Clinical translation of an immunomodulatory cell therapy that is designed to convert "cold" tumors to "hot": A phase 2B trial in 3L MSS/pMMR metastatic colorectal cancer.

BACKGROUND

A translational immunotherapy framework was designed to initiate sequential spatial and temporal immunomodulatory cascades using living, allogeneic, activated memory Th1 cells (AlloStim®), hypothesized to promote an immunomodulatory cascade in immunologically "cold" tumors. Microsatellite stable/proficient mismatch repair (MSS/pMMR) metastatic colorectal cancer (CRC) represents an immunotherapy-refractory "cold" tumor archetype with historically low response rates.

METHODS

To evaluate this framework, a Phase 2B, single-arm, multi-center proof-of-concept trial was conducted in third-line MSS/pMMR metastatic CRC patients, utilizing overall survival (OS) as the primary endpoint. AlloStim® was administered via a sequential schedule of weekly intradermal priming and subsequent intravenous infusions over three 5-week cycles, followed by optional monthly intravenous boosters.

RESULTS

Twenty-nine patients were enrolled (18 death events, 11 censored cases [37.9%]). The median OS was 16.4 months (492 days; 95% CI: 8.6-20.8 months). To account for non-proportional hazards, Restricted Mean Survival Time (RMST) evaluated at a 32-month temporal horizon demonstrated an average cohort life expectancy of 16.1 months (482 days; 95% CI: 12.3-19.8 months). Concurrently, 89% of evaluable patients met RECIST 1.1 criteria for progressive disease at Day 119, highlighting a profound survival-radiological discordance. The protocol was well tolerated; only 4% of total adverse events were ≥ Grade 3.

CONCLUSION

This study provides indirect clinical observations supporting the hypothesis that an active immunomodulatory framework may elicit an encouraging survival signal and extended life expectancy in refractory metastatic MSS/pMMR CRC, despite conventional radiological progression. These findings justify evaluation in a prospective, randomized controlled trial powered to validate this translational strategy.