A phase 2, multicenter, open-label study of AlloStim combined with anti-PD-L1immunotherapy as 4L therapy in patients with MSS/pMMR metastatic colorectal cancer.

TPS318 Background: Microsatellite stable (MSS)/mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) are immunologically 'cold' tumors that do not respond to immunotherapy. Cold tumors represent a formidable hurdle for checkpoint blockade immunotherapy approaches. Therefore, there is a need for novel strategies that could reprogram mCRC cold tumors to become inflamed hot tumors in a manner that might potentially convert low tumor mutational burden (TMB) tumors into checkpoint blockade responsive tumors. AlloStim is an experimental allogeneic, non-genetically manipulated, Th1-like activated living cell immunotherapy derived from healthy unrelated blood donors. The mechanism of action is designed to convert immunologically cold tumors into inflamed hot tumors. A case study of a single 3L MSS/pMMR mCRC patient primed with AlloStim followed by combination anti-PD-1/anti-CTLA4 checkpoint blockade resulted in a rare objective tumor response (Hirschfeld, et al, Translational Medicine Communications (2024) 9:15). The AlloStim priming results in an abundance of infiltrating interferon-gamma producing Th1 cells. Interferon-gamma has been shown to increase expression of PD-L1 in the TME. Therefore, it is hypothesized that the combination of AlloStim with an anti-PD-L1 checkpoint inhibitor might optimally evoke anti-tumor immune responses in this immunotherapy-refractory MSS/pMMR mCRC population. Methods: The study is a phase 2, multicenter, single-arm clinical trial of MSS/pMMR mCRC subjects in 4L that have been previously treated with an oxaliplatin-containing and irinotecan-containing chemotherapy regimen, anti-EGFR (RAS wt and left-sided), anti-VEGF and have progressed on 3L TAS-102 +/- bevacizumab or regorafenib or fruquinitinib. The study is evaluating weekly AlloStim priming from day 0 to day 49 followed by combination of AlloStim IV infusion (q2w) followed a week later by anti-PD-L1 (avelumab 800mg/q2w) from days 63 to day 98. Objective tumor response and disease control rate are the primary end-points. Overall survival is the secondary end-point. Clinically stable patients at day 112 can continue in an expansion phase with another round of combination AlloStim and avelumab from day 119 to day 154. CT scans are conducted at baseline, day 56 after AlloStim priming, day 112 after combination of alternating q2w infusions of AlloStim and avelumab and day 168 in all patients. CT scans will be analyzed by independent central readers using RECIST 1.1. Up to 50 patients will be enrolled with an interim analysis performed to assess efficacy after 20 patients become evaluable. The study is open and has not yet enrolled any patients at time of submission. Clinical trial information: NCT06557278 .