What side effects are associated with this type of intervention?

Common treatments for gastrointestinal cancer, particularly those involving genetically modified T-cells like anti-KRAS G12V mTCR cells, often include side effects such as cytokine release syndrome (CRS), which can cause fever, nausea, headache, rash, rapid heartbeat, low blood pressure, and difficulty breathing. Other potential side effects include neurotoxicity, leading to confusion, difficulty speaking, or seizures, and hematologic toxicities such as low blood cell counts, increasing the risk of infections, anemia, and bleeding. Patients may also experience fatigue, muscle pain, and gastrointestinal symptoms like diarrhea or constipation.

What prior FDA approvals exist?

Several FDA-approved treatments for gastrointestinal cancers involve targeted therapies and immunotherapies. Notably, drugs like trastuzumab, cetuximab, and bevacizumab have shown efficacy in targeting specific molecular pathways. Trastuzumab targets HER2-positive tumors, cetuximab targets the epidermal growth factor receptor (EGFR), and bevacizumab inhibits vascular endothelial growth factor (VEGF). These treatments, while not identical to the Anti-KRAS G12V mTCR cells, share a common approach of targeting specific molecules on cancer cells to inhibit tumor growth and progression.

What other types of research exist?

Promising novel alternatives to Anti-KRAS G12V mTCR cells for gastrointestinal cancer patients include: 1) Anti-TSHR CAR-T cells, which have demonstrated potent preclinical activity against differentiated thyroid cancer and could be explored for gastrointestinal cancers. 2) Antibody-drug conjugates like TAK-264 targeting guanylyl cyclase C, which have shown efficacy in metastatic adenocarcinoma of the stomach or gastroesophageal junction. 3) PI3K/PTEN/AKT/mTOR pathway inhibitors such as temsirolimus, which have shown promise in endometrial cancer and could be considered for gastrointestinal cancers. 4) Anti-progastrin humanized antibodies targeting cancer stem cells and Wnt signaling, which have shown efficacy in K-RAS mutated colorectal cancer models.

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CAR T-cell Therapy

Gene Transfer Therapy for Gastrointestinal Cancer

Phase 1 & 2

Recruiting

Led By James C Yang, M.D.

Research Sponsored by National Cancer Institute (NCI)

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Patients with measurable, metastatic, or unresectable malignancy expressing G12V mutated KRAS or G12V mutated NRAS and HRAS

Patients must be HLA-A*11:01 positive as confirmed by the NIH Department of Transfusion Medicine

Must not have

Large volume pulmonary irradiation

Concurrent opportunistic infections

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 6 weeks and 12 weeks following administration of the cell product, then every 3 months x3, then every 6 months x 2 years, then per pi discretion

Awards & highlights

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Possible side effects include reactions from the genetically modified cells or chemotherapy drugs like fatigue, nausea, infection risk increase; organ inflammation; allergic reactions; changes in blood counts; liver enzyme elevations. Specific risks will depend on individual health conditions.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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

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I am HLA-A*11:01 positive as confirmed by testing.

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My advanced cancer did not respond to or has returned after standard treatment.

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I am between 18 and 72 years old.

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I have up to 3 small brain tumors that don't cause symptoms.

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I am fully active or can carry out light work.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have received extensive radiation therapy to my lungs.

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I do not have any current infections.

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I do not have any active infections, bleeding disorders, or serious illnesses.

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I am currently taking steroid medication.

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I have had heart surgery or symptoms due to poor blood flow.

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My heart and lung functions are within safe limits.

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I am currently pregnant or breastfeeding.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 6 weeks and 12 weeks following administration of the cell product, then every 3 months x3, then every 6 months x 2 years, then per pi discretion

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~6 weeks and 12 weeks following administration of the cell product, then every 3 months x3, then every 6 months x 2 years, then per pi discretion

This trial's timeline: 3 weeks for screening, Varies for treatment, and 6 weeks and 12 weeks following administration of the cell product, then every 3 months x3, then every 6 months x 2 years, then per pi discretion for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Frequency and severity of treatment-related adverse events

Response rate

Trial Design

2Treatment groups

Experimental Treatment

Group I: 2/Phase IIExperimental Treatment4 Interventions

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

Group II: 1/Phase IExperimental Treatment4 Interventions

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

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Aldesleukin

2012

Completed Phase 4

~1620

Fludarabine

2012

Completed Phase 4

~1860

Cyclophosphamide

2010

Completed Phase 4

~2320

0 / 13Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for gastrointestinal cancer include targeted therapies and immunotherapies. Targeted therapies, such as those inhibiting the KRAS G12C mutation, work by specifically blocking the activity of mutated proteins that drive cancer growth. Immunotherapies, like immune checkpoint inhibitors, enhance the body's immune response against cancer cells by blocking proteins that suppress immune activity. The anti-KRAS G12V mTCR cells are a form of gene therapy where T-cells are genetically modified to target and destroy cancer cells expressing the KRAS G12V mutation. These treatments are crucial for gastrointestinal cancer patients as they offer more precise and effective options, potentially leading to better outcomes and fewer side effects compared to traditional chemotherapy.

MMP2 and MMP7 at the invasive front of gastric cancer are not associated with mTOR expression.