Undisclosed CISH inactivated TIL / Intima Biosci, University of Minnesota - LARVOL DELTA

Targeting the intracellular immune checkpoint CISH with CRISPR-Cas9-edited T cells in patients with metastatic colorectal cancer: a first-in-human, single-centre, phase 1 trial. (PubMed, Lancet Oncol) - P1/2 | "These results support the safety and potential antitumour activity of inhibiting the immune checkpoint CISH through the administration of neoantigen-reactive CISH-knockout TILs, with implications for patients with advanced metastatic cancers refractory to checkpoint inhibitor immunotherapies, and provide the first evidence that a novel intracellular checkpoint can be targeted with therapeutic effect."

Journal • P1 data • Anorexia • Colorectal Cancer • Fatigue • Gastrointestinal Cancer • Hematological Disorders • Infectious Disease • Microsatellite Instability • Oncology • Solid Tumor • Targeted Protein Degradation • MSI

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 (PRNewswire) - P1/2 | N=20 | NCT04426669 | Sponsor: Intima Bioscience, Inc. | "Intima Bioscience...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....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%])....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."

P1/2 data • Colorectal Cancer

First-in-human trial in patients with metastatic colorectal cancer using CRISPR-engineered tumor infiltrating lymphocytes in which the intracellular immune checkpoint CISH is inhibited (AACR 2025) - P1/2 | "CISH KO, neoantigen-reactive TILs were expanded, then infused following non-myeloablative lymphocyte depleting (LD) chemotherapy (cyclophosphamide & fludarabine) followed by high-dose IL-2. We provide the first clinical report of CISH checkpoint targeting via genetically modified T cell therapy, with complete response in a patient with mCRC. Persistence and expansion of unique TCR clonotypes detected in neoantigen responsive TIL was temporally consistent with spikes in CISH edited alleles detected by NGS assay; in the patient with CR, four of the clonotypes exhibiting prolonged persistence greater than one-year post-infusion exhibited significantly reduced or undetectable expression of CISH compared to the total infused TIL population. Given these findings, further investigation of CISH checkpoint inhibition, via gene and cell therapy, and next-generation small molecule drugging modalities, is underway."

Clinical • IO biomarker • Metastases • P1 data • Tumor-infiltrating lymphocyte • Colorectal Cancer • Melanoma • Microsatellite Instability • Oncology • Solid Tumor • MSI

SpaFlow: a Nextflow pipeline for QC and clustering of MxIF datasets. (PubMed, Bioinform Adv) - "We demonstrate the utility of SpaFlow in a case study involving 297 ovarian tumor cores, where SpaFlow successfully identified biologically meaningful cell populations, including tumor-infiltrating lymphocytes, efficiently and rapidly. Additionally, SpaFlow's reproducibility is validated using serial tonsil sections, confirming its capability to consistently identify distinctive cell populations across matched ROIs. SpaFlow is freely available with detailed documentation and examples at https://github.com/dimi-lab/SpaFlow."

Journal • Oncology • Ovarian Cancer • Solid Tumor

Colorectal adenosquamous carcinoma: clinicopathologic analysis of two large cohorts and literature review confirm poor prognosis and reveal prognostic aspects. (PubMed, Histopathology) - "Colorectal ASC usually presents at an advanced stage. Despite high rates of MMR deficiency and low tumour budding, TILs were generally low, and there is a high recurrence rate and poor prognosis."

Journal • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor

2019LS002: A Study of Metastatic Gastrointestinal Cancers Treated With Tumor Infiltrating Lymphocytes in Which the Gene Encoding the Intracellular Immune Checkpoint CISH Is Inhibited Using CRISPR Genetic Engineering (clinicaltrials.gov) - P1/2 | N=20 | Active, not recruiting | Sponsor: Intima Bioscience, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Jan 2024 ➔ Jan 2026 | Trial primary completion date: Sep 2023 ➔ Jan 2026

Enrollment closed • Trial completion date • Trial primary completion date • Colon Cancer • Colorectal Cancer • Esophageal Cancer • Gallbladder Cancer • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

Engineered Cellular Therapies for the Treatment of Thoracic Cancers. (PubMed, Cancers (Basel)) - "In this review, we discuss the prospect of chimeric antigen receptor-T (CAR-T) cells, natural killer (NK) cells, T cell receptor-engineered (TCR-T) cells, and tumor-infiltrating lymphocytes (TILs) as treatments for thoracic malignancies...Induced pluripotent stem cells (iPSCs) offer great promise as a source for both NK and T cell-based therapies due to their unlimited expansion potential. Here, we review clinical trial data, as well as recent basic scientific advances that offer insight into how we may overcome these obstacles, and provide an overview of ongoing trials testing novel strategies to overcome these obstacles."

Journal • Review • Hematological Disorders • Hematological Malignancies • Lung Cancer • Malignant Pleural Mesothelioma • Melanoma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • Thoracic Cancer

Unlocking the potential: Targeting metabolic pathways in the tumor microenvironment for Cancer therapy. (PubMed, Biochim Biophys Acta Rev Cancer) - "Here, we focus on the metabolic reprogramming of four principal cell subsets in the TME: CAFs, TAMs, TILs and TECs, and their interaction with tumor cells. We also summarize medications and therapies targeting these cells' metabolic pathways, particularly in the context of immune checkpoint blockade therapy."

Biomarker • Journal • Review • Tumor microenvironment • Oncology

Divergent immune microenvironments in two tumor nodules from a patient with mismatch repair-deficient prostate cancer. (PubMed, NPJ Genom Med) - "Patients with prostate cancer (PC) generally do not respond favorably to immune checkpoint inhibitors, which may be due to a low abundance of tumor-infiltrating lymphocytes even when mutational load is high...Immune cell deconvolution suggested that the hot nodule was enriched not only in CD8+ and CD4 + T lymphocytes, but also in M1 macrophages, activated NK cells, and γδ T cells compared to the cold nodule. This case highlights that MMRd/TMB-high PC can evolve to minimize an anti-tumor immune response, and nominates downregulation of antigen presentation machinery (HLA loss) as a potential mechanism of adaptive immune evasion in PC."

IO biomarker • Journal • Mismatch repair • Tumor mutational burden • Genito-urinary Cancer • Microsatellite Instability • Oncology • Prostate Cancer • Solid Tumor • CD4 • CD8 • CTLA4 • MSH2 • MSH6 • MSI • PD-L1 • TMB

Phase 2 Trial of Nivolumab and Ramucirumab for Relapsed Mesothelioma: HCRN-LUN15-299. (PubMed, JTO Clin Res Rep) - P2 | "This was a cooperative group, single-arm, phase 2 trial enrolling patients with unresectable mesothelioma after progression on more than or equal to one pemetrexed-containing regimen...Activation of tumor-infiltrating lymphocytes in response to treatment was associated with a trend toward improvement in PFS...Further investigation of this regimen in mesothelioma with nonepithelioid histology may be warranted. Clinical Trial Information: NCT03502746."

Journal • P2 data • Lung Cancer • Mesothelioma • Oncology • Solid Tumor • PD-L1

Interferon-expressing oncolytic adenovirus + chemoradiation inhibited pancreatic cancer growth in a hamster model. (PubMed, Cancer Sci) - "Past clinical trials of adjuvant therapy combined with interferon (IFN) alpha, fluorouracil, cisplatin, and radiation improved the 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC)...Notably, IFN-OAd + chemotherapy + radiation remarkably suppressed tumor growth and induced a higher number of tumor-infiltrating lymphocytes without severe side toxic effects in an immunocompetent and adenovirus replication-permissive hamster PDAC model...IFN-OAd has the potential to overcome the barriers to clinical application of IFN-based therapy through its tumor-specific expression of IFN, induction of antitumor immunity, and sensitization with chemoradiation. Combining IFN-OAd with gemcitabine + nab-paclitaxel + radiation might be an effective and clinically beneficial treatment for PDAC patients."

Journal • Oncolytic virus • Preclinical • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Association of Molecular Profiles and Mutational Status With Distinct Histological Lung Adenocarcinoma Subtypes. An Analysis of the LACE-Bio Data. (PubMed, Clin Lung Cancer) - "High TMB has a prognostic role in resectable lung ADC. The high TMB group had a poor outcome with AC, suggesting that this group may be better served with immune checkpoint therapy."

IO biomarker • Journal • Tumor mutational burden • Immune Modulation • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1 • TMB

Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. (PubMed, J Immunother Cancer) - "Investigational lifileucel demonstrated clinically meaningful activity in heavily pretreated patients with advanced melanoma and high tumor burden. Durable responses and a favorable safety profile support the potential benefit of one-time lifileucel TIL cell therapy in patients with limited treatment options in ICI-refractory disease."

Checkpoint inhibition • Journal • Metastases • Retrospective data • Tumor-infiltrating lymphocyte • Febrile Neutropenia • Hematological Disorders • Immune Modulation • Inflammation • Melanoma • Neutropenia • Oncology • Solid Tumor • Thrombocytopenia

[VIRTUAL] Targeting the apical intracellular checkpoint CISH unleashes T cell neoantigen reactivity and effector program (SITC 2020) - P1/2 | "Expression of the intracellular checkpoint CISH is elevated in human tumor infiltrating lymphocytes (TIL) and has been shown to inhibit neoantigen reactivity in murine TIL...Conclusions These pre-clinical data offer new insight into neoantigen recognition and serve as the basis for a recently initiated human clinical trial at the University of Minnesota (NCT04426669) evaluating inhibition of the novel intracellular immune checkpoint CISH in a CRISPR-engineered, neoantigen-specific T cell therapy for solid tumors. Updates from the clinical trial will be highlighted."

IO Biomarker • Tumor-specific neoantigens • Oncology • Solid Tumor • TP53

[VIRTUAL] Targeting the apical intracellular checkpoint CISH unleashes T cell neoantigen reactivity and effector program (SITC 2020) - P1/2 | "Expression of the intracellular checkpoint CISH is elevated in human tumor infiltrating lymphocytes (TIL) and has been shown to inhibit neoantigen reactivity in murine TIL...Conclusions These pre-clinical data offer new insight into neoantigen recognition and serve as the basis for a recently initiated human clinical trial at the University of Minnesota (NCT04426669) evaluating inhibition of the novel intracellular immune checkpoint CISH in a CRISPR-engineered, neoantigen-specific T cell therapy for solid tumors. Updates from the clinical trial will be highlighted."

IO Biomarker • Tumor-specific neoantigens • Oncology • Solid Tumor • TP53

A Study of Metastatic Gastrointestinal Cancers Treated With Tumor Infiltrating Lymphocytes in Which the Gene Encoding the Intracellular Immune Checkpoint CISH Is Inhibited Using CRISPR Genetic Engineering (clinicaltrials.gov) - P1/2 | N=20 | Recruiting | Sponsor: Intima Bioscience, Inc. | Trial completion date: Jan 2023 ➔ Jan 2024 | Trial primary completion date: Dec 2022 ➔ Sep 2023

Metastases • Trial completion date • Trial primary completion date • Colon Cancer • Colorectal Cancer • Esophageal Cancer • Gallbladder Cancer • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatology • Immune Modulation • Oncology • Pancreatic Cancer • Solid Tumor

Cancer Immunology: Impact of Radioembolization of Heptocellular Carcinoma on Immune Response Modulation. (PubMed, AJR Am J Roentgenol) - "This TARE-induced tumor immunogenicity occurs through enhancement of tumor-associated antigen expression, as well as recruitment and diversification of tumor-infiltrating lymphocytes...Early data are promising regarding the potential synergistic benefit from treatment algorithms that combine TARE and immunotherapies, and interest is growing in the clinical application of such combinations. This review provides an overview of cancer immunology, summarizes the available data regarding the biologic effects of TARE on local and systemic immune responses, and explores the potential role of the combination of TARE and immunotherapy for HCC."

IO biomarker • Journal • Review • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Liver Cancer • Oncology • Solid Tumor

CheckCell-2: CISH Inactivated TILs in the Treatment of NSCLC (clinicaltrials.gov) - P1/2 | N=70 | Not yet recruiting | Sponsor: Intima Bioscience, Inc. | Initiation date: Nov 2022 ➔ Feb 2023

Trial initiation date • Immune Modulation • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma

CheckCell-2: Phase 1/2 Study of CISH Inactivated TILs in the Treatment of NSCLC (clinicaltrials.gov) - P1/2 | N=70 | Not yet recruiting | Sponsor: Intima Bioscience, Inc.

New P1/2 trial • Immune Modulation • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma

A Study of Metastatic Gastrointestinal Cancers Treated With Tumor Infiltrating Lymphocytes in Which the Gene Encoding the Intracellular Immune Checkpoint CISH Is Inhibited Using CRISPR Genetic Engineering (clinicaltrials.gov) - P1/2 | N=20 | Recruiting | Sponsor: Intima Bioscience, Inc. | Trial completion date: Oct 2022 ➔ Jan 2023

Trial completion date • Colon Cancer • Colorectal Cancer • Esophageal Cancer • Gallbladder Cancer • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatology • Immune Modulation • Inflammation • Oncology • Pancreatic Cancer • Solid Tumor

TILs Show Better PFS vs Ipilimumab in Unresectable Melanoma (Cancer Network) - P3 | N=168 | NCT02278887 | "A randomized phase 3 trial presented at 2022 ESMO revealed better progression-free survival outcomes with tumor-infiltrating lymphocytes vs ipilimumab in stage IIIC/IV unresectable, treatment-refractory melanoma....After a median follow-up of 33.0 months, median progression-free survival (PFS) with the TIL therapy was 7.2 months (95% CI, 4.2-13.1) compared with 3.1 months for ipilimumab (95% CI, 3.0-4.3), which was statistically significant (HR, 0.50; 95% CI, 0.35-0.72; P < .001). The 6-month PFS rate was 52.7% with the TIL therapy compared with 21.4% for ipilimumab....The median OS was 25.8 months with TILs (95% CI, 18.2-not reached) vs 18.9 months with ipilimumab (95% CI, 13.8-32.6); however, these data were not yet statistically significant with follow-up ongoing (HR, 0.83; 95% CI, 0.54-1.27; P = .39)."

P3 data • Melanoma • Oncology • Solid Tumor

Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade. (PubMed, Med (N Y)) - "CISH negatively regulates human T cell effector function, and its genetic disruption offers a novel avenue to improve the therapeutic efficacy of adoptive TIL therapy."

IO biomarker • Journal • Tumor-specific neoantigens • Oncology • Solid Tumor

Quantity versus quality: Keys to adoptive cell therapy success in breast cancer. (PubMed, Med (N Y)) - "Over decades, reports of autologous tumor-infiltrating lymphocytes inducing partial and even complete responses in treatment-refractory tumors has spurred investigation into methods for refining and improving this process. Zacharias et al. report two partial and one complete response from a phase II study utilizing neoantigen-reactive TILs in patients with metastatic breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor

Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma. (PubMed, J Clin Oncol) - "Lifileucel demonstrated durable responses and addresses a major unmet need in patients with metastatic melanoma with limited treatment options after approved therapy, including the primary refractory to anti-PD-1 or PD-L1 therapy subset."

Clinical • Journal • Immune Modulation • Inflammation • Melanoma • Oncology • Solid Tumor

Assessment of the LOVO device for final harvest of novel cell therapies: a Production Assistance for Cellular Therapies multi-center study. (PubMed, Cytotherapy) - "The LOVO Cell Processing System provides an alternative to centrifuge-based technologies. The system employs a spinning membrane filter, exposing cells to minimal g-forces compared with centrifugation, and is automated and closed. This small multi-center study demonstrated the ability of the LOVO device to yield satisfactory cell viability and recovery of T cells and MSCs."

Journal • Oncology