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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new cancer treatment that involves extracting a person's white blood cells, modifying them in a lab to better target cancer, and then returning them to the patient. Known as anti-KRAS G12D mTCR PBL (a type of genetically modified T-cell therapy), this treatment aims to determine if these altered cells can safely shrink tumors in individuals with specific gastrointestinal cancers. Suitable candidates for this trial are adults with certain advanced cancers that have a specific molecule on their tumors, particularly if previous treatments were ineffective. Participants will undergo various treatments, including chemotherapy, and will need to stay in the hospital for recovery and follow-up visits. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity 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. However, you must have completed any prior systemic therapy before enrolling in the trial.

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

Research has shown that genetically modified T-cells, such as anti-KRAS G12D mTCR cells, have been studied for safety in previous research. These studies examined how well participants tolerated the treatment and any side effects they experienced. In trials with similar cell therapies, patients generally tolerated the treatment well, although some experienced mild to moderate side effects. These side effects were usually manageable and temporary.

For anti-KRAS G12D mTCR cells specifically, detailed safety data is not available in the sources. However, testing in both early and later stages of trials suggests a basic level of safety. Early trials often focus heavily on safety, while later trials indicate promise in terms of safety and effectiveness.

Participants in trials often receive treatments like chemotherapy along with the modified T-cells, which can lead to side effects from both the chemotherapy and the cell therapy. It is important for anyone considering joining a trial to discuss potential risks and benefits with their healthcare team. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about anti-KRAS G12D mTCR PBL therapy because it represents a cutting-edge approach to treating gastrointestinal cancer by harnessing the body's immune system. Unlike conventional treatments like chemotherapy or radiation, which target cancer cells more broadly, this therapy uses genetically modified T-cells to specifically target and attack cancer cells with the KRAS G12D mutation. This precision targeting could potentially lead to more effective treatment outcomes with fewer side effects. Additionally, the therapy includes a non-myeloablative, lymphodepleting regimen and high-dose aldesleukin to enhance T-cell activity, making it a promising alternative to existing options.

What evidence suggests that this treatment might be an effective treatment for gastrointestinal cancer?

Research shows that anti-KRAS G12D mTCR cells help the immune system find and attack cancer cells with the KRAS G12D mutation. In this trial, participants will receive these modified cells, designed to recognize and bind to cancer cells, potentially stopping their growth. Studies with similar treatments have shown tumor shrinkage, suggesting this method could be effective. Early results from treatments targeting KRAS mutations are promising, demonstrating tumor reduction and improved outcomes. Using these modified cells offers a new and exciting approach to treating cancer by directly targeting its genetic makeup. ^{1 2 3 6 7}

Who Is on the Research Team?

James C Yang, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. cancer.gov cancer.gov/publications/dictionaries/cancer-drug/def/anti-k-ras-g12d-mtcr-transduced-autologous-peripheral-blood-lymphocytes

anti-K-RAS G12D mTCR-transduced autologous ... HLA-A1101-positive PBLs are harvested from a K-RAS G12D-expressing cancer patient and transfected with a retroviral vector that encodes anti-K-RAS G12D mTCR.

2. mycancergenome.org mycancergenome.org/content/drugs/anti-k-ras-g12d-mtcr-transduced-autologous-peripheral-blood-lymphocytes/

anti-k-ras g12d mtcr-transduced autologous peripheral ... HLA-A1101-positive PBLs are harvested from a K-RAS G12D-expressing cancer patient and transfected with a retroviral vector that encodes anti-K-RAS G12D mTCR.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03745326

Study Details | NCT03745326 | Administering Peripheral ... This is a phase I/II, single center study of PBL transduced with anti-KRAS G12D mTCR in HLA-A*11:01 positive patients with advanced solid tumors expressing G12D ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12211582/

The complex journey of targeting RAS in oncology - PMC Ongoing research is focused on innovative approaches to overcome these obstacles and improve outcomes in patients with KRAS G12D-driven cancer.

5. clinicaltrial.be clinicaltrial.be/en/details/66396?per_page=100&recruiting=1&enrolling_by_invitation=0&active_not_recruiting=0&not_yet_recruiting=0&completed=0&only_recruiting=1&only_eligible=0

Administering Peripheral Blood Lymphocytes Transduced ... This is a phase I/II, single center study of PBL transduced with anti-KRAS G12D mTCR in HLA-A*11:01 positive patients with advanced solid tumors ...

6. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT03745326/

Clinical Trial: NCT03745326 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.

7. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/anti-k-ras-g12d-mtcr-transduced-autologous-peripheral-blood-lymphocytes

Clinical Trials Using Anti-K-RAS G12D mTCR-transduced ... Review the clinical trials studying anti-k-ras g12d mtcr-transduced autologous peripheral blood lymphocytes on this list and use the filters to refine the ...