Gene-Modified T Cells for Advanced Cancers

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Roswell Park Cancer Institute

Must not be taking: Corticosteroids, Immunosuppressive drugs

Disqualifiers: Severe autoimmune, Active infection, Brain metastases, others

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

Compensation: Varies

Number of Visits: 1

Duration: 1 week

15 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must not be on any other investigational agents and should not have used systemic steroids in the last 4 weeks before enrollment, except for certain allowed uses like inhaled or topical steroids.

What data supports the effectiveness of the treatment Gene-Modified T Cells for Advanced Cancers?

Research shows that genetically modifying T cells can enhance their ability to target and destroy cancer cells, even when natural tumor-specific T cells are rare. This approach has shown promise in clinical trials, demonstrating the potential to improve anti-tumor immunity and achieve significant tumor regression. ^{1 2 3 4 5}

What safety data exists for gene-modified T cell therapies in humans?

Gene-modified T cell therapies, like CAR-T and TCR therapies, have shown promise in treating certain cancers but come with safety concerns. These include potential side effects like cytokine release syndrome (a severe immune reaction), neurotoxicity (nerve damage), and off-target effects (unintended damage to healthy cells). However, ongoing research and clinical trials are working on strategies to manage and reduce these risks. ^{2 6 7 8 9}

How is the treatment Gene-Modified T Cells different from other treatments for advanced cancers?

Gene-Modified T Cells are unique because they are engineered to specifically target and attack cancer cells by modifying their surface receptors to recognize tumor-associated antigens. This approach enhances the T cells' ability to find and destroy cancer cells, which is different from traditional treatments that may not be as targeted. ^{1 2 4 10 11}

What is the purpose of this trial?

This phase I/IIa trial studies the side effects and best dose of gene-modified T cells when given with or without decitabine, and to see how well they work in treating patients with malignancies expressing cancer-testis antigens 1 (NY-ESO-1) gene that have spread to other places in the body (advanced). A T cell is a type of immune cell that can recognize and kill abnormal cells of the body. Placing a modified gene for NY-ESO-1 into the patients' T cells in the laboratory and then giving them back to the patient may help the body build an immune response to kill tumor cells that express NY-ESO-1. Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving gene-modified T cells with or without decitabine works better in treating patients with malignancies expressing NY-ESO-1.

Research Team

Philip McCarthy

Principal Investigator

Roswell Park Cancer Institute

Eligibility Criteria

This trial is for patients with advanced cancers like melanoma, ovarian, peritoneal or fallopian tube carcinoma, and synovial sarcoma that express the NY-ESO-1 gene. Participants need available tissue for testing or agree to a biopsy, have a caregiver nearby, meet medical criteria, use birth control, understand the study's nature and consent to it. They must not have brain metastases or severe autoimmune diseases.

Inclusion Criteria

Patients must understand the investigational nature of the study and provide informed consent

Patients must arrange for a caregiver available 24/7 and lodging within 45 minutes drive to the treatment center

My cancer is inoperable or has spread and falls into one of the specified categories.

Exclusion Criteria

You have had a serious autoimmune disease or inflammatory bowel disease in the past.

I am currently taking steroids or drugs that affect my immune system.

Pregnancy or breast-feeding

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients undergo leukapheresis and receive cyclophosphamide and/or decitabine followed by TGFbDNRII-transduced autologous tumor infiltrating lymphocytes infusion

1 week

Multiple visits for leukapheresis and infusions

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 15 years

Visits at weeks 1-4, 6, 8, 12, at 6 and 9 months, every 6 months for 5 years, then yearly for 10 years

Treatment Details

Interventions

• Decitabine
• Gene-Modified T Cells

Trial Overview The trial tests gene-modified T cells with/without decitabine in treating advanced malignancies expressing NY-ESO-1. It aims to find out how well these treatments work and their best doses by modifying patients' T cells to target tumor cells better.

Participant Groups

Group I: Cohort II (decitabine, cyclophosphamide, TCR/dnTGFbetaRII) Experimental Treatment 5 Interventions

Patients undergo leukapheresis on day -6 and receive decitabine IV over 1 hour on days -6 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2. Patients then receive TGFbDNRII-transduced autologous tumor infiltrating lymphocytes IV over 15 minutes on day 0. Eligible patients who showed initial response/disease control, may receive a second TGFbDNRII-transduced autologous tumor infiltrating lymphocytes infusion at any time after progression is confirmed.

Group II: Cohort I (cyclophosphamide, TCR/dnTGFbetaRII) Experimental Treatment 4 Interventions

Patients undergo leukapheresis on day -6 and receive cyclophosphamide IV over 2 hours on days -5 and -4. Patients then receive TGFbDNRII-transduced autologous tumor infiltrating lymphocytes IV over 15 minutes on day 0. Eligible patients who showed initial response/disease control, may receive a second TGFbDNRII-transduced autologous tumor infiltrating lymphocytes infusion at any time after progression is confirmed.

Who Is Running the Clinical Trial?

Roswell Park Cancer Institute

Lead Sponsor

Trials

427

Recruited

40,500+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Genetic modification of T cells to express receptors specific for tumor-associated antigens can redirect their function, enhancing their ability to target and eliminate tumor cells, which is crucial for treating common cancers.

Recent advances in gene design and cell production techniques have improved the clinical application of this adoptive immunotherapy, potentially leading to more effective treatments for patients with various types of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic redirection of T cells for cancer therapy. Westwood, JA., Kershaw, MH.[2010]

T cells are highly effective in targeting cancer due to their sensitivity and specificity to antigens, but challenges like the rarity of tumor-reactive T cells and their unpredictable persistence limit their use in therapies.

Advancements in genetic modification technologies are being explored to enhance T cell responses to tumor antigens, with ongoing research focused on leveraging the diverse characteristics of T cells to improve the efficacy and safety of cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetically retargeting CD8+ lymphocyte subsets for cancer immunotherapy. Turtle, CJ., Riddell, SR.[2022]

Adoptive transfer of antigen-specific T cells shows promise for treating viral infections in immunosuppressed patients, but achieving effective T-cell therapy for cancer is more challenging due to issues like T-cell tolerance and impaired survival in the body.

Genetic modification of T cells before transfer may help overcome obstacles such as tumor evasion tactics and improve the effectiveness of T-cell therapies for both cancer and infectious diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic modification of T cells for immunotherapy. Berger, C., Berger, M., Feng, J., et al.[2019]

T cells play a crucial role in fighting cancer, and recent advances in immunotherapy are focusing on enhancing their effectiveness through genetic engineering.

The introduction of tumor-specific receptors, such as Chimeric Antigen Receptors (CAR) and T cell receptors (TcR), shows promise in ongoing clinical trials, indicating a potential for strong anti-tumor responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Muscle CARs and TcRs: turbo-charged technologies for the (T cell) masses. Kalos, M.[2012]

Engineered T cell therapies, like CAR T cells and TCR T cell therapies, have shown remarkable efficacy in treating certain blood cancers, highlighting their potential as a powerful tool in cancer immunotherapy.

However, these therapies also pose unique safety challenges, such as cytokine release syndrome and neurotoxicity, which require careful nonclinical safety assessments to ensure patient safety during development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of engineered T cell therapies. Lebrec, H., Maier, CC., Maki, K., et al.[2022]

CAR-T cell therapies have shown significant clinical success in treating cancer by effectively targeting tumor-associated antigens, leading to complete and durable responses in many patients during early trials.

Despite their effectiveness, there are safety concerns regarding potential toxicities from engineered cells, prompting the exploration of strategies like integrating failsafe switches to enhance safety in cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineering Hematopoietic Cells for Cancer Immunotherapy: Strategies to Address Safety and Toxicity Concerns. Resetca, D., Neschadim, A., Medin, JA.[2018]

Genetic modification of T lymphocytes enhances their ability to recognize and attack tumor cells, which is crucial for improving cancer immunotherapy.

These modifications not only boost antitumor activity but also improve safety and allow for tracking of T cells using non-invasive imaging techniques, making them valuable for both research and treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting tumours with genetically enhanced T lymphocytes. Sadelain, M., Rivière, I., Brentjens, R.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Genetic redirection of T cells for cancer therapy. [2010]

2. England pubmed.ncbi.nlm.nih.gov

Challenges in T cell receptor gene therapy. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Genetically retargeting CD8+ lymphocyte subsets for cancer immunotherapy. [2022]

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

Genetic modification of T cells for immunotherapy. [2019]

5. Germany pubmed.ncbi.nlm.nih.gov

Muscle CARs and TcRs: turbo-charged technologies for the (T cell) masses. [2012]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of engineered T cell therapies. [2022]

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

Engineering Hematopoietic Cells for Cancer Immunotherapy: Strategies to Address Safety and Toxicity Concerns. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Immunotherapy with gene-modified T cells: limiting side effects provides new challenges. [2020]

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

The Flipside of the Power of Engineered T Cells: Observed and Potential Toxicities of Genetically Modified T Cells as Therapy. [2018]

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

Genetic modification of T lymphocytes for adoptive immunotherapy. [2017]

11. England pubmed.ncbi.nlm.nih.gov

Targeting tumours with genetically enhanced T lymphocytes. [2021]