Gene Transfer 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: Unknown

110 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new cancer treatment called Anti-KRAS G12V mTCR PBL, which modifies a person's white blood cells to target tumors with the KRAS G12V molecule. The goal is to determine if this treatment is safe and can reduce tumor size in individuals with certain gastrointestinal cancers. Suitable candidates are those whose cancer contains the KRAS G12V molecule and who have not responded to standard treatments. Participants will receive the modified cells and other supportive treatments while being closely monitored in the hospital. 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.

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.

Is there any evidence suggesting that anti-KRAS G12V mTCR cells are likely to be safe?

Research is testing anti-KRAS G12V mTCR cells for safety in people with certain types of cancer. Some studies have suggested that patients might tolerate these modified cells, but these are early trials. While there is some evidence of safety, not all possible side effects are known yet.

In these studies, patients receive the anti-KRAS G12V mTCR cells after chemotherapy. Participants also receive other medicines to enhance the cells' effectiveness and increase their white blood cell count. Early reports indicate that while side effects like low blood counts or infections can occur, the primary focus remains on testing the treatment's safety. However, as this trial is still in the early stages, more information is needed to fully understand the treatment's safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard chemotherapy and targeted therapies for gastrointestinal cancer, the anti-KRAS G12V mTCR PBL treatment offers a new approach by leveraging gene transfer technology. This treatment specifically targets the KRAS G12V mutation, a common driver of cancer growth, with modified T-cell receptors that enhance the body's immune response against cancer cells. Additionally, the use of a non-myeloablative, lymphodepleting regimen allows for more effective integration and action of these engineered cells, potentially leading to better outcomes. Researchers are excited because this method could provide more personalized and effective treatment with fewer side effects, marking a significant step forward in cancer therapy.

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

Research has shown that a new treatment using anti-KRAS G12V mTCR cells, a type of gene therapy, may help fight gastrointestinal cancers. In early lab studies, these specially modified cells successfully attacked cancer cells with the KRAS G12V mutation, often found in these cancers. The treatment alters white blood cells to better identify and combat cancer cells. Initial results suggest this method can reduce tumor size, but further research is needed to confirm these effects in people. This trial will test the treatment in two phases: Phase I will involve escalating doses of anti-KRAS G12V mTCR PBL, while Phase II will use the maximum tolerated dose. The main goal is to determine if this targeted approach can improve outcomes for patients with these specific types of tumors. ^{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 18-70 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

I do not have any current infections.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Anti-KRAS G12V mTCR PBL

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.

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 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+

Published Research Related to This Trial

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]

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]

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]

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]

In a study of 839 patients with KRAS-mutated metastatic colorectal cancer (mCRC), 17% had the KRAS G12C mutation, which was linked to a higher likelihood of lung and liver metastases and a lower chance of peritoneal spread.

Patients with the KRAS G12C mutation experienced shorter overall survival compared to those with other KRAS mutations, indicating a need for targeted therapies and tailored treatment approaches for this specific mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KRAS G12C Metastatic Colorectal Cancer: Specific Features of a New Emerging Target Population. Schirripa, M., Nappo, F., Cremolini, C., et al.[2021]

KRASG12C inhibitors, like AMG510, show limited efficacy in colorectal cancer due to high activation of receptor tyrosine kinases (RTKs) and a dominant resistance mechanism involving EGFR signaling, unlike in non-small cell lung cancer (NSCLC) where they are more effective.

Combining EGFR and KRASG12C inhibition has been shown to be a promising therapeutic strategy in colorectal cancer models, suggesting a potential new treatment approach for patients with KRASG12C mutations in this cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer. Amodio, V., Yaeger, R., Arcella, P., et al.[2022]

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]

In a study of 1,632 patients with metastatic colorectal cancer (mCRC), those with the KRAS G12C mutation experienced significantly shorter progression-free survival (PFS) and overall survival (OS) compared to those with non-G12C mutations, with median PFS of 9.4 months versus 10.8 months and OS of 21.1 months versus 27.3 months.

The KRAS G12C mutation was independently associated with poorer survival outcomes, highlighting the need for targeted therapies that specifically address this mutation in mCRC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Prognostic Impact of KRAS G12C Mutation in Patients with Metastatic Colorectal Cancer: A Multicenter Retrospective Observational Study. Chida, K., Kotani, D., Masuishi, T., et al.[2022]

Citations

1. withpower.com withpower.com/trial/phase-2-gastrointestinal-neoplasms-8-2017-de1cb

Gene Transfer Therapy for Gastrointestinal Cancer This Phase 1 & 2 medical study run by National Cancer Institute (NCI) is evaluating whether Anti-KRAS G12V mTCR PBL will have tolerable side effects ...

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

The complex journey of targeting RAS in oncology - PMC In preclinical studies, compared with WT KRAS, KRAS G12C was able to selectively bind and inhibit ERK phosphorylation in cell lines harboring ...

3. patlynk.com patlynk.com/trial/NCT03190941

Administering Peripheral Blood Lymphocytes Transduced ... This therapy is called gene transfer using anti-KRAS G12V mTCR cells. Objective: To see if anti-KRAS G12 V mTCR cells are safe and can shrink tumors.

4. f1000research.com f1000research.com/articles/12-1463

Targeting KRAS mutation in gastrointestinal cancers This article provides in-depth review of KRAS mutations, and recently completed and ongoing clinical trials targeting KRAS mutations in GI cancers.

5. sciencedirect.com sciencedirect.com/science/article/pii/S2059702921001162

Strategies to tackle RAS-mutated metastatic colorectal cancer A phase I/II trial is evaluating the administration of lymphocytes loaded with anti-KRASG12D or anti-KRASG12V mTCR in patients with KRASG12D/G12V MT cancers ( ...

6. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT03190941/

Clinical Trial: NCT03190941 Objective: To see if anti-KRAS G12 V mTCR cells are safe and can shrink tumors. Eligibility: Adults at least 18 years old with cancer that has ...

7. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/anti-k-ras-g12v-mtcr-transduced-autologous-peripheral-blood-lymphocytes?pn=1

Clinical Trials Using Anti-K-RAS G12V mTCR-transduced ... Review the clinical trials studying anti-k-ras g12v mtcr-transduced autologous peripheral blood lymphocytes on this list and use the filters to refine the ...