Associate Director Heme-Translational Medicine, Bristol Myers Squibb Summit, New Jersey, United States
Introduction: Cereblon E3 ligase modulator (CELMoD®) agents, including classic immunomodulatory (IMiD®) agents, have antitumor activity in MM. ALNUC is an IgG TCE that binds BCMA and CD3ε in a 2+1 format. ALNUC mediates myeloma cell killing by recruiting T cells to BCMA-expressing target cells, leading to T cell cytotoxic activity. Combining CELMoD agents with ALNUC may enhance antitumor activity. We evaluated the anti-MM potential of ALNUC + pomalidomide (POM) and novel CELMoD agents mezigdomide (MEZI) and iberdomide (IBER) in preclinical models.
Methods: To evaluate effects of CELMoD agents on ALNUC-mediated T cell anti-MM activity, healthy donor (HD) T cells and/or BCMA-expressing MM cell lines were pretreated with POM, MEZI, IBER, or DMSO for 16 h (T cells) or 72 h (MM cells) prior to coculture; ALNUC was added for 72 h and T cell activation and MM target cell depletion were measured. To evaluate CELMoD agent effects on artificially exhausted T cells, HD CD3+ T cells were pretreated with anti-CD3/CD28 beads and POM, MEZI, IBER, or DMSO for 7 d prior to coculture with MM cells and ALNUC. To determine if CELMoD treatment could reverse T cell dysfunction, pretreatment PBMCs from pts with MM who had response (n=2) or nonresponse (n=3) to ALNUC in a phase 1 trial (NCT03486067) were cocultured with H929 cells. Cocultures were pretreated with MEZI 1 nM for 24 h prior to adding ALNUC. The effects of concurrent and sequential MEZI and ALNUC were studied in a humanized mouse H929 MM xenograft model.
Results: In cocultures with HD T cells, pretreatment of MM cells with MEZI, IBER, and POM increased ALNUC-induced tumor-cell killing potency and efficacy across all cell lines vs ALNUC alone. ALNUC antitumor activity against the OPM-2 cell line was also enhanced by pretreating T cells with MEZI and IBER, but not POM. MEZI showed the greatest overall enhancement of ALNUC activity. In artificially exhausted HD T cells, enhanced antitumor activity was observed with MEZI and IBER, but not POM, vs DMSO. In a mouse MM xenograft model, priming or concurrent treatment with MEZI enhanced T cell activation, promoted T cell infiltration of tumor tissue, and increased ALNUC-induced tumor clearance. MEZI pretreatment of MM pt-derived PBMCs increased ALNUC-mediated antitumor activity vs control in samples from both responders and nonresponders.
Conclusions: Combining ALNUC with novel CELMoD agents enhanced T cell mediated antitumor activity in both in vitro and ex vivo MM models. MEZI showed the greatest ability to enhance TCE-mediated antitumor activity while reversing artificial T cell dysfunction/exhaustion. Priming and concurrent treatment with MEZI enhanced ALNUC-induced T cell infiltration and activation in a MM xenograft model. Enhancement of ALNUC T cell antitumor function by MEZI was confirmed using MM patient-derived PBMCs. These results provide a strong biological rationale for combining MEZI or IBER with ALNUC to enhance responses in pts with MM. Presented at ASH 2022. Paiva B et al. Abstract 3135.
