Dr Lou on the Rationale for Evaluating CISH Knockout TILs Using CRISPR-Cas9 Gene Editing in Metastatic GI Cancers

“We’ve seen an explosion of immunotherapy in the last decade, with the greatest success in [patients with] stage IV forms of melanoma or non–small cell lung cancer. [However], that success has not yet reached GI cancers… What we did was use CRISPR-Cas9–based gene editing as a tool to delete that gene from inside the cell and therefore offset the checkpoint, to allow the immune system to be retrained—rebooted, in essence—to go against the cancer in patients with metastatic GI cancer.”

Emil Lou, MD, PhD, FACP, an associate professor of medicine in the Division of Hematology, Oncology, and Transplantation at the University of Minnesota Medical School and a medical oncologist at M Health Fairview Masonic Cancer Clinic, discussed the rationale for the first-in-human, single-center phase 1 trial (NCT04426669) evaluating cytokine-inducible SH2-containing protein (CISH) knockout tumor-infiltrating lymphocytes (TILs) using CRISPR-Cas9 gene editing in patients with metastatic gastrointestinal (GI) cancers. This study was designed to investigate whether deletion of CISH, an intracellular immune checkpoint regulator, could enhance TIL activity and overcome resistance to immune checkpoint inhibitors in this population.

Lou explained that despite the broad expansion of immunotherapy across solid tumors, clinical success has remained largely confined to melanoma and non–small cell lung cancer. In contrast, GI cancers—particularly metastatic colorectal cancer (mCRC)—continue to demonstrate limited responsiveness to checkpoint blockade, with few durable remissions outside of microsatellite instability–high disease. Given that approximately 150,000 CRC cases are diagnosed annually in the US, including a rising proportion among younger adults, novel immunotherapeutic strategies are urgently needed for patients with metastatic disease, who currently experience median overall survival durations of only 20 to 30 months with standard-of-care chemotherapy.

Unlike conventional checkpoint inhibitors that target extracellular receptors such as PD-1 or CTLA-4, CISH functions intracellularly as a suppressor of T-cell activation and cytokine signaling. Lou and colleagues hypothesized that CRISPR-Cas9–mediated deletion of CISHwould remove this intracellular brake on immune function, thereby restoring and amplifying T-cell cytotoxicity against tumor cells. The CISHknockout strategy aims to reprogram TILs for enhanced persistence, cytokine secretion, and tumor-specific activity within the immunosuppressive tumor microenvironment that characterizes advanced GI malignancies.

According to Lou, this approach represents a mechanistic evolution in cancer immunotherapy, shifting from extracellular checkpoint blockade to intracellular immune engineering. By disrupting CISH, investigators seek to reinvigorate exhausted T cells and enable sustained antitumor activity that conventional antibody-based checkpoint inhibitors cannot achieve. The ongoing phase 1 study will evaluate the safety, feasibility, and preliminary efficacy of this CRISPR-based TIL therapy, with the broader goal of establishing proof-of-concept for intracellular checkpoint modulation as a next-generation immunotherapeutic strategy for patients with GI cancers resistant to standard immunotherapy approaches, he concluded.