Bergsagel, Marco

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.

Abstract BCMA is an ideal target antigen for myeloma immunotherapy as it is specifically expressed by plasma cells and T cell-engaging, BCMA-bispecific antibodies show potent tumor killing activity in human multiple myeloma (MM). However, a lack of longevity, potential immunotoxicity, and efficacy in high tumor burden situations are limitations to effective clinical utility. In order to optimize this therapeutic approach, we performed in vitro and in vivo assessments of a BCMA bispecific tool using the Vk*MYC immunocompetent mouse model of MM. Analysis at gene and protein level revealed variable levels of BCMA in Vk*MYC tumors, mirroring the heterogeneity of BCMA observed in human MM. In addition, we found that treatment with a gamma secretase inhibitor enhanced BCMA expression in Vk*MYC MM cells, similar to observations from patients. Having found the Vk*MYC model as a suitable model for BCMA targeted therapy, we treated Vk*MYC de novo and transplant mice with the BCMA targeting tool and established that the treatment was safe and efficacious (significant reduction in M-spike levels compared to control antibody). However, the response was transient and modest activity was noted in high tumor burden setting, likely because of poor T cell infiltration. Therefore, we hypothesized that combining BCMA therapy with agents capable of debulking the tumors would prolong and deepen therapeutic benefits and thus selected IMiDs for their anti-tumor and immunomodulatory properties. Because mice are resistant to therapy with IMiDs, we generated a humanized transgenic mouse strain with robust human CRBN expression and crossed it with the Vk*MYC mouse to obtain a novel immunocompetent, IMiD-responsive model, Vk*MYChCRBN. When combined with the IMiD pomalidomide (POM), bispecific-directed T cell control of MM was enhanced relative to bispecific alone. M-spike levels in two different transplantable models were reduced regardless of tumor burden. In addition, POM increased T cell effector activation, proliferation, and cytokine production. We also monitored transient weight loss unique to the bispecific-POM combination. Following this promising combinatorial result in vivo, we studied the relative roles of POM on target vs. effector cells by an in vitro killing assay using Vk*MYC tumor and splenocytes with or without expression of CRBN. Separately from the direct tumoricidal effects of POM on the tumor, we observed T cell-intrinsic effects of POM on the enhancement of BCMA-bispecific directed tumor lysis that correlated with T cell activation and proliferation. In summary, POM potentiated BCMA-CD3 bispecific directed T cell cytolysis of MM in the Vk*MYChCRBN animal model by enhancing effector cell activation, proliferation, cytokine production and directly reducing tumor burden. These results support ongoing preclinical studies of the benefits of combining standard of care therapy with potent T cell immunotherapy for MM. Citation Format: Erin W. Meermeier, Meaghen E. Sharik, Seth J. Welsh, Caleb K. Stein, Victoria M. Garbitt, Sochilt Brown, Kennedi T. Todd, Marco Bergsagel, P. Leif Bergsagel, Marta Chesi. Anti-BCMA bispecific tool therapy against Vk*MYC multiple myeloma is enhanced by IMiDs [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5630.