Gene Transfer Therapy for Metastatic Cancer

Overseen By NCI SB Immunotherapy Recruitment Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Systemic steroids

Disqualifiers: Pregnancy, Active infections, 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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 3-4 weeks

285 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene transfer therapy for individuals with certain types of metastatic cancer where standard treatments have failed. The goal is to determine if modifying a patient's own white blood cells in a lab can shrink tumors. This therapy, called Individual Patient TCR-Transduced PBL, uses autologous T-cells genetically engineered to express T-cell receptors reactive against neoantigens. Participants with specific cancers, such as breast, lung, or gastrointestinal, who have not responded to typical treatments, may be eligible. The trial includes multiple steps, such as hospital stays and follow-up care. 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 protocol does not specify if you must stop taking your current medications. However, participants must have completed any prior systemic therapy before enrollment, and concurrent systemic steroid therapy is not allowed.

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

Research has shown that gene transfer therapy using TCR-Transduced PBL, a type of white blood cell modified to fight cancer, can be safe for patients. Studies have found that these modified T-cells, designed to target specific cancer changes, usually do not cause serious side effects. In some cases, patients have had these T-cells in their blood for over two years without major problems.

For the treatment involving pembrolizumab, an additional drug used to boost the immune system, the safety outlook is also positive. The FDA has already approved pembrolizumab for other cancers, indicating a known safety record. However, the combination with gene transfer therapy is still under study to ensure safety when used together. Overall, this trial is in the middle stages, and while early safety results are promising, further research is needed to confirm these findings. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they employ a cutting-edge approach called TCR-transduced PBL therapy, which involves genetically modifying a patient's own immune cells to better recognize and attack cancer cells. Unlike traditional chemotherapy or radiation, which can damage healthy cells, this method aims to enhance the body's natural defenses with precision. Additionally, one treatment arm combines this personalized therapy with pembrolizumab, an immune checkpoint inhibitor, to potentially boost the immune response even further. This dual approach could offer a more targeted and effective strategy for tackling metastatic cancer than existing treatments.

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

Research has shown that a type of white blood cell therapy, known as gene transfer therapy, can help shrink tumors. This therapy uses specially engineered T-cells to target specific cancer mutations, potentially leading to tumor reduction. One study found that about 20% of these treated white blood cells remained active in the body for over two years, indicating long-lasting effects. In this trial, participants will receive TCR-transduced PBLs, the engineered T-cells, as a promising method for treating solid tumors. Some participants will also receive pembrolizumab in combination with the TCR-transduced PBLs. Early results suggest that this combination enhances the treatment's effectiveness by improving the immune system's ability to attack cancer. ^{1 2 4 5 6}

Who Is on the Research Team?

Steven A Rosenberg, 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 certain metastatic cancers that haven't responded to standard treatments. Participants must be in good physical condition, not have HIV or hepatitis, agree to use birth control, and sign consent forms. Pregnant women and those with major illnesses or hypersensitivity reactions are excluded.

Inclusion Criteria

You need to have certain levels of blood and chemical components in your body.

Willingness to practice birth control and undergo pregnancy testing

You do not have the HIV virus or hepatitis B or C.

Exclusion Criteria

I am currently pregnant or breastfeeding.

Receiving any other investigational agents

I am currently taking steroid medication.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Multiple visits for tests and leukapheresis

Care at Home

Participants care for themselves at home while their cells are modified in the lab

12 weeks

Treatment

Participants receive a non-myeloablative, lymphodepleting preparative regimen followed by infusion of modified cells and high-dose aldesleukin

3-4 weeks

Hospital stay for treatment

Pembrolizumab Administration

Participants on Arm 2 receive pembrolizumab prior to cell administration and three additional doses every three weeks following the cell infusion

9 weeks

Recovery

Participants recover in the hospital, receiving drugs and undergoing blood and urine tests

1-2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, with repeat screening tests at visits every few months for the first year, every 6 months for the second year, then as determined

2 years

Regular visits every few months

What Are the Treatments Tested in This Trial?

Interventions

• Individual Patient TCR-Transduced PBL

Trial Overview The study tests gene transfer therapy using the patient's own white blood cells engineered to attack cancer mutations. It involves leukapheresis, cell modification in a lab, hospital treatment including drug administration via catheter, recovery period with medications and follow-up visits.

How Is the Trial Designed?

Group I: 2/iTCR + Pembro Experimental Treatment 5 Interventions

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Individual Patient TCRTransduced PBL + high- or low-dose aldesleukin + pembrolizumab prior to cell administration and 3 additional doses every 3 weeksfollowing cell infusion

Group II: 1/iTCR Experimental Treatment 4 Interventions

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Individual Patient TCR-Transduced PBL + high- or low-dose aldesleukin

Individual Patient TCR-Transduced PBL is already approved in United States for the following indications:

Approved in United States as Afami-cel (Tecelra) for:

• Metastatic synovial sarcoma positive for MAGE-A4 and certain HLA proteins

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 antigen-specific immunotherapy can effectively target cancer without needing the patient's immune system to be fully functional, making it a promising treatment option for patients with poorly immunogenic tumors.

Using T cell receptor (TCR) gene transfer allows for the rapid production of antigen-specific T cells from a patient's own lymphocytes, which can lead to stable and effective immune responses, including the development of memory T cells for long-term protection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploiting T cell receptor genes for cancer immunotherapy. Xue, S., Gillmore, R., Downs, A., et al.[2018]

The study involved 15 patients with metastatic melanoma who received autologous lymphocytes genetically modified to express a tumor-specific T cell receptor, leading to durable engraftment of these engineered cells in the bloodstream for over 2 months.

Two patients showed significant and lasting regression of their metastatic melanoma lesions, indicating that genetically engineered T cells can effectively target and combat cancer, highlighting their potential as a promising cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cancer regression in patients after transfer of genetically engineered lymphocytes. Morgan, RA., Dudley, ME., Wunderlich, JR., et al.[2023]

A study analyzing 12 fresh metastatic melanoma samples found that 11 of them contained up to 5 tumor-reactive T-cell receptor (TCR) clonotypes, indicating a strong presence of T cells targeting tumor-specific neoantigens.

The research demonstrates the potential for a personalized TCR-gene therapy approach that can effectively target unique tumor antigens without needing to first identify their immunologic reactivity, paving the way for more tailored cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor- and Neoantigen-Reactive T-cell Receptors Can Be Identified Based on Their Frequency in Fresh Tumor. Pasetto, A., Gros, A., Robbins, PF., et al.[2021]

TCR gene therapy offers a promising alternative to traditional adoptive T cell transfer by allowing for the introduction of tumor-specific T cell receptors directly into patient T cells, potentially simplifying the process and enabling broader application across patient populations.

While TCR gene therapy has significant advantages, such as reducing the need for large-scale in vitro cell generation, it also presents unique challenges that need to be addressed, as highlighted by findings from in vitro studies, mouse models, and early phase I clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospects and limitations of T cell receptor gene therapy. Jorritsma, A., Schotte, R., Coccoris, M., et al.[2019]

The study developed advanced multiplex assays to evaluate the quality of T cell receptor (TCR) therapies, which are tailored to target cancer-specific neoantigens, potentially leading to more effective cancer treatments.

Using next-generation sequencing and droplet digital PCR, the researchers confirmed the identity and efficiency of engineered TCRs, and established a potency assay to measure T cell activation, providing a comprehensive approach to ensure the effectiveness of individualized TCR-T cell products.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessing TCR identity, knock-in efficiency, and potency for individualized TCR-T cell therapy. Camperi, J., Devarajan, S., McKay, A., et al.[2023]

Adoptive transfer of tumor-reactive lymphocytes has shown success in treating metastatic melanoma, leading to the development of T cell receptor (TCR) gene engineering to enhance normal T cells' ability to target tumors.

Initial clinical studies indicate that TCR gene-engineered T cells can effectively mediate tumor regression in patients, showcasing the potential of this approach for treating melanoma and other cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic engineering with T cell receptors. Zhang, L., Morgan, RA.[2023]

In a study involving 3 melanoma patients undergoing adoptive cell transfer (ACT) with TCR-engineered T cells targeting the MART-1 antigen, researchers found that highly functional T cells play a crucial role in the antitumor immune response.

The study emphasizes the importance of developing strategies to sustain the functionality of these T cells over time to enhance the long-term effectiveness of TCR-engineered ACT immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multifunctional T-cell analyses to study response and progression in adoptive cell transfer immunotherapy. Ma, C., Cheung, AF., Chodon, T., et al.[2022]

T cell receptor (TCR) gene therapy shows promise in treating malignant tumors by enabling T cells to specifically target and respond to tumor cells.

To improve the effectiveness of TCR-engineered T cell therapy, it is crucial to select the right TCRs and develop strategies that enhance T cell movement and accumulation in tumor tissues, potentially leading to better treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TCR-engineered T cells to treat tumors: Seeing but not touching? Debets, R., Donnadieu, E., Chouaib, S., et al.[2021]

Mutation-derived neoantigens are promising targets for cancer immunotherapy, particularly in the context of adoptive T cell transfer (ACT) therapy, which is evolving to include genetically engineered T cells with neoantigen-specific T cell receptors (TCRs).

The success of TCR-ACT therapy depends on both the identification of effective neoantigen-reactive TCRs and the state of the recipient T cells, highlighting the need for improved methods to quickly identify suitable TCR candidates for gene transfer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Promise of Personalized TCR-Based Cellular Immunotherapy for Cancer Patients. Arnaud, M., Bobisse, S., Chiffelle, J., et al.[2021]

A novel method using the Sleeping Beauty transposon system allows for the rapid and cost-effective genetic engineering of T cells from cancer patients, enhancing their ability to target unique neoantigens associated with tumors.

The engineered T cells demonstrated a strong and specific immune response against tumor cells expressing these neoantigens, suggesting that this approach could improve the efficacy of personalized T-cell therapies in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stable, Nonviral Expression of Mutated Tumor Neoantigen-specific T-cell Receptors Using the Sleeping Beauty Transposon/Transposase System. Deniger, DC., Pasetto, A., Tran, E., et al.[2018]

T-cell receptor (TCR) gene therapy has shown promise in redirecting T cells to target and eliminate cancer cells, demonstrating effective cytotoxic and helper T cell responses in both laboratory and human studies.

Recent advancements in modifying TCRs and improving vector delivery systems aim to enhance the safety and efficiency of TCR gene transfer, making it a potentially powerful tool in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cell receptor gene therapy for cancer: the progress to date and future objectives. Thomas, S., Hart, DP., Xue, SA., et al.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03412877

NCT03412877 | Administration of Autologous T-Cells ... We have developed approaches to identify these rare neoantigen reactive T-cells from common non-melanoma cancers, to isolate their T-cell receptors (TCR), and ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04536922

NCT04536922 | Administration of Autologous T-Cells ... We have developed approaches to identify rare neoantigen reactive T-cells from common non-melanoma cancers, to isolate their T-cell receptors (TCR), and to ...

3. nature.com nature.com/articles/s41591-024-03418-4

Personalized, autologous neoantigen-specific T cell ... We designed BNT221, a personalized, neoantigen-specific autologous T cell product derived from peripheral blood, and tested this in a 3 + 3 dose-finding study.

4. turnstonebio.com turnstonebio.com/wp-content/uploads/2024/07/Adoptive-transfer-of-personalized-neoantigen-reacti.pdf

Adoptive transfer of personalized neoantigen-reactive TCR ... This study provides early results suggesting that ACT with T cells genetically modified to express personalized neoantigen-reactive TCRs can be tolerated and ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12529609/

Neoantigen identification and TCR-T therapy development for ... Recently, T cells expressing engineered T cell receptor (TCR-T cells) have become recognized as a promising tumor cell therapy for solid tumors ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38992129/

Adoptive transfer of personalized neoantigen-reactive TCR ... This study provides early results suggesting that ACT with T cells genetically modified to express personalized neoantigen-reactive TCRs can be tolerated and ...