IMMU-84. CD38 overexpression in Glioblastoma enhances immunosuppressive microenvironment and reduces survival in mice

BACKGROUND Glioblastoma (GBM), a lethal primary brain malignancy, is characterized by dysregulated recruitment of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) which disrupts immune homeostasis, promotes tumor growth and immune evasion. Our early phase clinical trial of Daratumumab, a fully human anti-CD38 monoclonal antibody, demonstrated preliminary benefit in a small GBM patient cohort (n=15). Given CD38’s role as a multifunctional glycoprotein overexpressed in hematological malignancies where it regulates immune cell trafficking, we hypothesized that CD38 overexpression in GBM modulates the immune tumor microenvironment, enhancing immunosuppressive cell recruitment. METHODS We utilized CRISPRa system to enhance CD38 expression in GL-261 cells. A murine GBM model was generated by intracranial injection of CD38-overexpressing (CD38-OE) GL-261 cells or CD38-Wild Type (WT) Gl-261cells into C57BL/6 mice. We measured tumor progression using serial MRIs. We assessed overall survival (OS) using Kaplan–Meier analysis with log-rank testing. We performed multiplex flow cytometry and cytokine assays on brain tumor tissue obtained following perfusion. Data were analyzed using one-way ANOVA for flow cytometry, tumor volume, and cytokine levels, and unpaired t-tests for tumor volume and proliferation comparisons. RESULTS Median OS was significantly reduced in CD38-OE mice (26.5 days) versus CD38-WT (35.7 days; p=0.0001; n=11/group). Tumor size (in vivo) in CD38-OE vs CD38-WT at day 10 (7.65 mm³ vs. 2.9 mm³; p=0.0001) and day 17 (36.04 mm³ vs. 6.05 mm³; p=0.0003). Relative to CD38-WT, CD38-OE tumors showed increased infiltration of TAMs (8.45-fold; p=0.0001), monocytic MDSCs (12.53-fold; p=0.0004), polymorphonuclear MDSCs (14.31-fold; p=0.0001), and CD4⁺ T cells (22.05-fold; p=0.0001). Cytokine profiling indicated elevated CXCL10, TIMP-1, M-CSF, MCP-5, MIG, and SDF-1 in CD38-OE tumors (p<0.0001; data on file). CONCLUSION CD38 overexpression in GBM drives tumor progression by amplifying immunosuppressive TME remodeling, positioning CD38 as a compelling target for further clinical investigation, supported by preliminary efficacy of Daratumumab (NCT04922723) in GBM patients.