Abstract A025: Revolutionizing Multiple Myeloma Treatment: Advancing CAR T Cell Therapy Utilizing IL-7 Signaling and Dexamethasone

Abstract Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of multiple myeloma (MM), but lack of sustained remission hinders this therapy from being a true cure. To increase remission longevity, it has been hypothesized that a memory component needs to be instilled into the CAR T cell therapy. IL-7 receptor (IL-7R) stimulation is a key component for memory maintenance in T cells and using this pathway has the potential of increasing the clinical efficacy of CAR T cells. However, the IL-7R expression has great variability across different CAR T cell products and finding a method to increase IL-7R is greatly needed. Dexamethasone (dex) has been a mainstay for the treatment of MM for decades. While it’s widely believed that dex has a deleterious effect on CAR T cell functionality, we have previously shown that CAR T cells are not only unaffected by dex but dex will increase the expression of pro-persistence molecules such as IL-7R. Leveraging dex effects on IL-7R, we have shown that in vivo combination of CAR T cells with dex and IL7 led to enhanced persistence of CAR T cells and increased overall remission. To test the potential of this unique therapy, we are collaborating with NeoImmuneTech to use rhIL-7-hyFc (NT-I7, efineptakin alfa), a long-acting IL-7. To study the potential of this unique combination against MM, we conducted the study against both MM and extramedullary MM. eMM is an aggressive form of MM and has been observed to have poorer prognosis and higher incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). For this study, we injected NOD-scid IL2Rgammanull (NSG) mice, with MM.1R cells, a MM cell line that is resistant to dex, either intratibially for MM or subcutaneously for eMM. Once engrafted, we administered a single intravenous injection of anti-MM CAR T cells , intraperitoneal injection of dex, and subcutaneous injection of 2 doses of NT-I7. For MM, we observed that while all CAR T treated groups were capable of bringing mice into remission, only mice treated with CAR T, dex, and NT-I7 were capable of long-lasting remission up to 21 weeks. We attribute this remission to enhanced CAR T cell expansion and persistence in the CAR T, dex, and NT-I7 group when compared to CAR alone or CAR with either dex or NT-I7 alone. For eMM, we observed only CAR T cells with dex and NT-I7 have the capability of achieving remission and similar to the MM experiment, we attribute this to enhanced persistence of the CAR T cells driven by Dex and NT-I7 combination treatment. Overall, our study establishes a potential combination therapy which could enhance the efficacy and persistence of anti-MM CAR T cells. Our study also provides rationale for continuing dexamethasone treatment without risk of impacting CAR T cell function. Citation Format: Ryan Urak, Alexandra A Wolfarth, Sara Ferrnado-Martinez, Stephen Forman, Xiuli Wang. Revolutionizing Multiple Myeloma Treatment: Advancing CAR T Cell Therapy Utilizing IL-7 Signaling and Dexamethasone [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A025.