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Abstract
Background T cell engager antibodies (TCE) have generated impressive response rates in heavily pretreated multiple myeloma (MM) patients. However, primary resistance to TCE still occurs, and even patients that respond completely eventually relapse. The Vk*MYC mouse is an ideal MM model to study TCE: it is clinically predictive of drug activity, biologically faithful to MM, immunocompetent, displays the genomic diversity of human MM, and engineered to express the full human CRBN gene for IMiD sensitivity. Our preclinical work and data from clinical trials found that tumor burden is associated with primary resistance to an anti-BCMA/CD3 binding TCE. Moreover, we found that this correlated with the development of T cell exhaustion. Results from TCE clinical trials also suggest that the initial level of dysfunctional T cells correlates with inferior responses. Immunomodulatory imide drugs (IMiD) are a standard-of-care for MM that also enhance T cell responses. We previously found that the combination of TCE with the IMiD pomalidomide significantly deepened responses even in high tumor burden setting, but increased T cell exhaustion and introduced therapeutic toxicity.
Methods Here, we utilize Vk*MYChCRBN MM cells engrafted into hCRBN recipient mice to test if different dosing regimens of dexamethasone (Dex) in combination with the IMiD lenalidomide (Len), is sufficient to reduce tumor burden, dampen excessive inflammation, and promote more durable and safer response to a murine BCMA/CD3 TCE.
Results In the setting of transplantable Vk*MYC MM treated subcutaneously with TCE, we tested three groups that either received concurrent Len+Dex with TCE or were pre-treated with Dex or Len+Dex prior to TCE+Len+Dex. All three of these regimens were superior in increasing survival compared with single agent TCE (figure 1), increased co-stimulation expression on myeloid cells, and maintained strong T cell responses to the TCE, measured by IFN-γ release, T cell proliferation, and granzyme expression. However, these regimens also increased TREG in the tumor sites, reflected as cell frequency and as a ratio with effector T cells, and did not decrease expression of T cell markers associated with exhaustion: PD1, LAG3, and TIGIT.
Conclusions In an aggressive MM setting, early priming or concurrent treatment with agents that directly modulate tumor growth, here Len+Dex in the context of TCE therapy, increases overall survival compared with TCE alone. The combination of Len+Dex with TCE led to a stronger T cell response without compromising the safety profile of TCE therapy and may be a mechanism to increase primary responses to TCE for MM patients.
Acknowledgements The authors thank Gosia Nocula-Lugowska, Fang Jin, Aruna Bitra, Kristoffer Brannstrom, Carole Wang, Fan Yang, Rachel Roach, Chris Shea, Beth Leary, Angela Stauffer, and Eugenia Kryanov for their contributions.
Ethics Approval All experiments were performed under the approval of the Mayo Foundation Institutional Animal Care and Use Committee (Protocols #A00004485–19-R22; #A00001948–16-R22) and conformed to all the regulatory environmental safety standards.
Priming or concurrent treatment with Lenalidomide and Dexamethasone in the context of anti-BCMA/CD3 T cell engager therapy extends survival in the Vk*MYC murine model of multiple myeloma.
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