a pilot study using short-term cultured anti-tumor autologous lymphocytes

Conditions: Metastatic Melanoma

Summary: 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.

Eligibility criteria:
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.