Latest news with #EmilLou
Medscape
01-07-2025
- Health
- Medscape
CISH-Targeted TILs Show Promise in GI Cancer Trial
This transcript has been edited for clarity. Hello. I'm David Kerr, professor of cancer medicine at University of Oxford. I'd like to talk a little about a phase 1 trial that has just been published in the May edition of Lancet Oncology , a beautiful paper by Emil Lou and colleagues, in which they all looked at an extraordinarily complicated regimen of gene editing and then reinfusing tumor-infiltrating lymphocytes (TILs). This just shows how remarkable modern cancer medicine can be. I'd like to talk a little about the procedures involved, given the route of complexity. Initially, for patients in the phase 1 trial with metastatic advanced gastrointestinal cancer, the first step was to receive a non-myeloablative lymphocyte-depletion chemotherapy. This is cyclophosphamide and fludarabine. This is then followed by high-dose interleukin-2. The process of producing the gene-edited TILs is absolutely fascinating. The gene-editing target, the gene that we wanted to knock down, was a novel, internal immune checkpoint protein gene, CISH , which encoded a cytokine-inducible SH2 domain-containing protein. This is an internal immune checkpoint target and quite an interestingly novel one. That's the target to knock down. The process of building the therapy is completely fascinating. Autologous TILs were generated from tumor biopsy fragments from each individual patient, and samples of the TILs were then cultured with patient-derived lymphoblastic cell lines, ormonocyte-derived dendritic cells loaded with pools of synthetic 25-mer peptides containing tumor-specific mutations that were detected from whole-exome sequencing from the patient's tumor. Think about that for a second. The patients undergo biopsy. The TILs are taken off for culture — more on that later — but they were co-cultured with a source of patient-specific tumor-associated antigens, which were generated by whole-exome sequencing. Then, using 25-mer fragments of what they felt were the key tumor-specific antigens, were plumbed into the patients' own dendritic cells so that these antigens would be presented to at the time of co-culture with a patient, so in TILs. It boggles the mind. The TILs with demonstrated reactivity to the neoantigens in this co-culture experiment were selected and they were then subjected to the CRISPR gene editing in vitro. They knocked down CISH , the target that they were aiming for. Then the edited TILs underwent a rapid expansion protocol. They were cryopreserved, and then via some very sophisticated molecular quality control, infused back into the patients. Goodness gracious — I mean, it's extraordinary when you think about it. It was a phase 1 trial, so dose-escalating the number of cells. It's pretty well tolerated. As you would expect, there was some fatigue and some fever. Nobody died in the back of any of the treatment that was given in that way. In terms of effectiveness, these were patients with advanced disease who had undergone multiple previous lines of treatment. There were no severe cytokine-release syndromes, nothing of grade 3 or worse. No neurotoxicity. Six of 12 patients had stable disease by day 28. Four (33%) had stable disease ongoing at 56 days. One young adult who had microsatellite-unstable and mismatch repair-deficient MSI-high tumors — therefore they've already got an existing high neoantigen load — had a complete response. That was very pleasing. I say, again, this is an extraordinary piece of work, to think about the complexity involved in every step of that process — before the patients' own cells, the autologous cells, were manipulated and reinfused with moderately acceptable toxicity, I would say. It's a phase 1 trial, so you're not really looking for a big efficacy readout, but the one younger patient who had, if you like, a genetic predisposition to responding to immunotherapy anyway, had a complete response. I'd be really interested in what you think about it. Who knows what the cost of that would be in terms of the complexity — I keep using that word, don't I? — of every single step. Modern cancer medicine — don't you love it? Well done to the team for producing this phase 1 trial result. How generalizable it will be remains to be seen, given the multiple different steps that are required. It just shows you how, in my lifetime as a cancer doctor, four decades, remarkable progress has been. I'm very interested in any comments you'd have to make. As always, thanks for listening. For the time being, Medscapers, ahoy, and over and out.
Yahoo
03-05-2025
- Health
- Yahoo
Data from First-in-Human Trial targeting CISH, a Novel Immune Checkpoint, in Patients with Metastatic Colorectal Cancer Presented at 2025 American Association for Cancer Research (AACR) Annual Meeting
Study Administered CRISPR genetically engineered CISH-knockout Tumor Infiltrating Lymphocytes as a Model System to Evaluate the Safety and Efficacy of this Classically Undruggable Intracellular Target Ongoing and Durable Complete Response of Two Years Observed in Patient with Young Adult Colorectal Cancer Refractory to Multiple Lines of Chemotherapy and Immunotherapy Given these findings, Next-generation Small Molecule Drugging Strategies are Structurally Enabled in Advanced Development NEW YORK and CAMBRIDGE, England, May 1, 2025 /PRNewswire/ -- Intima Bioscience, a clinical stage oncology company focused on curative intent in solid tumor cancers, presented 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) Annual Meeting. "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 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 CISHThe 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. About Intima BioscienceIntima Bioscience is a clinical stage oncology company focused on curative intent in solid tumor cancer. Intima is developing a novel small molecule and cell therapy platform for targeting the immune checkpoint CISH in patients with solid tumor cancers. By advancing a mechanism of action for a promising, yet traditionally undruggable target, Intima seeks to democratize the promise of immunotherapy to patients suffering from cancer. Company Contactinfo@ Media ContactRosie Gillam, Edelman View original content to download multimedia: SOURCE Intima Bioscience Sign in to access your portfolio
