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

65 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Gastrointestinal (GI) cancer affects the organs (such as the stomach, large and small intestine, pancreas, colon, liver, and biliary system) of the digestive tract. In some participants who have had surgery for GI cancer, blood tests show that the cancer has spread despite being unable to be identified by scans. Certain gene mutations (changes) in GI cancer (such as KRAS or TP53) can be targeted by T cells, a type of immune cell, in individuals with specific HLA types (genes that help proteins in the body know what is self and non-self). Researchers want to see if they can stop GI cancer from returning or spreading in people with these gene mutations and specific HLA types. Objective: To test therapy with modified T-cells to prevent or delay the return of GI cancer after standard treatment. T-cells play a role in the body s immune system. Eligibility: People aged 18 to 72 years with GI cancer that was treated with standard therapy and is not seen on imaging scans. They must have specific gene mutations and HLA types. They also must have certain clinical or blood tests showing the cancer is spreading (elevating CA19-9 or detectable ctDNA). Design: Participants will be divided into 2 groups. Participants nor the study team can choose what Group to participate in; this is done by randomization , like flipping a coin. Participants will have a 1-to-1 chance of being in Group 1 or Group 2. Group 1 will receive T-cell therapy. Their own T-cells will be collected. In a lab, the cells will be combined with a virus that carries a protein to target cancer cells. Group 1 participants will stay in the hospital for 3 weeks or more. They will have chemotherapy, and their modified T-cells will be infused through a tube attached to a needle inserted into a vein. Group 1 participants will visit the clinic every 3 months for 1 year and then every 6 months for 5 years. Then they will have follow-up visits for another 10 years under a different protocol. Group 2 participants will not receive treatment with T-cells. They will visit the clinic every 3 months for 1 year and then every 6 months for 5 years.

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.

What data supports the effectiveness of the T-Cell Therapy for Cancer treatment involving KRAS TCR-Transduced PBL?

Research shows that T cells engineered to target specific KRAS mutations have successfully reduced tumor growth in pancreatic and colorectal cancers. These engineered T cells have demonstrated the ability to recognize and attack cancer cells with KRAS mutations, leading to tumor regression in some patients. ^{1 2 3 4 5}

Is T-cell therapy, including KRAS TCR-Transduced PBL, generally safe for humans?

Research on T-cell therapies, including those targeting KRAS mutations, shows promising safety data. Studies in mice found no harmful effects, and a human trial with CRISPR-edited T cells reported only mild side effects, suggesting these therapies are generally safe. ^{1 3 5 6 7}

How does T-Cell Therapy for Cancer differ from other treatments for cancer?

T-Cell Therapy for Cancer is unique because it involves engineering T cells to specifically target KRAS mutations, which are common in many cancers like pancreatic and colorectal cancer. This approach uses T-cell receptors (TCRs) to recognize and attack cancer cells with these mutations, offering a more precise and potentially effective treatment compared to traditional therapies. ^{1 2 3 5 8}

Research Team

Nicholas D Klemen, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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 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]

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]

References

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

Engineered KRAS G12D-Reactive T Cells Show Promise in Pancreatic Cancer. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Identification of T-cell Receptors Targeting KRAS-Mutated Human Tumors. [2019]

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

Gene editing enables T-cell engineering to redirect antigen specificity for potent tumor rejection. [2021]

5. Germany 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. [2023]

6. France pubmed.ncbi.nlm.nih.gov

Safety evaluation of the mouse TCRα - transduced T cell product in preclinical models in vivo and in vitro. [2022]

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

Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer. [2022]

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

Targeting KRAS mutations with HLA class II-restricted TCRs for the treatment of solid tumors. [2021]