TIL + Pembrolizumab for Melanoma

Recruiting at 1 trial location

Overseen By NCI/Surgery Branch Recruitment Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Steroids, Investigational agents

Disqualifiers: Pregnancy, Immunodeficiency, Infections, Autoimmune, 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

Compensation: Varies

Number of Visits: 10

Duration: 4-6 weeks

170 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that patients must have completed any prior systemic therapy at the time of enrollment, which might imply stopping certain treatments. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment TIL + Pembrolizumab for Melanoma?

Research shows that tumor-infiltrating lymphocytes (TILs) and pembrolizumab, a drug that blocks a protein called PD-1, can help the immune system fight cancer. While studies specifically on melanoma are limited, similar treatments have shown promise in other cancers, suggesting potential benefits for melanoma as well. ^{1 2 3 4 5}

Is the combination of TIL and Pembrolizumab safe for humans?

Pembrolizumab, also known as KEYTRUDA, has been shown to have a generally acceptable safety profile in various studies, including those for melanoma and multiple myeloma. Some side effects have been reported, such as diarrhea and lung inflammation, but they were manageable and resolved without lasting effects. ^{3 4 6 7 8}

How is the TIL + Pembrolizumab treatment for melanoma different from other treatments?

The TIL + Pembrolizumab treatment is unique because it combines tumor-infiltrating lymphocytes (TIL), which are immune cells extracted from the patient's own tumor, with pembrolizumab, a drug that helps the immune system attack cancer cells. This combination aims to enhance the body's immune response against melanoma, offering a novel approach compared to standard treatments that typically involve only drugs like pembrolizumab. ^{4 7 8 9 10}

What is the purpose of this trial?

Background: Cell therapy is an experimental cancer therapy. It takes young tumor infiltrating lymphocytes (Young TIL) cells from a person s tumors and grows them in a lab. Then they are returned to the person. Researchers think adding the drug pembrolizumab might make the therapy more effective. Objective: To test if adding pembrolizumab to cell therapy is safe and effective to shrink melanoma tumors. Eligibility: People ages 18-72 years with metastatic melanoma OF THE SKIN Design: Participants will be screened with: Physical exam CT, MRI, or PET scans X-rays Heart and lung function tests if indicated Blood and urine tests Before treatment, participants will have: A piece of tumor taken from a biopsy or during surgery in order to grow TIL cells Leukapheresis: Blood flows through a needle in one arm and into a machine that removes white blood cells. The rest of the blood returns through a needle in the other arm. An IV catheter placed in the chest for getting TIL cells, aldesleukin, and pembrolizumab (if assigned) Participants will stay in the hospital for treatment. This includes: Daily chemotherapy for 1 week For some participants, pembrolizumab infusion 1 day after chemotherapy TIL cell infusion 2-4 days after chemotherapy, then aldesleukin infusion every 8 hours for up to 12 doses Filgrastim injections to help restore your blood counts Recovery for 1-3 weeks After treatment, participants will: Take an antibiotic and an antiviral for at least 6 months, as applicable If assigned, have pembrolizumab treatment every 3 weeks for 3 more doses. They may have another round. Have 2-day follow-up visits every 1-3 months for 1 year and then every 6 months

Research Team

Stephanie L Goff, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults aged 18-70 with metastatic melanoma of the skin, who have had at least one prior treatment. Eligible participants may have up to three small, stable brain tumors and must practice birth control. Excluded are those with severe allergies, immune deficiencies, active infections or major illnesses, pregnant or breastfeeding women, and anyone on systemic steroids.

Inclusion Criteria

Measurable metastatic melanoma with at least one lesion that is resectable for TIL generation

Confirmation of diagnosis of metastatic melanoma by the Laboratory of Pathology of NCI

Patients must have received at least one prior therapy for metastatic melanoma

Exclusion Criteria

Patients who are receiving any other investigational agents

Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant

Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for physical exams, imaging, and lab tests

Treatment

Participants receive a non-myeloablative lymphodepleting regimen, TIL infusion, and high-dose IL-2. Some participants also receive pembrolizumab.

4-6 weeks

Inpatient stay for chemotherapy, TIL infusion, and IL-2 administration

Recovery

Participants recover from treatment and receive supportive care including filgrastim injections.

1-3 weeks

Inpatient stay for recovery and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, with pembrolizumab administered every 3 weeks for 3 more doses if applicable.

1 year

2-day follow-up visits every 1-3 months

Long-term Follow-up

Participants continue to be monitored for progression-free survival and overall survival.

2 years

Follow-up visits every 6 months

Treatment Details

Interventions

• Pembrolizumab
• Young TIL

Trial Overview The trial is testing if adding pembrolizumab (an immunotherapy drug) to adoptive cell therapy using tumor infiltrating lymphocytes (TIL) plus IL-2 is safe and effective for shrinking melanoma tumors. Participants will receive chemotherapy followed by TIL infusion and possibly pembrolizumab.

Participant Groups

Group I: 3/ACT TIL (Pembro contraindicated) Experimental Treatment 4 Interventions

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young TIL + highdose aldesleukin (IL-2)

Group II: 2/ACT TIL + Pembro Experimental Treatment 5 Interventions

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +young TIL + highdose aldesleukin (IL-2) + pembrolizumab

Group III: 1/ACT TIL Experimental Treatment 4 Interventions

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +young TIL + highdose aldesleukin (IL-2)

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 of 107 patients with advanced non-small cell lung cancer (NSCLC) treated with pembrolizumab, a high number of stromal CD4 tumor-infiltrating lymphocytes (TILs) was linked to better progression-free survival (PFS) and overall survival (OS), indicating their potential as a prognostic marker.

Intratumoral CD8 TILs were also found to be significant predictors of overall survival, suggesting that both types of TILs could help identify which patients might benefit most from PD-1 blockade therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic significance of tumor infiltrating lymphocytes on first-line pembrolizumab efficacy in advanced non-small cell lung cancer. Kaira, K., Yamaguchi, O., Kawasaki, T., et al.[2023]

In a study of 1017 melanoma patients, those with any type of tumor-infiltrating lymphocytes (TILs) showed higher rates of tumor regression and lower rates of sentinel lymph node positivity compared to those without TILs, suggesting that TILs may play a role in tumor response.

While brisk TILs (bTILs) were associated with better recurrence-free survival rates (84% at 5 years) compared to non-brisk (nbTILs) and absent TILs, there was no significant link between TIL status and disease-specific survival or response to immune checkpoint blockade therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic Significance of Primary Tumor-Infiltrating Lymphocytes in a Contemporary Melanoma Cohort. Straker, RJ., Krupp, K., Sharon, CE., et al.[2023]

Prior treatments with anti-PD-1 and BRAF-targeted therapies showed limited effectiveness in activating tumor infiltrating lymphocytes (TIL) in patients with metastatic melanoma.

Understanding the mechanisms of action for TIL and anti-PD-1 therapies can help explain varying outcomes in clinical trials and guide the development of more effective cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TIL in Melanoma-Similar Approaches, Different Results, Unanswered Questions. Sznol, M.[2022]

In a Phase II clinical trial involving 22 patients with rare solid tumors, one dose of the anti-PD-1 antibody pembrolizumab led to increased CTLA-4 expression in CD4+ tumor-infiltrating lymphocytes (TIL), indicating a potential change in TIL phenotype after treatment.

However, the CD8+ TIL population showed a reduced ability to secrete cytokines post-treatment, suggesting that while PD-1 blockade may alter TIL characteristics, it could also impair their functional response in some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure to anti-PD-1 causes functional differences in tumor-infiltrating lymphocytes in rare solid tumors. Creasy, CA., Forget, MA., Singh, G., et al.[2020]

In a study using both immune-deficient nude mice and normal A/J mice, the use of anti-PD-1 and anti-PD-L1 antibodies effectively suppressed tumor growth in A/J mice, highlighting the critical role of T lymphocytes in the antitumor immune response.

The research found that increased infiltration of activated CD8+ tumor-infiltrating lymphocytes (TILs) was associated with smaller tumor sizes, suggesting that enhancing CD8+ TIL infiltration could be a promising strategy for treating neuroblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD69 on Tumor-Infiltrating Cells Correlates With Neuroblastoma Suppression by Simultaneous PD-1 and PD-L1 Blockade. Inoue, S., Takeuchi, Y., Horiuchi, Y., et al.[2023]

In the GEM-Pembresid trial, pembrolizumab was tested as a consolidation treatment in multiple myeloma patients with persistent disease, but it only resulted in a decrease in M-protein in 1 out of 17 patients, indicating limited efficacy in this population.

While pembrolizumab had an acceptable safety profile, with some adverse events leading to treatment discontinuation, it did not enhance treatment responses, suggesting that it may not be beneficial as a consolidation therapy for patients with persistent measurable disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab as Consolidation Strategy in Patients with Multiple Myeloma: Results of the GEM-Pembresid Clinical Trial. Puig, N., Corchete-Sánchez, LA., Pérez-Morán, JJ., et al.[2020]

In a study of 103 Chinese patients with advanced melanoma, pembrolizumab demonstrated a 16.7% objective response rate, indicating its effectiveness as a second-line treatment, particularly in aggressive melanoma subtypes.

The treatment was well tolerated, with 84.5% of patients experiencing treatment-related adverse events, but only a small percentage (8.7%) had severe side effects, and no treatment-related deaths occurred.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib Study of Pembrolizumab as Second-Line Therapy for Chinese Patients With Advanced or Metastatic Melanoma (KEYNOTE-151). Si, L., Zhang, X., Shu, Y., et al.[2020]

Pembrolizumab is a monoclonal antibody that blocks the PD-1/PD-L1 interaction, which is crucial for preventing the immune system from attacking tumors, making it a key player in cancer immunotherapy.

It has been approved by the FDA for treating patients with advanced melanoma who have not responded to previous treatments, highlighting its efficacy in managing difficult cases of this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New developments in the management of advanced melanoma - role of pembrolizumab. Improta, G., Leone, I., Donia, M., et al.[2020]

A systematic review of four trials involving 3425 patients found that lower doses of pembrolizumab (2 mg/kg every 3 weeks) are equally effective as higher doses (10 mg/kg) in treating advanced melanoma and non-small-cell lung cancer (NSCLC).

The safety profile of pembrolizumab was similar across different doses, suggesting that the lower dose may be sufficient for routine treatment without compromising efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: a systematic review. Abdel-Rahman, O.[2018]

In a real-world study of 532 patients with advanced melanoma treated with pembrolizumab, the median overall survival was 21.8 months, indicating its effectiveness outside of clinical trials.

Patients with better performance status (ECOG 0-1), normal LDH levels, and no recent corticosteroid use had significantly improved overall survival, highlighting the importance of these factors in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience with pembrolizumab in patients with advanced melanoma: A large retrospective observational study. Liu, FX., Ou, W., Diede, SJ., et al.[2022]

References

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

Prognostic significance of tumor infiltrating lymphocytes on first-line pembrolizumab efficacy in advanced non-small cell lung cancer. [2023]

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

Prognostic Significance of Primary Tumor-Infiltrating Lymphocytes in a Contemporary Melanoma Cohort. [2023]

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

TIL in Melanoma-Similar Approaches, Different Results, Unanswered Questions. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

Exposure to anti-PD-1 causes functional differences in tumor-infiltrating lymphocytes in rare solid tumors. [2020]

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

CD69 on Tumor-Infiltrating Cells Correlates With Neuroblastoma Suppression by Simultaneous PD-1 and PD-L1 Blockade. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Pembrolizumab as Consolidation Strategy in Patients with Multiple Myeloma: Results of the GEM-Pembresid Clinical Trial. [2020]

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

A Phase Ib Study of Pembrolizumab as Second-Line Therapy for Chinese Patients With Advanced or Metastatic Melanoma (KEYNOTE-151). [2020]

8. New Zealand pubmed.ncbi.nlm.nih.gov

New developments in the management of advanced melanoma - role of pembrolizumab. [2020]

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

Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: a systematic review. [2018]

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

Real-world experience with pembrolizumab in patients with advanced melanoma: A large retrospective observational study. [2022]