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

20 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the CRISPR-Edited TIL Therapy for Gastrointestinal Cancer?

Research shows that using CRISPR to edit TILs (tumor-infiltrating lymphocytes) can enhance their ability to fight cancer by removing PD-1, a protein that usually helps cancer cells hide from the immune system. This approach has shown promise in other cancers like melanoma and colorectal cancer, suggesting it could be effective for gastrointestinal cancer as well. ^{1 2 3 4 5}

Is CRISPR-edited TIL therapy safe for humans?

CRISPR-edited TIL therapy has been tested in humans, and studies show it is generally safe. In a trial with patients having advanced non-small-cell lung cancer, all treatment-related side effects were mild (grade 1/2), and no severe negative effects were reported. ^{1 2 6 7 8}

How is CRISPR-Edited TIL Therapy different from other treatments for gastrointestinal cancer?

CRISPR-Edited TIL Therapy is unique because it uses gene editing to enhance the effectiveness of immune cells (TILs) by removing a protein called PD-1, which normally inhibits the immune response against cancer. This approach aims to improve the body's natural ability to fight cancer, offering a novel strategy compared to traditional treatments. ^{1 2 3 4 7}

Research Team

Emil Lou, MD, PhD

Principal Investigator

Division of Hematology, Oncology and Transplantation, University of Minnesota

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

References

1. United States pubmed.ncbi.nlm.nih.gov

Highly efficient PD-1-targeted CRISPR-Cas9 for tumor-infiltrating lymphocyte-based adoptive T cell therapy. [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Expanded Alternatives of CRISPR-Cas9 Applications in Immunotherapy of Colorectal Cancer. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

CRISPR-engineered T cells in patients with refractory cancer. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Revealing and harnessing CD39 for the treatment of colorectal cancer and liver metastases by engineered T cells. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Programmed cell death ligand 1 disruption by clustered regularly interspaced short palindromic repeats/Cas9-genome editing promotes antitumor immunity and suppresses ovarian cancer progression. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Engineering NK-92 Cell by Upregulating CXCR2 and IL-2 Via CRISPR-Cas9 Improves Its Antitumor Effects as Cellular Immunotherapy for Human Colon Cancer. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Simultaneous Genetic Ablation of PD-1, LAG-3, and TIM-3 in CD8 T Cells Delays Tumor Growth and Improves Survival Outcome. [2022]