Neoadjuvant chemokine modulation of the tumor microenvironment (TME) in resectable metastatic colorectal cancer: Results from a phase I study.

Abstract

2606 Background: Our preclinical studies using ex vivo explant cultures of resected metastatic colorectal cancer (CRC) tissues and in vivo mouse models showed that the combination of interferon alpha (IFNα) with toll-like receptor-3 (TLR-3) ligands and inhibitors of prostaglandin synthesis selectively induces effector T cell-attracting chemokines (CXCL9, CXCL10, CXCL11, and CCL5) in tumor microenvironments (TME), but not in adjacent healthy tissues, allowing for their systemic application to modulate TME. The chemokine-modulating (CKM) regimen, consisting of IFNα, rintatolimod (a selective TLR3 agonist), and celecoxib (a COX-2 inhibitor), also suppresses CCL22, a Treg-attracting chemokine in the TME. Based on these preclinical data, we hypothesized that a systemic CKM regimen would be safe and effective in modulating the TME of metastatic CRC. Methods: Nine chemotherapy-naïve patients with metastatic or recurrent CRC confined to the abdomen/pelvis and expected to have a complete resection received increasing doses of IFNa2b in a Phase I study to establish a recommended phase II dose of CKM for efficacy studies. The adaptive dose-escalation evaluated IFNα2b at 5, 10, and 20 million units (MU)/m2/day IV (Monday–Friday for 1 week pre-surgery), in combination with fixed doses of rintatolimod (200 mg IV; Monday–Friday) and celecoxib (200 mg orally twice daily; Monday–Friday). Results: No dose-limiting toxicities were observed, and 20 MU/m² of IFNα2b was identified as the recommended Phase II dose. All treated patients underwent R0 resection, as planned. Common treatment-related adverse events were flu-like symptoms (chills, fever, fatigue) and transient laboratory abnormalities (anemia, leukopenia), mostly grade 1–2. Two patients (13%) developed grade 3–4 neutropenia, which resolved without sequelae. There were no unexpected perioperative complications attributable to the regimen. Preliminary analysis of resected tumor tissues showed evidence of immune modulation in CKM-treated patients: increased ratios of CD8+ CTLs to FoxP3+ Tregs, with concomitant elevation of the effector chemokines (CCL5 and CXCL10), along with reduced expression of the Treg-recruiting chemokine CCL22, compared to 77 patients undergoing upfront tumor resections. Conclusions: Neoadjuvant CKM regimen is safe and feasible in resectable metastatic CRC and is associated with improved ratios of CD8+ CTLs to FoxP3+ Tregs in the TME. Further studies combining CKM with immune checkpoint inhibitors and/or chemotherapy are warranted to evaluate the impact of preoperative TME modulation on long-term oncologic outcomes in CRC. Clinical trial information: NCT01545141 .