Adoptive Cell Therapy for Bladder Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Immunosuppressants, Chemotherapy

Disqualifiers: HIV, Hepatitis B/C, Autoimmune, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 3 weeks

12 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop using any immunosuppressive medications, like corticosteroids, at least 14 days before joining. However, certain types of corticosteroids, like inhaled or topical ones, are allowed. If you're on other medications, the protocol doesn't specify, so it's best to discuss with the trial team.

What data supports the effectiveness of the treatment Adoptive Cell Therapy with Tumor-infiltrating Lymphocytes (TIL) for bladder cancer?

Adoptive Cell Therapy using TIL has been successful in treating metastatic melanoma, showing a median overall survival of 52 months, and has potential for bladder cancer as TILs can be expanded from bladder tumors. Additionally, TIL therapy has shown promise in decreasing bladder tumor growth in animal studies. ^{1 2 3 4 5}

Is adoptive cell therapy with tumor-infiltrating lymphocytes generally safe for humans?

Adoptive cell therapy using tumor-infiltrating lymphocytes has shown promise in treating cancers like melanoma, but it can have side effects mainly due to the chemotherapy and high-dose interleukin-2 used in the process. These side effects are usually reversible, though rare neurological effects have been reported. ^{1 3 6 7 8}

How is adoptive cell therapy with TIL different from other bladder cancer treatments?

Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) is unique because it uses the patient's own immune cells, specifically T cells from their tumor, to fight cancer. This personalized approach aims to enhance the body's natural ability to target and destroy cancer cells, which is different from traditional treatments like chemotherapy or radiation that do not specifically target the immune system. ^{1 2 3 4 6}

What is the purpose of this trial?

The purpose of the study is to evaluate the feasibility, safety and tolerability of intravesical adoptive cell therapy using TIL (tumor infiltrating lymphocytes) in participants with urothelial cell carcinoma (UCC) non-muscle invasive bladder cancer (NMIBC).

Research Team

Michael Poch, MD

Principal Investigator

Moffitt Cancer Center

Eligibility Criteria

This trial is for individuals who have been treated with BCG for high-grade non-muscle invasive bladder cancer (NMIBC) and show evidence of the disease. They must be in good health, understand the study, and consent to participate. Key eligibility includes a performance status of 0-1, adequate organ function, no recent intravesical chemotherapy or immunosuppressive drugs, no uncontrolled illnesses or certain infections like HIV or hepatitis B/C.

Inclusion Criteria

My bladder cancer is mostly urothelial and hasn't spread deep into the muscle.

I can provide a tissue sample for the trial, either from a needed treatment or a low-risk procedure.

I have a high-grade bladder cancer but haven't had muscle invasion, and I'm fit for participation.

Exclusion Criteria

I've been cancer-free for 2 years, except for certain early-stage or in situ cancers.

Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results

I haven't needed IV antibiotics for infections in the last week.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intravesical adoptive cell therapy using TIL, administered four times over three weeks

3 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Long-term follow-up

Participants are monitored for progression-free survival and overall response rate

12 months

Treatment Details

Interventions

• Adoptive Cell Therapy with Tumor-infiltrating Lymphocytes (TIL)

Trial Overview The trial is testing adoptive cell therapy using TIL (tumor infiltrating lymphocytes) delivered directly into the bladder to see if it's safe and tolerable for treating urothelial cell carcinoma in NMIBC patients who have previously received BCG therapy.

Participant Groups

Group I: Treatment with Adoptive Cell Therapy Experimental Treatment 1 Intervention

TIL from bladder biopsies will be propagated and cultured with interleukin-2 (IL-2) to a target goal of \>30 million cells. These TIL then undergo rapid clonal expansion (REP) by incubation with anti-CD3 monoclonal antibody (mAb), resulting in \>500-fold expansion. After 4-6 weeks culture time intravesical TIL will be administered via intravesical infusion, consisting of up to 3.2e8 cells in 40 mL aliquot. Intravesical therapy will be administered for up to 2 hours. This treatment will occur four times (Day 0, Day 7, Day 14 and Day 21).

Adoptive Cell Therapy with Tumor-infiltrating Lymphocytes (TIL) is already approved in United States, European Union for the following indications:

Approved in United States as TIL Therapy for:

• Melanoma
• Research trials for other cancers including bladder, breast, ovarian, renal cell, head-and-neck, non-small cell lung cancers, prostate cancer, sarcoma, and pancreatic carcinomas

Approved in European Union as TIL Therapy for:

• Melanoma
• Research trials for other cancers including bladder, breast, ovarian, renal cell, head-and-neck, non-small cell lung cancers, prostate cancer, sarcoma, and pancreatic carcinomas

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Findings from Research

This study successfully expanded tumor-infiltrating lymphocytes (TIL) from 70% of primary bladder tumors and all lymph node metastases, indicating a feasible approach for developing adoptive cell therapy in bladder cancer patients.

The addition of an agonistic 4-1BB antibody enhanced TIL expansion from primary tumors, suggesting a potential strategy to improve the effectiveness of TIL therapy, which could lead to better treatment options for patients with advanced bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expansion of tumor infiltrating lymphocytes (TIL) from bladder cancer. Poch, M., Hall, M., Joerger, A., et al.[2021]

Adoptive cellular therapy (ACT) using tumor-infiltrating lymphocytes (TILs) showed promising results in treating bladder cancer, with systemic ACT leading to reduced tumor growth and enhanced T cell infiltration in treated mice.

Intravesical delivery of TILs directly into the bladder was effective in controlling tumor growth without the need for prior chemotherapy or interleukin-2, highlighting a potential less invasive treatment option for bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic and intravesical adoptive cell therapy of tumor-reactive T cells can decrease bladder tumor growth in vivo. Bunch, BL., Morse, J., Asby, S., et al.[2021]

Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has shown promising results in treating melanoma and may be applicable to other cancers, but its clinical development faces challenges such as therapeutic resistance and treatment-related toxicity.

Ongoing research is focused on enhancing the efficacy of TIL-based ACT by improving the selection and manufacturing of tumor-reactive TILs, which could help overcome current limitations and expand its use in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-infiltrating lymphocytes for adoptive cell therapy: recent advances, challenges, and future directions. Granhøj, JS., Witness Præst Jensen, A., Presti, M., et al.[2022]

Bladder cancer patients have high levels of myeloid derived suppressor cells (MDSCs) in their urine, which suppress T cell proliferation, indicating a challenging immune environment for treatment.

Intravesical gemcitabine can effectively deplete MDSCs and other immune cells in bladder tumors, enhancing the effectiveness of adoptive cell therapy with T cells, leading to improved anti-tumor responses when used in combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting myeloid-derived suppressor cells with gemcitabine to enhance efficacy of adoptive cell therapy in bladder cancer. Bazargan, S., Bunch, B., Ojwang', AME., et al.[2023]

Adoptive cell therapy using PD-1-expressing tumor-infiltrating lymphocytes (TILs) combined with an anti-PD-1 antibody significantly enhances the anti-tumor response in a melanoma mouse model, demonstrating improved efficacy against solid tumors.

This approach maintains the high specificity of TILs for tumor cells while overcoming limitations posed by the tumor immune microenvironment, suggesting potential for broader application in other cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Coupling programmed cell death 1-positive tumor-infiltrating T cells with anti-programmed cell death 1 antibody improves the efficacy of adoptive T-cell therapy. Chu, J., Wang, C., Ma, Q., et al.[2022]

In a study analyzing tumor-infiltrating lymphocytes (TILs) from metastatic melanoma patients, neoantigen-specific CD4+ T cells were found to be crucial, showing effective responses against tumors, even in non-responders.

The research highlights the need to focus on neoantigen-specific CD4+ T cells in adoptive cell therapy (ACT) protocols, as they can enhance antitumor immunity and provide a potent source of tumor-specific effectors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoantigen-specific CD4+ tumor-infiltrating lymphocytes are potent effectors identified within adoptive cell therapy products for metastatic melanoma patients. Hall, MS., Teer, JK., Yu, X., et al.[2023]

The TIL 3.0 method, which uses IL-2 combined with agonistic antibodies, significantly enhances the expansion of tumor-infiltrating lymphocytes (TIL) from non-small cell lung cancer (NSCLC) tumors, producing 5.3 times more TIL compared to the traditional TIL 1.0 method.

TIL 3.0 not only increases the quantity of CD8+ TIL but also maintains a diverse T-cell repertoire that closely resembles the original tumor's clonal hierarchy, suggesting a greater potential for effective adoptive cell transfer therapies in NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined IL-2, agonistic CD3 and 4-1BB stimulation preserve clonotype hierarchy in propagated non-small cell lung cancer tumor-infiltrating lymphocytes. Shah, P., Forget, MA., Frank, ML., et al.[2022]

A 53-year-old melanoma patient developed Guillain-Barré syndrome (GBS) 19 days after receiving tumor-infiltrating lymphocyte (TIL) therapy, highlighting a potential neurological side effect of this immunotherapy.

The patient's GBS was treated successfully, leading to full recovery after 21 months, suggesting that while TIL therapy can have serious side effects, they may be manageable and reversible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Guillain-Barré syndrome after adoptive cell therapy with tumor-infiltrating lymphocytes. Orcurto, A., Hottinger, A., Wolf, B., et al.[2021]

References

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

Expansion of tumor infiltrating lymphocytes (TIL) from bladder cancer. [2021]

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

Systemic and intravesical adoptive cell therapy of tumor-reactive T cells can decrease bladder tumor growth in vivo. [2021]

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

Tumor-infiltrating lymphocytes for adoptive cell therapy: recent advances, challenges, and future directions. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Targeting myeloid-derived suppressor cells with gemcitabine to enhance efficacy of adoptive cell therapy in bladder cancer. [2023]

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

Coupling programmed cell death 1-positive tumor-infiltrating T cells with anti-programmed cell death 1 antibody improves the efficacy of adoptive T-cell therapy. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Neoantigen-specific CD4+ tumor-infiltrating lymphocytes are potent effectors identified within adoptive cell therapy products for metastatic melanoma patients. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Combined IL-2, agonistic CD3 and 4-1BB stimulation preserve clonotype hierarchy in propagated non-small cell lung cancer tumor-infiltrating lymphocytes. [2022]

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

Guillain-Barré syndrome after adoptive cell therapy with tumor-infiltrating lymphocytes. [2021]