Chalabi et al. report the safety, feasibility, and efficacy of using ICI (anti-CTLA-4 + anti-PD-1) as neoadjuvant therapy in patients with mismatch repair (MMR)-deficient (dMMR) and MMR-proficient (pMMR) colorectal cancer. 100% (20/20) of dMMR tumors and ~25% (4/15) pMMR tumors demonstrated a pathological response, including many pathological CRs. Neoadjuvant ICI led to a significant increase in INFγ and CXCL13 expression and CD8+ T cell infiltration in both dMMR and pMMR tumors. TCR clonality was significantly changed post-treatment in pMMR, but not in dMMR tumors. CD8+PD-1+ T cell infiltration was predictive of pMMR tumor response.
Contributed by Shishir Pant
PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab + nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86-100%) dMMR tumors, with 19 major pathological responses (MPRs,
Author Info: (1) Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. m.chalabi@nki.nl. Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterda
Author Info: (1) Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. m.chalabi@nki.nl. Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. m.chalabi@nki.nl. Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. m.chalabi@nki.nl. (2) Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Oncode Institute, Utrecht, the Netherlands. (3) Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Oncode Institute, Utrecht, the Netherlands. (4) Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (5) Surgical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (6) Biometrics, Netherlands Cancer Institute, Amsterdam, the Netherlands. (7) Biometrics, Netherlands Cancer Institute, Amsterdam, the Netherlands. Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands. (8) Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (9) Surgical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands. (10) Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (11) Radiology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (12) Bioimaging Facility, Netherlands Cancer Institute, Amsterdam, the Netherlands. (13) Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Oncode Institute, Utrecht, the Netherlands. (14) Oncode Institute, Utrecht, the Netherlands. Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands. (15) Core Facility Molecular Pathology & Biobanking, Netherlands Cancer Institute, Amsterdam, the Netherlands. (16) GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands. Radiology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (17) Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (18) Gastroenterology & Hepatology, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands. (19) Surgery, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands. (20) Biometrics, Netherlands Cancer Institute, Amsterdam, the Netherlands. (21) Surgical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (22) Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (23) Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (24) Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (25) Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (26) Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Oncode Institute, Utrecht, the Netherlands. (27) Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. e.voest@nki.nl. Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. e.voest@nki.nl. Oncode Institute, Utrecht, the Netherlands. e.voest@nki.nl. (28) Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
