Intima Bioscience’s CRISPR-Enhanced TILs Show Promise Against Advanced GI Cancers in First-in-Human Trial

NEW YORK and CAMBRIDGE, England – May 1, 2025 – Intima Bioscience, a company focused on developing innovative oncology therapies for solid tumors, today announced the presentation of data from a first-in-human study evaluating the CRISPR-based knockout of the intracellular immune checkpoint CISH in T cells administered to patients with metastatic colorectal cancer. The findings were shared at the 2025 American Association for Cancer Research (AACR) Annual Meeting.

Dr. Emil Lou, the principal investigator of the clinical trial and a professor at the University of Minnesota, emphasized the significance of this approach, stating, “While Immuno-Oncology has made remarkable strides over the past decade, primarily by targeting cell surface proteins, promising intracellular checkpoints like CISH, which hold substantial anti-cancer potential, have long been considered challenging to target pharmacologically. This initial human study utilizing CRISPR/Cas9 to delete CISH serves as a crucial model to assess the feasibility of CISH checkpoint inhibition as a novel strategy in solid tumor immunotherapy.”

In a prominent oral presentation at the AACR Meeting, Dr. Lou detailed the initial outcomes of administering neoantigen-reactive tumor-infiltrating lymphocytes (TILs) with CISH knocked out – CISH being a gene encoding the cytokine-inducible SH2-containing protein – to individuals with metastatic colorectal cancer. The study’s results were also simultaneously published in The Lancet Oncology. The analyzed data encompassed 12 patients who had undergone multiple prior lines of treatment, including standard chemotherapy and biologic agents.

Dr. Christopher A. Klebanoff, a senior advisor to the study and an immunotherapy expert from Memorial Sloan Kettering Cancer Center (MSK), highlighted the broader implications: “This marks the first clinical investigation into the genetic disruption of CISH, potentially heralding a new class of immune checkpoints with broad anti-cancer activity, independent of a tumor’s surface PD-L1 expression. Numerous genomic analyses have consistently identified these intracellular immune checkpoints as highly promising therapeutic targets, offering a path to advance immunotherapy beyond the current limitations of the PD1/PD-L1 axis.”

Key findings from this proof-of-concept clinical trial include:

• The most frequent severe adverse events observed were anticipated hematological issues related to the pre-treatment lymphodepleting chemotherapy or expected effects of IL-2 administration (in all 12 patients). Notably, no instances of high-grade cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome were reported. Furthermore, no serious adverse events or patient deaths were attributed to targeting the CISH checkpoint.
• One patient with young adult/early onset Stage IV colorectal cancer, whose disease had proven resistant to multiple lines of chemotherapy and immunotherapy, achieved a sustained clinical complete response lasting for over two years.
• In-depth molecular and genetic analysis of this exceptional responder demonstrated the ongoing presence of CISH-inhibited T cells, coinciding with the sustained complete response to the treatment.
• Reflecting the advanced stage of the treated patient population, the median progression-free survival observed in the trial was 57 days, and the median overall survival was 129 days.
• A related scientific manuscript titled “CISH, a novel intracellular immune checkpoint, in comparison and combination to existing and emerging cancer immune checkpoints,” offering a comprehensive evaluation of the single-agent and combination anti-cancer activity of CISH relative to other prominent immune checkpoints, has been submitted for peer review as a preprint.

Dr. Lou further commented, “In metastatic colorectal cancer, where therapeutic options are limited and prognosis is generally poor, CISH represents a promising novel target that could potentially overcome the limitations of current immunotherapies. We believe these findings, including the remarkable complete response linked to CISH knockout, strongly support the potential of CISH checkpoint inhibition in addressing this significant unmet medical need and underscore the possibility of developing small molecule drugs targeting CISH to broaden patient access beyond this initial cell therapy clinical trial.”

About CISH:

The cytokine-inducible SH2-containing protein CISH is an intracellular immune checkpoint within cancer cells that acts as a negative regulator of T-cell receptor (TCR) signaling and the recognition of cancer neoantigens. CISH inhibits antigen-specific cytokine release and T cell expansion through its ability to bind PLC-γ1, a key mediator in TCR complex signaling. Blocking CISH function in T cells is hypothesized to help overcome immune evasion mechanisms, regardless of the tumor type or PD-L1 expression levels.