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

270 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: A person s tumor is studied for mutations. When cells are found that can attack the mutation in a person s tumor, the genes from those cells are studied to find the parts that make the attack possible. White blood cells are then taken from the person s body, and the gene transfer occurs in a laboratory. A type of virus is used to transfer the genes that make those white blood cells able to attack the mutation in the tumor. The gene transfer therapy is the return of those white blood cells back to the person. Objective: To see if gene transfer therapy of white blood cells can shrink tumors. Eligibility: People with certain metastatic cancer for which standard treatments have not worked. Design: Participants may complete screening under another protocol. Screening includes: * Getting tumor cells from a previous procedure * Medical history * Physical exam * Scans * Blood, urine, heart, and lung tests The study has 8 stages: 1. Screening tests repeated over 1-2 weeks. Participants will have leukapheresis: Blood is removed by a needle in one arm. A machine removes white blood cells. The rest of the blood is returned by a needle in the other arm. 2. Care at home over approximately 12 weeks. 3. Stopping therapy for 4-6 weeks while their cells are changed in a lab. 4. Hospital stay approximately 3-4 weeks for treatment. An IV catheter will be placed in the chest to administer drugs. 5. Patients on Arm 2 of the study will receive the first dose of pembrolizumab while in the hospital. Three additional doses will be given after the cell infusion 3 weeks apart. 6. Receiving changed cells by catheter. Then getting a drug over 1-5 days to help the cells live longer. 7. Recover in the hospital for 1-2 weeks. Participants will get drugs and have blood and urine tests. 8. Participants will take an antibiotic and maybe an antiviral for at least 6 months after treatment. They will have repeat screening tests at visits every few months for the first year, every 6 months for the second year, then as determined. ...

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.

What data supports the effectiveness of this treatment for metastatic cancer?

Research shows that T-cell receptor (TCR) gene therapy, which involves modifying T-cells to target cancer cells, has demonstrated promising antitumor effects in humans. Studies have shown that TCR-engineered T cells can mediate tumor regression and are functionally competent, suggesting potential effectiveness for treating metastatic cancer. ^{1 2 3 4 5}

Is gene transfer therapy for metastatic cancer generally safe in humans?

The research articles do not provide specific safety data for gene transfer therapy in humans, but they discuss the potential of T-cell receptor (TCR) therapies to target cancer cells. While these studies focus on the effectiveness and development of the therapy, they do not directly address safety outcomes. ^{1 2 6 7 8}

How is the treatment Individual Patient TCR-Transduced PBL different from other treatments for metastatic cancer?

This treatment is unique because it involves genetically engineering a patient's own T-cells to specifically target cancer cells, which can lead to a more precise attack on the tumor compared to traditional therapies. It uses T-cell receptors (TCRs) to recognize and attack cancer cells, potentially offering a more personalized and effective approach for patients with metastatic cancer. ^{3 4 9 10 11}

Research Team

Steven A Rosenberg, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

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

Willingness to practice birth control and undergo pregnancy testing

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

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

Exclusion Criteria

Receiving any other investigational agents

I am currently pregnant or breastfeeding.

I am currently taking steroid medication.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

Multifunctional T-cell analyses to study response and progression in adoptive cell transfer immunotherapy. [2022]

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

The Promise of Personalized TCR-Based Cellular Immunotherapy for Cancer Patients. [2021]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Genetic engineering with T cell receptors. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Exploiting T cell receptor genes for cancer immunotherapy. [2018]

5. England pubmed.ncbi.nlm.nih.gov

T-cell receptor gene therapy for cancer: the progress to date and future objectives. [2019]

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

Tumor- and Neoantigen-Reactive T-cell Receptors Can Be Identified Based on Their Frequency in Fresh Tumor. [2021]

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

Stable, Nonviral Expression of Mutated Tumor Neoantigen-specific T-cell Receptors Using the Sleeping Beauty Transposon/Transposase System. [2018]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Assessing TCR identity, knock-in efficiency, and potency for individualized TCR-T cell therapy. [2023]

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

Cancer regression in patients after transfer of genetically engineered lymphocytes. [2023]

10. England pubmed.ncbi.nlm.nih.gov

TCR-engineered T cells to treat tumors: Seeing but not touching? [2021]

11. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Prospects and limitations of T cell receptor gene therapy. [2019]