On May 1, 2025 Intima Bioscience, a clinical stage oncology company focused on curative intent in solid tumor cancers, reported data from a first-in-human study using CRISPR knockout of the intracellular immune checkpoint CISH in T cells administered to patients with metastatic colorectal cancer at the 2025 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Intima Bioscience, MAY 1, 2025, View Source [SID1234652462]).
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"Over the last decade, the fast-growing field of Immuno-Oncology has nearly entirely focused on neutralizing cell surface targets. Inhibiting promising intracellular checkpoint targets like CISH have dramatic anti-cancer potential, but have traditionally been thought to be undruggable," said Emil Lou, M.D., Ph.D., Principal Investigator of the clinical trial and Professor of Hematology and Oncology at the University of Minnesota. "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."
In a featured oral presentation at the AACR (Free AACR Whitepaper) Meeting, Dr. Lou provided the first report of the effects of administering neoantigen reactive TILs with knockout of CISH, a gene which encodes cytokine-inducible SH2-containing protein, in patients with metastatic colorectal cancer. The study’s results were contemporaneously published in The Lancet Oncology. This dataset consisted of 12 patients who had received multiple lines of therapy, including standard-of-care chemotherapy and biologic agents.
"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. Multiple genomic screens have converged on nominating these intracellular immune checkpoints as highly promising therapeutic targets to advance immunotherapy beyond the current limits of the PD1/PD-L1 paradigm," said Christopher A. Klebanoff, M.D., a senior advisor to the study and immunotherapy expert at Memorial Sloan Kettering Cancer Center (MSK), Associate Attending, Laboratory Head, and Member, Immuno-Oncology Program (IOP).
Key points from this proof-of-concept clinical trial:
The most common severe adverse events included expected hematological events attributable to the preparative lymphodepleting chemotherapy regimen or expected effects of IL-2 (12 patients [100%]). No episodes of high-grade cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome were observed. No serious adverse events or patient deaths resulted from targeting the CISH checkpoint.
A patient with young adult/early onset Stage IV colorectal cancer resistant to multiple lines of chemotherapy and immunotherapy was treated on this trial and developed a clinical complete response which is ongoing after more than two years.
Detailed molecular and genetic analysis of this patient demonstrated ongoing persistence of CISH inhibited T cells synchronous with the ongoing complete response to this treatment.
As a testament to the end stage nature of the treated patient population, the median progression-free survival on this trial was 57 days, and median overall survival was 129 days.
A companion scientific paper entitled "CISH, a novel intracellular immune checkpoint, in comparison and combination to existing and emerging cancer immune checkpoints" comprehensively evaluates the intrinsic single agent and combination anti-cancer activity of CISH relative to other prevailing immune checkpoints. This preprint has been submitted for peer review.
Dr. Lou added: "In metastatic colorectal cancer, where treatment options are limited and survival outcomes are uniformly fatal, CISH represents a promising new target that may overcome the limitations of current immunotherapies. 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."
NB: The National Cancer Institute of the NIH formally defines an exceptional response as a complete response in which less than 10% of patients respond overall.
About CISH
The cytokine-inducible SH2-containing protein CISH is an intracellular cancer immune checkpoint that functions as a negative modulator of T-cell receptor (TCR) signaling and cancer neoantigen recognition. CISH negatively regulates antigen-specific cytokine release and T cell expansion via its capacity to bind PLC-γ1, a proximal mediator of TCR complex signaling. Inhibition of CISH in T cells is believed to help overcome immune evasion regardless of tumor type or PD-L1 expression.