Genetically Modified T-Cell Therapy for Gastrointestinal Cancer

Overseen By NCI SB Immunotherapy Recruitment Center

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Steroids, Investigational agents

Disqualifiers: Pregnancy, Infections, Immunodeficiency, others

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

Compensation: Varies

Number of Visits: 2

70 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: A new cancer therapy takes white blood cells from a person, grows them in a lab, genetically changes them, then gives them back to the person. Researchers think this may help attack tumors in people with certain cancers. It is called gene transfer using anti-KRAS G12D mTCR cells. Objective: To see if anti-KRAS G12D mTCR cells are safe and cause tumors to shrink. Eligibility: Adults ages 18-72 who have cancer with a molecule on the tumors that can be recognized by the study cells Design: Participants will be screened with medical history, physical exam, scans, photography, and heart, lung, and lab tests. An intravenous (IV) catheter will be placed in a large vein in the chest. Participants will have leukapheresis. Blood will be removed through a needle in an arm. A machine will divide the blood and collect white blood cells. The rest of the blood will be returned to the participant through a needle in the other arm. A few weeks later, participants will have a hospital stay. They will: * Get 2 chemotherapy medicines by IV over 5 days. * Get the changed cells through the catheter. Get up to 9 doses of a medicine to help the cells. They may get a shot to stimulate blood cells. * Recover in the hospital for up to 3 weeks. They will provide blood samples. Participants will take an antibiotic for at least 6 months. Participants will have several follow-up visits over 2 years. They will repeat most of the screening tests and may have leukapheresis. Participants blood will be collected for several years.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must have completed any prior systemic therapy before enrolling in the trial.

What data supports the effectiveness of the treatment for gastrointestinal cancer?

Research shows that genetically modified T cells targeting the KRAS G12D mutation have led to tumor regression in patients with pancreatic cancer, suggesting potential effectiveness for similar mutations in gastrointestinal cancers. ^{1 2 3 4 5}

Is genetically modified T-cell therapy for gastrointestinal cancer safe for humans?

Research on genetically modified T-cell therapy targeting KRAS mutations, like KRAS G12D, shows promise in treating cancers such as pancreatic cancer. While specific safety data is limited, studies have reported tumor regression in patients, suggesting potential safety and effectiveness, but more research is needed to fully understand the safety profile. ^{1 2 3 4 5}

What makes the genetically modified T-cell therapy for gastrointestinal cancer unique?

This treatment is unique because it uses genetically modified T-cells to specifically target and attack cancer cells with the KRAS G12D mutation, which is a common mutation in gastrointestinal cancers. Unlike traditional treatments, this approach involves engineering the patient's own immune cells to recognize and fight the cancer, offering a personalized and potentially more effective therapy. ^{1 2 3 4 5}

Research Team

James C Yang, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults aged 18-72 with certain advanced cancers (like colorectal, pancreatic, stomach) that haven't responded to standard treatments or who have declined them. They must not be pregnant, HIV positive, or have hepatitis B/C. Participants need functioning major organs and no severe immune deficiencies or allergies to the trial drugs.

Inclusion Criteria

Platelet count greater than or equal to 80,000/mm^3

Serum creatinine less than or equal to 1.6 mg/dL

I've had minor surgery or targeted radiotherapy recently but have recovered.

Exclusion Criteria

For select patients with a clinical history prompting cardiac evaluation: last known LVEF less than or equal to 45%.

I do not have any current infections that could weaken my immune system.

Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Leukapheresis and Cell Preparation

Participants undergo leukapheresis to collect white blood cells, which are then genetically modified in the lab.

A few weeks

1 visit (in-person)

Chemotherapy and Cell Infusion

Participants receive chemotherapy over 5 days, followed by infusion of genetically modified cells and supportive medication.

3 weeks

Hospital stay

Follow-up

Participants are monitored for safety and effectiveness after treatment, with several follow-up visits over 2 years.

2 years

Several visits (in-person)

Treatment Details

Interventions

• anti-KRAS G12D mTCR PBL

Trial Overview The trial is testing a new therapy where patients' white blood cells are modified in a lab to target cancer cells with a specific mutation (G12D variant of mutated RAS). Patients will receive chemotherapy and then their engineered cells back via IV along with other supportive medications over several weeks.

Participant Groups

Group I: 2/Phase II Experimental Treatment 4 Interventions

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-KRAS G12D mTCR PBL + high-dose aldesleukin

Group II: 1/Phase I Experimental Treatment 4 Interventions

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-KRAS G12D mTCR PBL + highdose aldesleukin

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Engineered T cells targeting the KRAS G12D mutation showed the ability to reduce metastases in a patient with pancreatic cancer, indicating a promising therapeutic approach.

This case highlights the potential of T cell receptor (TCR) engineering in specifically targeting cancer mutations, which could lead to more effective treatments for difficult-to-treat cancers like pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineered KRAS G12D-Reactive T Cells Show Promise in Pancreatic Cancer. [2023]

The study identified a KRASG12V-specific TCR that effectively targets tumors in colorectal cancer, particularly through engineered CD4+ T cells, which showed significant tumor-killing efficacy in both in vitro and xenograft mouse models.

This TCR is particularly promising for the Chinese population as it recognizes specific HLA subtypes (HLA-DPB1*03:01 and DPB1*14:01), providing broader applicability for precision immunotherapy in treating solid tumors like pancreatic and colorectal cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting KRASG12V mutations with HLA class II-restricted TCR for the immunotherapy in solid tumors. Ai, Q., Li, F., Zou, S., et al.[2023]

A patient with metastatic pancreatic cancer experienced a significant tumor regression of 72% after receiving a single infusion of genetically engineered T cells targeting the KRAS G12D mutation, with the response lasting for at least 6 months.

The engineered T cells remained active in the patient's bloodstream, constituting over 2% of all circulating T cells six months post-treatment, indicating sustained efficacy of the TCR gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer. Leidner, R., Sanjuan Silva, N., Huang, H., et al.[2023]

KRAS mutations, particularly G12D and G12V, are common in pancreatic and colorectal cancers, making them promising targets for immunotherapy.

In a study using HLA-A*11:01 transgenic mice, T cells engineered to recognize these KRAS mutations significantly reduced tumor growth in a xenograft model, suggesting potential for effective treatment in human cancers with these mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of T-cell Receptors Targeting KRAS-Mutated Human Tumors. Wang, QJ., Yu, Z., Griffith, K., et al.[2019]

Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) or TCR gene-modified T cells targeting mutant KRAS neo-antigens shows promise for treating advanced pancreatic ductal adenocarcinoma (PDAC), a cancer that has seen little progress in treatment for over 40 years.

To enhance the production of TILs specific to mutant KRAS, researchers developed a novel approach using tandem mini gene-modified autologous T cells (TMG-T) as artificial antigen-presenting cells, successfully generating TIL cultures that are specifically reactive to the mKRAS (G12V) mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expansion of KRAS hotspot mutations reactive T cells from human pancreatic tumors using autologous T cells as the antigen-presenting cells. Wang, S., Zhang, X., Zou, X., et al.[2023]

References

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

Engineered KRAS G12D-Reactive T Cells Show Promise in Pancreatic Cancer. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Targeting KRASG12V mutations with HLA class II-restricted TCR for the immunotherapy in solid tumors. [2023]

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

Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer. [2023]

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

Identification of T-cell Receptors Targeting KRAS-Mutated Human Tumors. [2019]

5. Germany pubmed.ncbi.nlm.nih.gov

Expansion of KRAS hotspot mutations reactive T cells from human pancreatic tumors using autologous T cells as the antigen-presenting cells. [2023]