CRISPR-Edited TIL Therapy for Gastrointestinal Cancer

Overseen By Cancer Center Clinical Trials Office

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Intima Bioscience, Inc.

Must not be taking: Systemic steroids, Investigational agents

Disqualifiers: Pregnancy, Immunodeficiency, Infections, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for gastrointestinal cancer using genetically edited cells called Tumor Infiltrating Lymphocytes (TILs). Researchers aim to determine if these CRISPR-modified cells can safely and effectively target cancer cells. The study consists of two parts, each exploring different doses and treatment methods. Suitable candidates have metastatic gastrointestinal cancer that hasn't responded to standard treatments and can remain near the trial site in the Twin Cities area. As a Phase 1 trial, this research seeks to understand how the treatment works in people, offering participants the chance to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but it does mention that more than four weeks must have passed since your last systemic therapy before starting the trial treatment. It's best to discuss your current medications with the trial team to get specific guidance.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that a new treatment using CRISPR-edited immune cells, known as Tumor Infiltrating Lymphocytes (TIL), holds promise for treating gastrointestinal cancer. In a study involving 12 patients with advanced cancer, the treatment proved generally safe. The gene-editing process caused no serious side effects, indicating that humans tolerate the therapy well. This offers a favorable safety profile for those considering joining the trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Unlike standard treatments for gastrointestinal cancer, which often involve chemotherapy or radiation, the CRISPR-Edited Tumor-Infiltrating Lymphocyte (TIL) therapy is unique because it uses a patient's own immune cells that have been genetically edited. This treatment targets cancer by enhancing the body's natural immune response through CRISPR technology, which inactivates the CISH gene in TILs, potentially leading to a more robust attack on cancer cells. Researchers are excited about these treatments because they offer a personalized approach that may improve outcomes by directly targeting the tumor environment, and they use a non-myeloablative regimen that could result in fewer side effects compared to more aggressive therapies.

What evidence suggests that this trial's treatments could be effective for gastrointestinal cancer?

Research has shown that a new treatment using CRISPR-edited immune cells, known as Tumor Infiltrating Lymphocytes (TILs), could be promising for treating gastrointestinal cancer. In this trial, participants will receive CISH-inactivated TILs, specifically designed to target a part of the cancer cells, enhancing their effectiveness. This therapy has already succeeded in treating melanoma, a skin cancer, and is now being tested for other cancers in the digestive system. The precise design of these TILs enables them to work even when other treatments fail, offering hope for people with gastrointestinal cancers. Early results suggest this method can enhance the body's ability to fight cancer more effectively. ^{2 4 5 6 7}

Who Is on the Research Team?

Emil Lou, MD, PhD

Principal Investigator

Division of Hematology, Oncology and Transplantation, University of Minnesota

Are You a Good Fit for This Trial?

Adults aged 18-70 with metastatic gastrointestinal cancers who've had at least one standard treatment can join. They need a measurable tumor for TIL generation, stable brain metastases if present, good organ function, no systemic steroids or recent investigational drugs, and must stay near the University of Minnesota post-treatment.

Inclusion Criteria

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.

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.

Adequate organ function within 14 days of study enrollment defined as: Serum ALT and AST ≤ 5.0 x ULN Serum creatinine ≤ 1.6 mg/dl Total bilirubin ≤ to 2.0 mg/dl, except in patients with Gilbert's Syndrome, who must have a total bilirubin ≤ 3.0 mg/dl.

Exclusion Criteria

Age ≥ 65 years and/or

Hematology within 7 days of starting lymphodepleting chemotherapy:

Documented LVEF ≤ 45% tested in patients:

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine, followed by escalating doses of CISH inactivated TIL and high-dose aldesleukin

4 weeks

Weekly visits for monitoring and treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments every 4 weeks for the first three months, then every 8 weeks thereafter

Up to 2 years or until disease progression

Regular visits every 4 to 8 weeks

Extension

Participants may continue to be monitored for overall survival and progression-free survival

Up to 2 years or until disease progression

What Are the Treatments Tested in This Trial?

Interventions

• Tumor-Infiltrating Lymphocytes (TIL)

Trial Overview The trial is testing genetically-engineered Tumor Infiltrating Lymphocytes (TIL) where CISH gene is CRISPR-edited to boost immune response against cancer. It includes pre-treatment with Fludarabine and Cyclophosphamide followed by Aldesleukin after TIL infusion.

How Is the Trial Designed?

Group I: CISH CRISPR TIL / Phase II Arm Experimental Treatment 4 Interventions

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

Group II: CISH CRISPR TIL / Phase I Arm Experimental Treatment 4 Interventions

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

Who Is Running the Clinical Trial?

Intima Bioscience, Inc.

Lead Sponsor

Trials

2

Recruited

90+

Masonic Cancer Center, University of Minnesota

Collaborator

Trials

285

Recruited

15,700+

Citations

1. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(25)00083-X/abstract

Targeting the intracellular immune checkpoint CISH with ... We successfully manufactured CISH knockout TIL products for 19 (86%) of the patients, of whom 12 (63%) received autologous CISH knockout TIL ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40315882/

Targeting the intracellular immune checkpoint CISH with ... We successfully manufactured CISH knockout TIL products for 19 (86%) of the patients, of whom 12 (63%) received autologous CISH knockout TIL infusion. The ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04426669

NCT04426669 | A Study of Metastatic Gastrointestinal ... Tumor Infiltrating Lymphocytes (TIL) have shown efficacy in certain cancers, principally in melanoma. Efficacy in more common solid tumors has been demonstrated ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S147020452500083X

Targeting the intracellular immune checkpoint CISH with ... Therefore, CRISPR-edited TIL therapy was used as a model system to demonstrate the safety and efficacy of CISH immune checkpoint inhibition. We searched PubMed ...

5. nature.com nature.com/articles/s43018-025-01020-2

Tumor-infiltrating lymphocyte therapies in gastrointestinal ... These studies demonstrate the therapeutic potential of precision-engineered TIL therapies in overcoming immunotherapy resistance in gastrointestinal cancers.

6. med.umn.edu med.umn.edu/news/new-gene-editing-therapy-shows-early-success-fighting-advanced-gi-cancers

New gene-editing therapy shows early success in fighting ... By deactivating a gene called CISH, the researchers found that modified TILs were better able to recognize and attack cancer cells. The ...

7. ddw-online.com ddw-online.com/crispr-til-therapy-shows-early-success-in-gi-cancers-34884-202505/

CRISPR TIL therapy shows early success in GI cancers The treatment was tested in 12 highly metastatic, end-stage patients and found to be generally safe, with no serious side effects from the gene ...