A Pilot Study Using Short-Term Cultured Anti-Tumor Autologous Lymphocytes

A Pilot Study Using Short-Term Cultured Anti-Tumor Autologous Lymphocytes Following a Lymphocyte Depleting Regimen in Metastatic Melanoma

To determine the feasibility and safety of administering a regimen of TIL/IL-2, using a cell product manufactured in the Yale Advanced Cell Therapy Laboratories, in subjects with metastatic melanoma who are not responding or have progressed after receiving prior therapy with a PD-1/PD-L1 antagonist used alone or in combination with anti-CTLA-4. Additionally, a second cohort of patients with metastatic melanoma who are not responding or have progressed after receiving prior therapy with a PD-1/PD-L1 antagonist alone or in combination with anti-CTLA-4 will receive anti-PD-1 and anti-CTLA-4 therapy with Nivolumab and Ipilimumab.

The objectives of this study have been expanded since its original registration to inlcude an additional cohort of patients (now designated Cohort 1 and Cohort 2). Cohort 1 is the original group of patients described in the initial registration of the study.

Cohort 1 Objectives:

• To determine the feasibility and safety of administering a regimen of TIL/IL-2, using a cell product manufactured in the Yale Advanced Cell Therapy Laboratories, in subjects with metastatic melanoma who are not responding or have progressed after receiving prior therapy with a PD-1/PD-L1 antagonist used alone or in combination with anti-CTLA-4.
• To assess for evidence of clinical activity.
• To conduct a preliminary assessment of the TCR clonotypes present in marker positive CD8+ cells (4-1BB, LAG-3, TIM-3, PD-1) versus marker-negative CD8+ T-cells early in the expansion cultures and compare to clonotypes late in the final product and in peripheral blood lymphocytes (PBL) 1 and 2 months post infusion.

Cohort 2 Objectives:

• To determine the feasibility and safety of administering a regimen of TIL/IL-2, using a cell product manufactured in the Yale Advanced Cell Therapy Laboratories, followed by anti-PD-1 and anti-CTLA-4 therapy with Nivolumab and Ipilimumab in subjects with metastatic melanoma who are not responding or have progressed after receiving prior therapy with a PD-1/PD-L1 antagonist alone or in combination with anti-CTLA-4.
• To evaluate the efficacy of TIL/IL-2 therapy in combination with subsequent anti-PD-1 Nivolumab and anti-CTLA-4 Ipilimumab by assessing the objective response rate by immune-related RECIST (irRECIST).
• To conduct a preliminary assessment of the TCR clonotypes present in marker positive CD8+ cells (e.g. 4-1BB, LAG-3, TIM-3, PD-1) versus marker-negative CD8+ T-cells early in the expansion cultures and compare to clonotypes late in the final product and in peripheral blood lymphocytes (PBL) 1 and 2 months post infusion.

Inclusion Criteria:

For Cohorts 1 and 2:

• Metastatic melanoma;
• A metastatic lesion at least 1.5 cm in diameter that can be removed surgically
• Measurable or evaluable disease not including the resected lesion
• ECOG PS of 0 or 1 prior to cell harvest
• Assessment by the treating physician that ECOG performance status of no higher than 2 can be maintained at least for the period of cell generation, lymphoablation, cell infusion and IL-2 administration (for at least 6 weeks following cell harvest)
• Tumor refractory to or progressing following prior PD-1/PD-L1 therapy alone or in combination with an anti-CTLA-4 agent
• Ability to understand risks and benefits of the treatment and to give informed consent

Exclusion Criteria:

For Cohorts 1 and 2:

• Received prior cell transfer therapy that included non-myeloablative or ablative chemotherapy
• Any significant major organ dysfunction (see protocol)
• Residual toxicity > gr1 from immune checkpoint inhibitor other than persistent endocrinopathy on hormone replacement; all symptoms of prior colitis and enteritis must have resolved completely as assessed by history
• Any contraindication to neutropenia or thrombocytopenia for up to 2 weeks (no active major infection, no site of active, clinically significant bleeding)
• Concurrent major medical illnesses
• Any form of immunodeficiency
• Requirement for steroids > 10 mg prednisone daily or equivalent
• Severe hypersensitivity to any of the agents used in this study
• Contraindications for IL-2 administration

At the time of lymphoablation subjects must meet baseline eligibility criteria with the following additions and exceptions:

• Confirmation by lab that cell product can be ready for harvest and infusion within 7 days

For Cohort 2 only:

At the time of the start of anti-PD-1/anti-CTLA-4 therapy, subjects must meet baseline eligibility criteria with the following additions and exceptions:

• Patient cannot have a steroid requirement > 10 mg prednisone daily or equivalent
• Patients who have received prior PD-1/PD-L1 antagonist therapy and developed severe autoimmune disease precluding further immune checkpoint therapy
• Any organ dysfunction that makes the subject ineligible for anti-PD1 and anti-CTLA-4 treatment as deemed by the treating investigator
• ECOG PS of 0-2
• Hgb of at least 8.0 gm/dl (may be transfused to this level)
• Creatinine not greater than 2.5 mg/dl
• AST or ALT not > 5x ULN and total bilirubin not > 2.5 mg/dl
• No clinically significant change in major organ function compared to initial eligibility evaluation
• Prior to initiating the lymphoablation regimen, there can be no untreated brain lesion > 1.0 cm, and/or with significant evidence of hemorrhage. Subjects may begin lymphoablation no less than 1 full day after completing WBRT or stereotactic radiotherapy for brain lesions.