Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Research, Combination therapy, Translational Research, Assays, Plasma Cell Disorders, Genomics, Diseases, Treatment Considerations, Immunology, Lymphoid Malignancies, Computational biology, Biological Processes, Microbiome, Profiling, Study Population, Animal model, Machine learning
We tested the therapeutic efficacy of single-agent DAC and sequential combinations of DAC followed by anti-PD-1 monoclonal antibody (mAb) in the immunocompetent, syngeneic 5TGM1 model. 5TGM1 mice with early or late-stage MM were treated with 4 cycles of DAC (1 mg/kg), every 3 days, starting on days 7 and 14 post-tumor injection respectively. DAC (1 mg/kg) limited MM burden by in vivo bioluminescence imaging and reduced serum paraprotein by ELISA. We observed that DAC increased the number of infiltrating CD4+ and CD8+ T cells and significantly reduced the number of CD138+ MM cells in the BM microenvironment of both the early and late-MM 5TGM1 mice by flow cytometry and immunohistochemistry. DAC activated CD8+ T cells and increased the expression of PD-1 on CD4+ and CD8+ T cells. Treatment with DAC substantially prolonged mouse survival, without systemic toxicity in early-MM and late-MM 5TGM1 mice. DAC priming followed by 4 cycles of PD-1 mAb (starting 24 hr after DAC) modestly improved the efficacy of anti-PD-1 mAb in mice with early disease but not mice with established disease. We then tested the epigenetic priming effects of a lower dose of DAC (0.1mg/kg) in early-MM 5TGM1 mice. While neither DAC nor anti-PD-1 mAb limited MM progression or prolonged survival, we observed a pronounced decrease in tumor burden and overall survival benefit in mice treated with DAC and anti-PD-1 mAb. The median overall survival in mice treated with DAC and anti-PD-1 mAb was prolonged by 10 days compared to DAC alone (Log-rank test, Mantel Cox, adjusted p value <0.005).
Given the discovery that the gut microbiome improves the efficacy of PD-1 and that several bacterial derived metabolites are epigenetic modifiers, we profiled the gut microbiome of early-MM 5TGM1 mice treated with PBS or DAC by shallow shotgun sequencing. No significant differences in alpha and beta diversity metrics were observed between PBS and DAC treated mice. Differential abundance analysis using univariate comparisons identified healthy gut commensals including several Lactobacillus species and butyrate producers that were markedly depleted in untreated mice. Using Random Forest prediction classifier method, a supervised machine learning algorithm and SHapley Additive exPlanations (SHAP), a post-hoc explainability algorithm, we further validated that healthy gut commensals including Lactobacillus were the most significant microbiota features differentiating DAC vs PBS treated mice.
Our findings suggest that epigenetic priming with transient low dose DAC followed by a PD-1 blockade may be a promising approach in MM. Although preliminary, DAC priming may increase the efficacy of anti-PD-1 mAb by increasing the activation and expansion of CD8+ T cells and enriching gut microbiota that promote immune fitness and preserve gut barrier integrity. Further investigation into how hypomethylation impacts immunosurveillance in MM is ongoing.
Disclosures: Feinman: K36 Therapeutics: Other: Spouse; Merck: Other: Spouse; BMS: Other: Spouse; Sanofi: Other: Spouse; Sebia: Other: Spouse; Karyopharm: Other: Spouse; Pfizer: Other: Spouse; Janssen Oncology: Other: Spouse; Neximmune: Other: Spouse; Roche: Other: Spouse; Prothena: Other: Spouse. Biran: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Research Funding; Sanofi: Honoraria, Speakers Bureau; Amgen: Research Funding; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria. Siegel: Sanofi: Honoraria; Prothena: Honoraria; Roche: Honoraria; Pfizer: Honoraria; Merck: Honoraria; Envision Pharma: Honoraria; COTA: Current holder of stock options in a privately-held company; K36 Therapeutics: Honoraria; BMS: Honoraria; Sebia: Honoraria; Envision Pharma: Honoraria.
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