TBio-4101 + Chemo + IL-2 for Skin Cancer

Overseen By Yvonne Nguyen

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Heart disease, Immunodeficiency, Pregnancy, others

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

Compensation: Varies

Number of Visits: 3

17 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that any systemic therapy, including anti-cancer monoclonal antibodies, must be stopped at least 4 weeks before starting the lymphodepleting therapy. Additionally, participants taking systemic steroid therapy or immunosuppressive medications are excluded from the trial.

What evidence supports the effectiveness of the treatment TBio-4101 + Chemo + IL-2 for skin cancer?

Research shows that tumor-infiltrating lymphocytes (TILs) combined with interleukin-2 (IL-2) can lead to tumor regression in melanoma, a type of skin cancer. This suggests that the combination of TILs and IL-2, as part of the treatment, may be effective in treating skin cancer. ^{1 2 3 4 5}

What safety information is available for the combination of TBio-4101, chemotherapy, and IL-2 in treating skin cancer?

Interleukin-2 (IL-2) has been studied extensively and is known to cause reversible but often severe side effects, such as low blood pressure, swelling, and kidney issues, especially at higher doses. These side effects require careful monitoring and supportive care in a critical-care setting. Other common side effects include fever, fatigue, nausea, and muscle pain, but these are generally manageable and reversible. ^{5 6 7 8 9}

How is the TBio-4101 + Chemo + IL-2 treatment for skin cancer different from other treatments?

This treatment is unique because it combines TBio-4101, a form of interleukin-2 (a protein that boosts the immune system), with chemotherapy and tumor-infiltrating lymphocytes (TILs), which are immune cells that target cancer cells. This combination aims to enhance the body's immune response against skin cancer, potentially offering greater effectiveness than using these components separately. ^{1 3 5 10 11}

What is the purpose of this trial?

This trial is testing a new treatment that uses a patient's own immune cells, grown in a lab, to fight advanced melanoma that cannot be removed by surgery or has spread. The goal is to see if this approach is safe and effective. Using a patient's own immune cells to fight cancer has shown promise in treating advanced melanoma.

Research Team

Amod Sarnaik, MD

Principal Investigator

Moffitt Cancer Center

Eligibility Criteria

This trial is for adults aged 18-75 with unresectable or metastatic melanoma, including various types like cutaneous and ocular melanoma. Participants must have adequate organ function, an ECOG status of 0 or 1, and be willing to practice birth control. Those with treated brain metastases, a negative pregnancy test (if applicable), and the ability to sign consent can join. Excluded are pregnant women, those with severe heart issues or immunodeficiency disorders, active infections requiring IV antibiotics, history of severe allergies to study drugs, certain lung function impairments, autoimmune diseases needing steroids in the past 6 months.

Inclusion Criteria

I am willing and able to undergo a procedure to collect my blood cells.

I can carry out all my usual activities without help.

My organs and bone marrow are working well.

Exclusion Criteria

You have had a serious allergic reaction to the study drugs in the past.

I am not on steroids or immunosuppressive medications.

I have an autoimmune disease and have been on high-dose steroids in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepleting Chemotherapy

Participants receive cyclophosphamide and fludarabine to prepare for TIL infusion

7 days

Daily visits for chemotherapy administration

TIL Infusion

Participants receive TBio-4101 TIL product intravenously

1 day

1 visit (in-person)

IL-2 Administration

Participants receive interleukin-2 (IL-2) after TIL infusion

Up to 3 days

Multiple visits (in-person) for IL-2 administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 24 months

Treatment Details

Interventions

• Cyclophosphamide
• Fludarabine
• Interleukin-2
• TBio-4101

Trial Overview The trial tests TBio-4101 therapy using tumor infiltrating lymphocytes after lymphodepleting chemotherapy followed by interleukin-2 (IL-2) in participants with advanced melanoma. It aims to assess if this approach is feasible and safe while also evaluating its effectiveness against the cancer.

Participant Groups

Group I: Infusion of TBio-4101 TIL Experimental Treatment 4 Interventions

TBio-4101 is a tumor-infiltrating lymphocyte (TIL) product: participants tumor tissue is surgically removed and immune T-cells are taken out of the tumor and multiplied, or grown, in the laboratory. TIL product infused intravenously over 20 to 30 minutes within 2 to 4 days after the last dose of fludarabine Participants will also receive: * Cyclophosphamide dose 60 mg/kg/day for 2 days administered IV in 250 mL dextrose 5% in water infused simultaneously with Mesna 15 mg/kg/day delivered over 1 hour per day for 2 days. Fludarabine 25 mg/m2/day is delivered by intravenous piggyback daily over 15-30 minutes for 5 days. * Interleukin-2 (IL-2)- will be given to participants through IV after they receive the infusion of the TIL. IL-2 is administered at a dose of 600,000 IU/kg (based on actual body weight) IV every 8-12 hours beginning within 24 hours of TIL infusion for a maximum of 6 doses.

Interleukin-2 is already approved in United States, European Union for the following indications:

Approved in United States as Aldesleukin for:

• Metastatic melanoma
• Metastatic renal cell carcinoma

Approved in European Union as PROLEUKIN for:

• Metastatic renal cell carcinoma

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Turnstone Biologics, Corp.

Industry Sponsor

Trials

7

Recruited

120+

Findings from Research

Transducing tumor-infiltrating lymphocytes (TILs) with a truncated IL-2 gene allows these cells to produce high levels of IL-2 and proliferate independently, suggesting a promising approach for enhancing adoptive immunotherapy in melanoma treatment.

Although the TILs can initially proliferate autonomously due to the autocrine loop created by IL-2 production, the expression of the IL-2 gene decreases after 2 to 3 weeks, indicating a need for strategies to maintain IL-2 expression over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced interleukin-2 production in human tumor-infiltrating lymphocytes engineered by 3'-truncated interleukin-2 gene. Yamaue, H., Kashmiri, SV., De Filippi, R., et al.[2019]

In a study involving 69 patients with metastatic melanoma, unselected young tumor-infiltrating lymphocytes (TILs) showed a higher response rate (35%) compared to CD8(+)-enriched TILs (20%), although the difference was not statistically significant.

The research suggests that unselected young TILs may be more effective and easier to prepare than CD8(+)-enriched TILs, as the latter did not demonstrate superior therapeutic potency despite being more complex to produce.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma. Dudley, ME., Gross, CA., Somerville, RP., et al.[2021]

In a five-year trial involving 49 patients with relapsing metastatic stage III melanoma, the combination of tumor-infiltrating lymphocytes (TIL) and interleukin-2 (IL-2) did not show a statistically significant improvement in disease-free survival compared to a control group that received no treatment.

The safety profile of TIL + IL-2 was good, with no significant differences in relapse rates or mortality between the treatment and control groups, suggesting that while the treatment was safe, it did not provide the expected benefits over abstention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor infiltrating lymphocytes as adjuvant treatment in stage III melanoma patients with only one invaded lymph node after complete resection: results from a multicentre, randomized clinical phase III trial. Khammari, A., Nguyen, JM., Leccia, MT., et al.[2020]

In a study of 31 melanoma patients treated with intralesional IL-2, 32% achieved a pathologic complete response (pCR), which was linked to significantly improved progression-free survival (PFS).

The presence of a higher CD8+ T cell infiltrate in lesions correlated with better treatment outcomes, suggesting that an enhanced immune response may be a key mechanism behind the efficacy of IL-2 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pathologic complete response to intralesional interleukin-2 therapy associated with improved survival in melanoma patients with in-transit disease. Hassan, S., Petrella, TM., Zhang, T., et al.[2015]

The administration of IL-2 in clinical trials for advanced malignant melanoma shows that the dose and schedule significantly affect both the immune response and the side effects experienced by patients.

Using a standardized dose and schedule of IL-2 across multiple trials allows for better comparison of results regarding toxicity and clinical effectiveness, paving the way for more effective combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interleukin-2 alone and in combination with other cytokines in melanoma: the investigational approach at the University of Texas M.D. Anderson Cancer Center. Parkinson, DR., Talpaz, M., Lee, KH., et al.[2019]

In a phase-I study involving 12 melanoma patients, recombinant interleukin 2 (rIL2) was administered safely at doses ranging from 100 to 800 micrograms/m2, with no major organ toxicity observed, although side effects like fever and low serum potassium were noted.

The treatment led to a rapid depletion of peripheral blood lymphocytes followed by a significant rebound in their numbers and enhanced cytotoxicity against tumor cells, indicating a potential immune response, but no major objective tumor responses were achieved.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo activation of lymphocytes in melanoma patients receiving escalating doses of recombinant interleukin 2. Gambacorti-Passerini, C., Radrizzani, M., Marolda, R., et al.[2019]

Recombinant interleukin-2 is an effective immunomodulating agent that has shown promising results in treating renal cell carcinoma and melanoma, particularly in patients who do not respond well to conventional therapies.

While it can lead to significant adverse effects like hypotension and renal dysfunction, these effects are generally reversible, and its administration requires careful monitoring in a critical-care setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant interleukin-2: a biological response modifier. Kintzel, PE., Calis, KA.[2007]

In a phase I clinical trial involving 33 patients with advanced colon cancer or malignant melanoma, recombinant interleukin-2 (rIL-2) was found to enhance immune function, showing significant immune modulation at doses of 1 x 10(7) and 3 x 10(7) U/m2/d, including increased natural killer (NK) activity and lymphocyte counts.

The maximum tolerated dose was established at 3 x 10(7) U/m2/d, with moderate and reversible side effects, and two patients with melanoma achieved partial responses, suggesting that this IL-2 regimen could be a promising approach for immune enhancement in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I clinical trial of recombinant interleukin-2 by periodic 24-hour intravenous infusions. Creekmore, SP., Harris, JE., Ellis, TM., et al.[2017]

Interleukin-2 (IL-2) is crucial for activating T cells and has shown the ability to induce tumor regressions in both animal models and humans, primarily through the activation of cytotoxic effector cells like lymphokine-activated killer (LAK) cells.

Ongoing Phase I and II trials are investigating various administration methods of IL-2, both alone and in combination with other treatments, to enhance its antitumor effects while managing its dose-related toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The immunotherapy of human cancer with interleukin 2: present status and future directions. Kolitz, JE., Mertelsmann, R.[2019]

TILs (tumor-infiltrating lymphocytes) from melanoma patients showed good proliferation and targeted cytotoxicity against tumor cells before IL-2 therapy, but their ability to proliferate decreased significantly during and after IL-2 treatment.

Despite the reduced responsiveness of TILs to IL-2 during therapy, there was a notable decrease in live tumor cells in all nine patients studied, indicating that IL-2-based therapies can effectively reduce tumor burden even if TILs become temporarily less responsive.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunological properties of melanoma tumor-infiltrating lymphocytes before and after IL-2-based biotherapies. Itoh, K., Balch, CM., Murray, JL., et al.[2007]

In a study of 20 patients with metastatic malignant melanoma previously treated with interleukin-2, 55% achieved an objective partial response to combination chemotherapy (BCDT), indicating that this treatment can still be effective even after IL-2 therapy.

The most common side effect was mild nausea in all patients, but persistent thrombocytopenia limited further treatment, highlighting the need for careful monitoring of blood cell counts during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effective chemotherapy for melanoma after treatment with interleukin-2. Richards, JM., Gilewski, TA., Ramming, K., et al.[2019]

References

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

Enhanced interleukin-2 production in human tumor-infiltrating lymphocytes engineered by 3'-truncated interleukin-2 gene. [2019]

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

Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma. [2021]

3. Germany pubmed.ncbi.nlm.nih.gov

Tumor infiltrating lymphocytes as adjuvant treatment in stage III melanoma patients with only one invaded lymph node after complete resection: results from a multicentre, randomized clinical phase III trial. [2020]

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

Pathologic complete response to intralesional interleukin-2 therapy associated with improved survival in melanoma patients with in-transit disease. [2015]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Interleukin-2 alone and in combination with other cytokines in melanoma: the investigational approach at the University of Texas M.D. Anderson Cancer Center. [2019]

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

In vivo activation of lymphocytes in melanoma patients receiving escalating doses of recombinant interleukin 2. [2019]

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

Recombinant interleukin-2: a biological response modifier. [2007]

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

A phase I clinical trial of recombinant interleukin-2 by periodic 24-hour intravenous infusions. [2017]

9. England pubmed.ncbi.nlm.nih.gov

The immunotherapy of human cancer with interleukin 2: present status and future directions. [2019]

10. Greece pubmed.ncbi.nlm.nih.gov

Immunological properties of melanoma tumor-infiltrating lymphocytes before and after IL-2-based biotherapies. [2007]

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

Effective chemotherapy for melanoma after treatment with interleukin-2. [2019]