First-in-Human Data Highlight Potential of Intracellular Checkpoint Inhibition in Metastatic Colorectal Cancer
Microscopic image of colon cancer cell - Generated with Google Gemini AI
First-in-human data has demonstrated the feasibility and potential efficacy of targeting the intracellular immune checkpoint CISH in patients with heavily pretreated metastatic colorectal cancer.1,2
The results were featured in an featured oral presentation at the 2025 American Association for Cancer Research (AACR) Annual Meeting and simultaneously published in The Lancet Oncology and represent a step forward in the pursuit of novel immunotherapeutic strategies for solid tumors. This study marks the first clinical validation of genetically disrupting CISH to enhance antitumor immunity, potentially overcoming limitations associated with current cell surface-targeting immunotherapies.
The phase 1 study (NCT04426669) evaluated the effects of administering autologous neoantigen-reactive tumor-infiltrating lymphocytes (TILs) with CRISPR/Cas9-mediated knockout of the CISH gene in 12 patients with advanced metastatic colorectal cancer who had progressed through multiple prior lines of therapy, including standard chemotherapy and biologic agents. Notably, the treatment demonstrated a favorable safety profile, with the most common severe adverse events being hematological effects from the lymphodepleting chemotherapy and anticipated effects of IL-2. Importantly, no high-grade cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome was observed, and no serious adverse events or patient deaths were attributed to CISH targeting.
The cytokine-inducible SH2-containing protein (CISH) functions as an intracellular immune checkpoint, negatively regulating T-cell receptor signaling and the recognition of cancer neoantigens. By inhibiting CISH, researchers aim to enhance antigen-specific cytokine release and T cell expansion, potentially overcoming mechanisms of immune evasion regardless of tumor type or PD-L1 expression.
The clinical findings included an exceptional complete response in a patient with young adult/early-onset stage IV colorectal cancer refractory to prior treatments. This complete response has been ongoing for over 2 years, with detailed molecular analysis confirming the persistent presence of CISH-inhibited T cells correlating with the sustained clinical benefit.
While the median progression-free survival was 57 days and the median overall survival was 129 days in this heavily pretreated population, the response underscores the potential of CISH inhibition in a subset of patients with limited therapeutic options.
“This first-in-human study used CRISPR/Cas9 deletion of CISH as a model system to evaluate the viability of CISH checkpoint inhibition as a novel strategy for solid tumor immunotherapy,” stated Emil Lou, MD, PhD, principal investigator of the clinical trial and professor of hematology and oncology at the University of Minnesota.
Christopher A. Klebanoff, MD, a senior advisor to the study and immunotherapy expert at Memorial Sloan Kettering Cancer Center (MSK), highlighted the broader implications of these findings. “This is the first clinical trial to test genetic disruption of CISH as a harbinger of a new class of immune checkpoints that have pan cancer activity and are not limited by any given tumor’s surface PD-L1 expression,” he explained. Klebanoff further noted that multiple genomic screens have identified these intracellular checkpoints as promising targets to advance immunotherapy beyond the current PD-1/PD-L1 paradigm.
“We believe these data, including an exceptional complete response attributed to CISH knockout, resoundingly support the potential role of CISH checkpoint inhibition in addressing this significant unmet need and underline the possibility of small molecule drugging of CISH to democratize access to patients beyond this proof-of-concept cell therapy clinical trial,” added Lou. The ability to target CISH with small molecule inhibitors could potentially broaden the accessibility of this therapeutic approach beyond complex cell-based therapies.
