AlloStim® Immunotherapy Demonstrates Strong Survival Signal in Third-Line Microsatellite Stable Metastatic Colorectal Cancer: Results of a Phase 2B Clinical Trial

Third-line metastatic colorectal cancer (CRC) is refractory to chemotherapy and the available third-line therapies have limited efficacy with significant toxicities. Approximately 95% of metastatic CRC patients present with microsatellite stable (MSS)/proficient mis-match repair (pMMR) genotype that are resistant to immunotherapy. Therefore, there remains a high unmet need for new treatment options for these patients. Background/Objectives: The aim of this Phase IIB single-arm clinical study was to evaluate a protocol using a novel living immune cell drug called “AlloStim®” in third-line metastatic CRC patients with MSS/pMMR genotype tumors. The protocol was designed to incorporate multiple spatial and temporal immunomodulatory mechanisms, including: enhancing the circulating Th1/Th2 balance; converting immunologically ‘cold’ tumors to ‘hot’ inflamed tumors; creating conditions for immunological cell death and in-situ vaccination aimed at priming a patient-specific, anti-tumor adaptive immune response; and, modifying the tumor microenvironment in order to overcome tumor immunoavoidance and immunosuppression obstacles. Methods: AlloStim® was administered weekly in intradermal and intravenous doses in 3-five-week cycles, followed by optional monthly intravenous booster infusions. The intradermal AlloStim® doses are designed to elicit anti-alloantigen-specific Th1 immunity upon rejection of the fully allogeneic AlloStim® cells by the host. The intravenous doses are designed to cause a rejection response that results in release of systemic inflammatory cytokines that serve to activate by-stander host memory Th1 cells and NK cells. Activated Th1 memory and NK cells extravasate and infiltrate metastatic tumor lesions converting them from ‘cold’ to ‘hot’. The activated NK cells mediate immunological tumor cell death of MHC I negative tumors and the infiltrating Th1 cells create an inflammatory micro-environment, together creating an in-situ anti-tumor vaccine which results in tumor-specific immunity customized to each individual patient. Results: 29 third-line MSS/pMMR metastatic colorectal cancer patients were recruited from 4 cancer centers in the USA. The median overall survival (OS) was 16.4 months (95% CI: 8.6-18mo). Survival at 12 months was 60% and was 39% at 18 months. The immunotherapy was well tolerated with mostly mild treatment-related adverse events. Conclusion: AlloStim® immunotherapy demonstrated a strong survival signal in immunotherapy-refractory third-line metastatic MSS/pMMR CRC compared to historical controls of active drugs in this indication. These findings support advancement to well-designed, prospective, randomized-controlled clinical studies powered to confirm the survival signal. (ClinicalTrials.gov ID: NCT04444622).