Abstract 886: Response to g-NK is associated with higher CD8+ T cells and lower MDSC in bone marrow of multiple myeloma patients

Abstract Patients with relapsed/refractory (R/R) multiple myeloma (MM) have poor outcomes and no curative therapies. In an ongoing, open-label Phase I/II trial of g-NK cells (IDP-023), we recently reported a mean maximum decrease in serum M-protein or light chain of 73% in eight R/R myeloma patients, with three patients achieving a reduction of 84% or greater (Patel, Merino et al, SITC 2024). G-NK are a subgroup of adaptive NK cells that are epigenetically reprogrammed to exhibit higher antibody-dependent cytotoxicity following engagement of CD16 than conventional NK cells. G-NK also lack the inhibitory checkpoint NKG2A enabling them to kill HLA-E+ target cells. Because the impact of the tumor microenvironment (TME) on outcomes after cellular therapy is poorly understood, we collected bone marrow samples for cytometry time-of-flight (CyTOF) with a commercial 37 marker panel designed to identify immune populations in patients treated at the University of Minnesota. Four patients had bone marrow collected for this analysis. One patient (#004) achieved a partial response (PR) by International Myeloma Working Group (IMWG) criteria in monoclonal protein and had improvement in the activity of lytic lesions on their PET scan thirty days after treatment. One patient (#003) had a minimal response (MR) and the other two patients had stable disease (SD) by IMWG. Interestingly, two of the three patients with relatively stable monoclonal protein in the blood (MR or SD) had significant improvement in PET scans after NK-cell therapy (#003, #001). One of the patients with SD (#001) and improvement in lytic lesions as measured by PET, maintained SD for five months before proceeding to their next therapy. Patients #001 and #004 had post-treatment bone marrow samples showing decreased expression of the exhaustion marker PD1 by CD8+ T cells. The patients who had improvement of their lesions on PET saw decreases in T cell expression of the inflammatory markers CXCR3 and CD38. The patient (#001) with SD and improvement in bone lesions that lasted five months saw a 5x increase in CD8+ T cells in his post-treatment biopsy with near complete clearance of MDSC (<1%). Additionally, our data suggest that the pre-treatment condition of the bone marrow may be predictive of anti-tumor activity. For example, of the four evaluable patients, the patient who achieved a PR had the highest percentage of CD8+ T cells and lowest percentage of myeloid derived suppressor cells (MDSC) at baseline. The patient with SD and no improvement by PET had the highest % of MDSC, the lowest CD8+ T cell percentage, and the highest expression of PD-1 on CD8+ T cells of all the patients. Collectively, these data suggest that g-NK cell therapy can alter the TME and may promote MM control by influx of non-exhausted T cells. Furthermore, the amount of MDSC in the bone marrow at time of treatment may be inversely correlated with anti-tumor activity. Citation Format: Aimee M. Merino, Zachary Davis, Jacob Rugloski, Madison Shackelford, Matt Collinson-Pautz, Austin Bigley, Stefanie Mandl-Cashman, Jeffrey A. Miller. Response to g-NK is associated with higher CD8+ T cells and lower MDSC in bone marrow of multiple myeloma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 886.