Tumor Burden Limits Bispecific Antibody Efficacy through T-cell Exhaustion Averted by Concurrent Cytotoxic Therapy

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

Research output: Contribution to journalArticlepeer-review

Abstract

BCMA/CD3-targeting bispecific antibodies (BsAb) are a recently developed immunotherapy class that shows potent tumor killing activity in multiple myeloma. Here, we investigated a murine BCMA/CD3-targeting BsAb in the immunocompetent Vk*MYC model and its immunomodulatory imide drug (IMiD)-sensitive derivative Vk*MYChCRBN model of multiple myeloma. 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 proinflammatory 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. SIGNIFICANCE: BCMA-targeted therapy induces deep but transient clinical responses. We developed an immunocompetent, IMiD-sensitive genetically engineered mouse model and show that IMiDs potentiate T-cell activation, increasing short-term efficacy of anti-BCMA/CD3 BsAb, but exacerbate T-cell exhaustion. Surprisingly, by reducing tumor burden and depleting regulatory T cells, cyclophosphamide prevents BsAb-induced T-cell exhaustion and promotes long-term multiple myeloma control.See related commentary by Louvet et al., p. 297.

Original languageEnglish (US)
Pages (from-to)354-369
Number of pages16
JournalCancer discovery
Volume2
Issue number4
DOIs
StatePublished - Jul 1 2021

ASJC Scopus subject areas

  • Oncology

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