shi, Caleb K Stein, Marco Bergsagel, Bryant Chau, Matthew L Wheeler, Natalie Bezman, Feng Wang, Pavel Strop, P Leif Bergsagel, Marta Chesi
• Journal: Blood cancer discovery (Blood Cancer Discov) Vol. 2 Issue 4 Pg. 354-369 (07 2021) ISSN: 2643-3249 [Electronic] United States
• PMID: 34258584 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies, Bispecific

Topics

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