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

NCT04426669 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: 2019LS002
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

A clinical trial to assess the safety and efficacy of genetically-engineered, neoantigen-specific Tumor Infiltrating Lymphocytes (TIL) in which the intracellular immune checkpoint CISH has been inhibited using CRISPR gene editing for the treatment of Gastro-Intestinal (GI) Cancer.

Conditions

Gastrointestinal Epithelial Cancer; Gastrointestinal Neoplasms; Cancer of Gastrointestinal Tract; Cancer, Gastrointestinal; Gastrointestinal Cancer; Colo-rectal Cancer; Pancreatic Cancer; Gall Bladder Cancer; Colon Cancer; Esophageal Cancer; Stomach Cancer

Keywords

Adoptive Cell Therapy, Immunotherapy, Gene Therapy, CISH checkpoint, CRISPR

Outcome Measures

Primary Outcomes (3)

• Maximum tolerated dose (MTD)

  Highest dose at which less than or equal to 1 of 6 patients experienced a DLT or the highest dose level studied if DLTs are not observed at any of the dose levels

  28 Days Post IL-2

• Preliminary efficacy of tumor reactive autologous lymphocytes with knockout of CISH gene in patients with refractory metastatic gastrointestinal epithelial cancers: changes in diameter

  Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST v1.1 criteria

  Every 4 Weeks for the first three months, then every 8 weeks thereafter, up to 2 years

• Safety of tumor reactive autologous lymphocytes with knockout of the CISH gene - Incidence of Adverse Events

  Incidence of Adverse Events

  2 Years or Disease Progression

Secondary Outcomes (3)

• Progression-Free Survival (PFS)

  2 Years or Disease Progression

• Overall Survival (OS)

  2 Years or Disease Progression

• Toxicity profiles resulting from treatment using these engineered tumor-infiltrating lymphocytes

  2 Years or Disease Progression

Study Arms (2)

CISH CRISPR TIL / Phase I Arm

EXPERIMENTAL

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +escalating doses of CISH inactivated TIL + high-dose aldesleukin

Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Tumor-Infiltrating Lymphocytes (TIL); Drug: Aldesleukin

CISH CRISPR TIL / Phase II Arm

EXPERIMENTAL

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of CISH inactivated TIL

Drug: Cyclophosphamide; Drug: Fludarabine; Biological: Tumor-Infiltrating Lymphocytes (TIL); Drug: Aldesleukin

Interventions

Cyclophosphamide DRUG

Day -6 and Day -5: Cyclophosphamide 60 mg/kg/dose as a 2 hour intravenous infusion with Mesna 15 mg/kg/dose, 1st dose prior to Cyclophosphamide infusion then at 3,6,9 and 12 hours later.

CISH CRISPR TIL / Phase I Arm; CISH CRISPR TIL / Phase II Arm

Fludarabine DRUG

Day -7 to Day -3 : Fludarabine 25 mg/m\^2/dose as a 1 hour intravenous infusion per institutional guidelines once a day for 5 doses beginning on Day -7. Fludarabine will be started approximately 1 to 2 hours after the cyclophosphamide on Day -6 and Day -5.

CISH CRISPR TIL / Phase I Arm; CISH CRISPR TIL / Phase II Arm

Tumor-Infiltrating Lymphocytes (TIL) BIOLOGICAL

Day 0 : Each bag of autologous CISH inactivated TIL for infusion will be administered intravenously (IV) on the Patient Care Unit over 10-20 minutes at assigned dose level.

CISH CRISPR TIL / Phase I Arm; CISH CRISPR TIL / Phase II Arm

Aldesleukin DRUG

Days 1-4 : Aldesleukin at 720,000 U/kg as an intravenous infusion, every 8 -12 hours but, no more than 24 hours apart as tolerated for up to 6 doses.

Also known as: Interleukin-2, IL-2

CISH CRISPR TIL / Phase I Arm; CISH CRISPR TIL / Phase II Arm

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of metastatic gastrointestinal epithelial cancer with progressive disease following at least one first line standard therapy. When available, archived tissue from original diagnosis will be obtained for research related testing.
• Must have measurable disease per RECIST 1.1 with at least one lesion identified as resectable for TIL generation (minimum volume of tumor tissue required is 1 cm\^2 as single mass or fragments) and at least one other lesion meeting the RECIST criteria for measurable to serve as an indicator of disease response. The location of the tumor for TIL generation and method used to obtain (i.e. laparoscopy, endoscopic ultra sound, etc.) will be determined based on an individual patient's disease.
• Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible. Patients must not be receiving systemic steroids.
• Brain metastases are assessed using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.
• Age ≥ 18 years and ≤ 70 years.
• Clinical performance status of ECOG 0 or 1.
• Serology testing within 3 months of study enrollment (tumor collection):
• Seronegative for HIV antibody. (The investigational treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immunocompetence and thus may be less responsive to the study treatment and more susceptible to its toxicities.)
• Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
• Seronegative for anti-HBc, HBV/HCV/HIV-1 NAT, anti-HTLV-I/II, anti-T.cruzi, West Nile Virus NAT, anti-CMV, and RPR. (Note: Other blood viral testing may be required as updated on the FDA website: https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/TissueSafety/ucm095440.htm#approved)
• Hematology within 14 days of study enrollment:
• Absolute neutrophil count \> 1000/mm\^3 without the support of filgrastim
• WBC ≥ 3000/mm\^3
• Platelet count ≥ 75,000/mm\^3
• Hemoglobin \> 8.0 g/dl. Subjects may be transfused to reach this cutoff.

You may not qualify if:

• Pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant. Women of childbearing potential (defined as menses within previous 12 month and/or FSH ≤ 40 IU/L) must have a negative pregnancy test (serum or urine) within 7 days of enrollment. A repeat negative pregnancy test is required within 7 days of beginning the preparative chemotherapy.
• Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
• Concurrent opportunistic infection (The treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune-competence may be less responsive to the treatment and more susceptible to its toxicities).
• Active systemic infections requiring anti-infective treatment, coagulation disorders or any other active major medical illnesses.
• Concurrent systemic steroid therapy.
• History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.
• History of coronary revascularization or ischemic symptoms.
• Documented LVEF ≤ 45% tested in patients:
• Age ≥ 65 years and/or
• With clinically significant atrial and/or ventricular arrhythmias, including but not limited to: atrial fibrillation, ventricular tachycardia, second- or third-degree heart block, or have a history of ischemic heart disease and/or chest pain. Patients \< 65 years of age who present with cardiac risk factors (e.g., diabetes, hypertension, obesity) may undergo cardiac evaluation as noted above.
• Clinically significant patient history that in the judgment of the PI would compromise the patient's ability to tolerate high-dose aldesleukin.
• Documented FEV1 ≤ 50% predicted tested in patients with:
• A prolonged history of cigarette smoking (approximately 20 packs/year within the past 2 years) and/or
• Symptoms of respiratory dysfunction
• Receiving any investigational agents.

Sponsors & Collaborators

• Masonic Cancer Center, University of Minnesota: collaborator
• Intima Bioscience, Inc.: lead

Study Sites (1)

Masonic Cancer Center, University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Related Publications (5)

• Palmer DC, Guittard GC, Franco Z, Crompton JG, Eil RL, Patel SJ, Ji Y, Van Panhuys N, Klebanoff CA, Sukumar M, Clever D, Chichura A, Roychoudhuri R, Varma R, Wang E, Gattinoni L, Marincola FM, Balagopalan L, Samelson LE, Restifo NP. Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance. J Exp Med. 2015 Nov 16;212(12):2095-113. doi: 10.1084/jem.20150304. Epub 2015 Nov 2.

  PMID: 26527801 BACKGROUND

• Osborn MJ, Webber BR, Knipping F, Lonetree CL, Tennis N, DeFeo AP, McElroy AN, Starker CG, Lee C, Merkel S, Lund TC, Kelly-Spratt KS, Jensen MC, Voytas DF, von Kalle C, Schmidt M, Gabriel R, Hippen KL, Miller JS, Scharenberg AM, Tolar J, Blazar BR. Evaluation of TCR Gene Editing Achieved by TALENs, CRISPR/Cas9, and megaTAL Nucleases. Mol Ther. 2016 Mar;24(3):570-81. doi: 10.1038/mt.2015.197. Epub 2015 Oct 27.

  PMID: 26502778 BACKGROUND

• Tran E, Ahmadzadeh M, Lu YC, Gros A, Turcotte S, Robbins PF, Gartner JJ, Zheng Z, Li YF, Ray S, Wunderlich JR, Somerville RP, Rosenberg SA. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science. 2015 Dec 11;350(6266):1387-90. doi: 10.1126/science.aad1253. Epub 2015 Oct 29.

  PMID: 26516200 BACKGROUND

• Johnson MJ, Sumstad D, Folsom TD, Slipek NJ, DeFeo AP, Growe M, Kadidlo D, Thyagarajan B, Starr TK, Lou E, Choudhry M, Moriarity BS, Webber BR, McKenna DH. Clinical manufacture of CRISPR/Cas9-based cytokine-induced SH2 protein knock-out tumor-infiltrating lymphocytes for gastrointestinal cancers. Cytotherapy. 2025 Oct;27(10):1229-1239. doi: 10.1016/j.jcyt.2025.06.007. Epub 2025 Jun 21.

  PMID: 40673842 DERIVED

• Lou E, Choudhry MS, Starr TK, Folsom TD, Bell J, Rathmann B, DeFeo AP, Kim J, Slipek N, Jin Z, Sumstad D, Klebanoff CA, Ladner K, Sarkari A, McIvor RS, Murray TA, Miller JS, Rao M, Jensen E, Ankeny J, Khalifa MA, Chauhan A, Spilseth B, Dixit A, Provenzano PP, Pan W, Weber D, Byrne-Steele M, Henley T, McKenna DH, Johnson MJ, Webber BR, Moriarity BS. 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. Lancet Oncol. 2025 May;26(5):559-570. doi: 10.1016/S1470-2045(25)00083-X. Epub 2025 Apr 29.

  PMID: 40315882 DERIVED

MeSH Terms

Conditions

Gastrointestinal Neoplasms; Colonic Neoplasms; Pancreatic Neoplasms; Gallbladder Neoplasms; Esophageal Neoplasms; Stomach Neoplasms

Interventions

Cyclophosphamide; fludarabine; aldesleukin; Interleukin-2

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Colonic Diseases; Intestinal Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Endocrine System Diseases; Biliary Tract Neoplasms; Biliary Tract Diseases; Gallbladder Diseases; Head and Neck Neoplasms; Esophageal Diseases; Stomach Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors

Study Officials

• Emil Lou, MD, PhD

  Division of Hematology, Oncology and Transplantation, University of Minnesota

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 8, 2020
• First Posted: June 11, 2020
• Study Start: May 15, 2020
• Primary Completion: May 28, 2025
• Study Completion: January 22, 2026
• Last Updated: February 23, 2026

Record last verified: 2026-02

Locations

US (1)