A phase 2 study of intravenous pembrolizumab and intratumorally injected autologous dendritic cells (DCs) in refractory colorectal cancer (CRC).

TPS319 Background: Immune checkpoint inhibitors (ICIs) have shown limited benefit in CRC outside the microsatellite instability high (MSI-H) population. Deficient cytotoxic T lymphocyte (CTL) trafficking to the tumor microenvironment (TME) and excess pro-tumorigenic cytokines and immunosuppressive cells may contribute to primary ICI resistance in microsatellite stable (MSS) CRC. Selective enrichment of T cells with specific chemokine receptors may enhance antitumor immunity. Studies highlight the role of IL-12 in improving progression-free survival (PFS) and overall survival (OS) in patients on DC therapies. Our group developed ST-aDC1s, optimized for high production of high levels of IL-12 and CTL-attracting chemokines when injected intratumorally. In preclinical models, ST-aDC1s combined with anti-PD-1/PD-L1 therapy showed therapeutic synergy, suggesting ST-aDC1s as a promising alternative to traditional DC vaccines for inducing CTL entry into tumors. Methods: We designed an open-label, non-randomized, phase 2 study of intratumoral autologous ST-αDC1 combined with pembrolizumab in recurrent/metastatic unresectable MSS CRC. Eligible patients must have prior treatment with, or contraindication to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF, and anti-EGFR therapy (if RAS wild type), be anti-PD-1/PD-L1 therapy naïve, have ECOG PS ≤1, and have at least two target lesions, one amendable to biopsy and injection. Leukapheresis will collect monocytes for ST-αDC1 generation. Patients will receive intratumoral ST-αDC1s (6 million) on days 1 and 8 with biopsies, and an optional dose on day 50 before a third pembrolizumab dose. Pembrolizumab 200 mg IV will start on day 8, given every 3 weeks for 4 doses during the study period. Pembrolizumab will continue as conventional care afterwards. CT scans will occur after 2 and 4 doses of pembrolizumab. A safety lead-in cohort will include six patients, with up to 17 patients enrolled. The primary endpoint is objective response rate (ORR) at 12 weeks per RECIST 1.1. Secondary endpoints are safety, PFS, OS, and ORR per iRECIST. Correlative analysis will assess baseline levels and post-treatment changes in infiltrating T cells, CD4/CD8 ratios, FoxP3+ Tregs, and Teff-attracting and Treg-favoring chemokines from biopsy specimens, and immune cell subsets and cytokine levels from peripheral blood. With an expected ORR under 5% for standard treatment, 17 patients are required to show at least a 25% ORR with 81.2% power and a one-sided type I error rate of 0.05. A Simon two-stage Optimal design will enroll 9 patients in stage 1, and if ≥1 response occurs, 8 more patients will be added in stage 2. If ≥3 responses are observed, the treatment will be deemed promising for further study. Clinical trial information: NCT05518032 .