T-Cell Therapy for Cancer

Overseen By Nicholas D Klemen, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Chemotherapy

Must not be taking: Immunosuppressants

Disqualifiers: Immunodeficiency, Autoimmune disease, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

Duration: 3 weeks or more

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new T-cell therapy to determine if it can prevent or delay the return of gastrointestinal (GI) cancer after standard treatments. The therapy modifies a person's immune cells to target specific gene mutations found in some GI cancers. Suitable candidates for this trial have undergone surgery for GI cancer, show signs of cancer spread through certain blood tests, and possess specific genetic markers. Participants will be randomly assigned to receive either the T-cell therapy (KRAS TCR-Transduced PBL) or regular follow-up care. The goal is to determine if T-cell therapy is more effective in preventing cancer recurrence. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that four weeks must have passed after any prior systemic therapy for cancer before randomization, suggesting a possible need to pause certain treatments. It's best to discuss your specific medications with the trial team.

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

Research has shown that T-cell therapy targeting KRAS mutations may help treat cancer. In previous studies, some patients who received these modified T-cells experienced halted cancer growth, while others had stable disease for a period. This treatment has been tested in individuals with advanced cancer and KRAS mutations.

Regarding safety, the therapy has generally been well-tolerated. However, patients might experience side effects, especially since this treatment often includes chemotherapy and boosts the immune system. Common side effects include tiredness, fever, and low blood cell counts.

This trial is currently in Phase 2, meaning researchers are still gathering detailed safety information. This phase typically involves more participants than earlier ones, aiding in understanding how the treatment affects different people. While full safety details are still being collected, earlier findings suggest the treatment might be manageable for some. Those considering joining a trial should discuss potential risks and benefits with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for cancer, which often involve chemotherapy, radiation, or surgery, KRAS TCR-Transduced PBL therapy is unique because it uses genetically engineered T-cells to directly target cancer cells. This approach harnesses the body's immune system, specifically modifying T-cells to recognize and attack cancer cells with a KRAS mutation, a common mutation in many types of cancer. Researchers are excited about this treatment because it offers a more personalized and potentially less toxic alternative to traditional cancer therapies, with the prospect of improved effectiveness by specifically targeting the cancer's genetic makeup.

What evidence suggests that this trial's treatments could be effective for GI cancer?

Research has shown that a new treatment called T-cell therapy could be promising for gastrointestinal cancer with KRAS mutations. In this trial, some participants will receive TCR T-cells and aldesleukin. This involves using T-cells, a type of immune cell, modified to find and attack cancer cells with specific gene changes. Studies have found that these modified T-cells can slow tumor growth in both lab tests and animal studies. Specifically, T-cells designed to target KRAS mutations have demonstrated the ability to recognize and fight cancer cells. Early trials reported positive results, suggesting this method might help prevent cancer from returning or spreading. Meanwhile, other participants in this trial will undergo surveillance and follow-up without cellular therapy. ^{1 6 7 8 9}

Who Is on the Research Team?

Nicholas D Klemen, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

This trial is for adults aged 18-72 with GI cancer that's been treated but might be spreading, as shown by blood tests. They need specific gene mutations (KRAS or TP53) and HLA types. People can't join if they don't meet the age requirement, lack the necessary genetic profile, or have visible cancer on scans.

Inclusion Criteria

I agree to use effective birth control methods.

Discontinuation of breastfeeding during study treatment

Viral testing requirements

Exclusion Criteria

Left ventricular ejection fraction (LVEF) <= 45%

Forced expiratory volume in the first second (FEV1) <= 50% predicted

Unequivocal radiographic evidence of residual tumor

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Group 1 participants receive TCR T-cell therapy with chemotherapy and aldesleukin, while Group 2 participants undergo surveillance.

3 weeks or more

In-hospital stay for 3 weeks or more for Group 1

Follow-up

Participants are monitored for recurrence-free survival and overall survival with regular clinical evaluations and radiographic assessments.

5 years

Every 3 months for 1 year, then every 6 months for 5 years

Long-term follow-up

Participants continue follow-up visits for another 10 years under a different protocol.

10 years

What Are the Treatments Tested in This Trial?

Interventions

• KRAS TCR-Transduced PBL

Trial Overview The study compares two groups: one receives T-cell therapy where their own immune cells are modified in a lab to target cancer cells; another group doesn’t get this treatment. Participants are randomly assigned to either group and followed up for years to see if the therapy prevents cancer from returning.

How Is the Trial Designed?

Group I: 1/ TCR T-cells and aldesleukin Experimental Treatment 4 Interventions

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + TCR T cells + aldesleukin

Group II: 2/ No cellular therapy Active Control 1 Intervention

Surveillance and follow-up

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]

Four KRAS-specific T-cell receptors (TCRs) were successfully isolated from a pancreatic cancer survivor, showing stable expression and functionality in T cells, indicating their potential for targeted cancer therapy.

These TCRs demonstrated the ability to recognize multiple KRAS mutations, suggesting that they could be effective in targeting a wide range of cancers with KRAS mutations, making them promising candidates for TCR-based immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting KRAS mutations with HLA class II-restricted TCRs for the treatment of solid tumors. Dillard, P., Casey, N., Pollmann, S., et al.[2021]

The TCRα-modified T cell product showed no signs of tumorigenic or mutagenic activity in vitro, indicating that the viral vectors used for its generation are safe and do not cause genetic damage.

In mouse models, the adoptive transfer of TCRα-engineered T cells did not disrupt normal body functions and showed no acute toxicity or harmful immune reactions, suggesting a favorable safety profile for potential clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of the mouse TCRα - transduced T cell product in preclinical models in vivo and in vitro. Kalinina, A., Bruter, A., Persiyantseva, N., et al.[2022]

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]

Using CRISPR-Cas9 technology to specifically integrate an engineered TCR gene into the TCR alpha constant locus reduces the risk of insertional mutagenesis and mispairing with endogenous TCRs, enhancing the safety of T cell modifications.

This method not only successfully redirects the specificity of T cells in vitro but also demonstrates effective tumor rejection in an in vivo xenograft model, indicating strong potential for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene editing enables T-cell engineering to redirect antigen specificity for potent tumor rejection. Albers, JJ., Ammon, T., Gosmann, D., et al.[2021]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4775432/

Identification of T-cell Receptors Targeting KRAS-mutated ... T cells from cancer patients can recognize peptides derived from mutated KRAS variants (20–22), indicating the existence of immune reactivity to mutated KRAS.

2. sciencedirect.com sciencedirect.com/science/article/pii/S2667237525000852

Article Generation of T cell responses against broad KRAS ... T cells generated through this process were able to slow tumor growth in vitro and in vivo. The approach could be used as the basis for the ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa2119662

Neoantigen T-Cell Receptor Gene Therapy in Pancreatic ... Of the transduced T cells, approximately 29% expressed the 9mer TCR that targets a 9 amino acid–long KRAS G12D peptide and approximately 71% ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.TPS792

Phase I study of autologous CD8+ and CD4+ transgenic T ... The prognosis of patients with activating KRAS mutations remains poor. Preliminary anti-tumor activity has been observed with T cell receptor ( ...

5. cell.com cell.com/cancer-cell/fulltext/S1535-6108(25)00215-6

Mutant KRAS peptide targeted CAR-T cells engineered for ... Here, we harness multiple genetic approaches to develop a CAR-T cell therapy targeting tumors. First, we screen binders targeting oncogenic KRAS ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.2547

Safety and efficacy of Sleeping Beauty TCR-T cells ... Best overall responses were partial response for Patient 1 with six month progression-free survival, stable disease for Patient 2 and ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04146298

NCT04146298 | Mutant KRAS G12V-specific TCR ... This clinical trial will evaluate the safety and activity of mutant KRAS G12V-specific TCR transduced T cell therapy for advanced pancreatic cancer patients.

8. cell.com cell.com/cell-reports-methods/fulltext/S2667-2375(25)00085-2

Generation of T cell responses against broad KRAS ... T cells generated through this process were able to slow tumor growth in vitro and in vivo. The approach could be used as the basis for the ...

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1535610825002156

Mutant KRAS peptide targeted CAR-T cells engineered for ... In this report, we demonstrate techniques for expanding the therapeutic window of CAR-T cells targeting human tumors using single-chain variable ...