Gene Transfer Therapy for Gastrointestinal Cancer

Overseen by James C Yang, M.D.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: Steroids, Investigational agents

Disqualifiers: Pregnancy, Infections, Immunodeficiency, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests a new cancer treatment where a patient's white blood cells are modified in a lab to target specific cancer cells. It is aimed at adults aged 18-72 with advanced cancers that have a specific mutation (KRAS G12V) and have not responded to other treatments. The modified cells are reintroduced into the patient to seek out and destroy the cancer cells.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on systemic steroid therapy or any other investigational agents during the trial.

What data supports the effectiveness of the treatment Anti-KRAS G12V mTCR PBL for gastrointestinal cancer?

Research shows that TCR-engineered T cells targeting KRASG12V mutations have been effective in treating solid tumors like pancreatic cancer, with significant tumor-killing effects observed in lab and animal studies. Additionally, a similar TCR gene therapy targeting a different KRAS mutation led to a 72% reduction in tumor size in a pancreatic cancer patient, suggesting potential effectiveness for gastrointestinal cancers. ^{1 2 3 4 5}

What makes the Anti-KRAS G12V mTCR PBL treatment unique for gastrointestinal cancer?

The Anti-KRAS G12V mTCR PBL treatment is unique because it involves gene transfer therapy that specifically targets the KRAS G12V mutation, which is a known driver of resistance in certain cancers. This approach is different from traditional treatments as it uses modified immune cells to directly target and attack cancer cells with this specific mutation, offering a more personalized and potentially effective treatment option. ^{3 5 6 7 8}

Research Team

James C Yang, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults aged 18-70 with certain types of cancer (like gastrointestinal, colon, colorectal, pancreatic, or stomach) that have a specific molecule called KRAS G12V. They must have tried standard treatments or be unable to receive them and agree to use birth control. People can't join if they're pregnant/breastfeeding, on steroids, have immune deficiencies or severe infections, heart/pulmonary issues related to the trial drugs.

Inclusion Criteria

Willingness to practice birth control

My cancer is advanced, cannot be surgically removed, and has a specific genetic mutation.

Confirmation of the diagnosis of cancer by the NCI Laboratory of Pathology

Exclusion Criteria

I have received extensive radiation therapy to my lungs.

History of severe immediate hypersensitivity reaction to specific medications

Primary immunodeficiency

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy

Participants receive a non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine over 5 days

1 week

Inpatient stay

Cell Infusion and Activation

Participants receive anti-KRAS G12V mTCR cells via catheter, followed by a drug to activate the cells and another to increase white blood cell count

1 week

Inpatient stay

Recovery

Participants recover in the hospital for 1-2 weeks with lab and blood tests

1-2 weeks

Inpatient stay

Follow-up

Participants are monitored for safety and effectiveness after treatment, with visits every few months for 2 years

2 years

Visits every few months, including lab tests, imaging studies, and physical exams

Treatment Details

Interventions

• Anti-KRAS G12V mTCR PBL (CAR T-cell Therapy)

Trial Overview The study tests a new therapy where patients' white blood cells are modified in the lab to target cancer cells with KRAS G12V mutation. It involves chemotherapy followed by cell infusion and supportive medications in hospital over several weeks with follow-up visits for up to two years.

Participant Groups

Group I: 2/Phase II Experimental Treatment 4 Interventions

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-KRAS G12V 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 G12V mTCR PBL + high-dose aldesleukin

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

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]

The KRAS G12V mutation can be effectively detected in the plasma of colorectal cancer patients using droplet digital PCR (ddPCR), providing a non-invasive method for monitoring the disease.

In a study of 10 colorectal cancer patients, 9 showed detectable levels of the KRAS G12V mutation in their plasma, with significantly higher levels found in patients with metastatic disease compared to those without metastasis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KRAS G12V Mutation Detection by Droplet Digital PCR in Circulating Cell-Free DNA of Colorectal Cancer Patients. Olmedillas López, S., García-Olmo, DC., García-Arranz, M., et al.[2022]

KRAS mutations, particularly the G12C variant, are common in lung adenocarcinoma, and new targeted inhibitors have shown promising response rates of 32% to 46% in clinical trials, leading to FDA approvals for treatment.

Despite these advancements, rapid tumor resistance to G12C inhibitors poses challenges, highlighting the need for combination therapies and further research to understand and overcome resistance mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Direct GDP-KRASG12C inhibitors and mechanisms of resistance: the tip of the iceberg. Rosen, JC., Sacher, A., Tsao, MS.[2023]

Mouse hepatic progenitor cells (HPCs), specifically Oval cells, can incorporate the KRAS G12D mutation from colorectal cancer cells, indicating a mechanism for malignant transformation.

These mutated HPCs not only acquire the KRAS mutation but also demonstrate tumor-forming capabilities in vitro, suggesting their potential role in liver metastasis from colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oncological transformation in vitro of hepatic progenitor cell lines isolated from adult mice. Olivera-Salazar, R., García-Arranz, M., Sánchez, A., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

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

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

KRAS G12C Metastatic Colorectal Cancer: Specific Features of a New Emerging Target Population. [2021]

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

The Prognostic Impact of KRAS G12C Mutation in Patients with Metastatic Colorectal Cancer: A Multicenter Retrospective Observational Study. [2022]

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

EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

KRAS G12V Mutation Detection by Droplet Digital PCR in Circulating Cell-Free DNA of Colorectal Cancer Patients. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Direct GDP-KRASG12C inhibitors and mechanisms of resistance: the tip of the iceberg. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Oncological transformation in vitro of hepatic progenitor cell lines isolated from adult mice. [2022]