In Vivo Persistence of Adoptively-Transferred TIL Cultured With Akti in People With Metastatic Melanoma

Background: * Adoptive cellular immunotherapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) can mediate regression of bulky metastatic melanoma when administered with high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen consisting of cyclophosphamide and fludarabine. * Regression of tumor in mouse models and humans strongly correlates with anti-tumor T cells that exhibit features of immunologic memory and have a capacity to persist for long periods after adoptive-transfer into tumor-bearing hosts. * In our preclinical work with TIL, we have identified a pharmacologic inhibitor of AKT that promotes features of immunologic memory in TIL (as evidenced by transcriptomic, proteomic, metabolomic, and functional assays described in the Background section). Consistently, AKT inhibition of human TIL significantly enhances persistence after adoptive-transfer into an immunodeficient mouse model. * We therefore aim to evaluate whether pharmacologic inhibition of AKT in TIL may enhance persistence after adoptive-transfer into patients with advanced melanoma. Objectives: * Primary objective: * To determine whether ACT using TIL cultured in a pharmacologic inhibitor of AKT (during ex vivo expansion) results in enhanced in vivo persistence of TIL after adoptive transfer into autologous patients with advanced melanoma. * Secondary objectives: * Determine the toxicity profile of this treatment regimen. * Determine whether ACT using a combination of AKTi-treated and conventional TIL can mediate tumor regression by RECIST (Response Evaluation Criteria in Solid Tumors) guidelines in patients with advanced melanoma. Eligibility: * Age greater than or equal to 18 and less than or equal to 70 years * Evaluable metastatic melanoma * Metastatic melanoma lesion suitable for surgical resection for the preparation of TIL * No contraindications to high-dose aldesleukin administration * No concurrent major medical illnesses or any form of immunodeficiency Design: * Patients with metastatic melanoma will undergo ACT in conventional manner, with the exception that half of tumor fragments from which TIL are isolated will be cultured in the presence of a pharmacologic AKT inhibitor. Prior to infusion of TIL, the AKT inhibitor (hereafter AKTi) will be washed from the therapeutic TIL product and will not be systemically administered. Each patient will receive a 1:1 mixture of conventional TIL and AKTi-treated TIL. To evaluate persistence of AKTi-treated and conventional TIL after adoptive co-transfer, we will perform high-throughput deep sequencing of the TCR V-beta CDR3 region of TIL from the infusion-bag and from peripheral blood when sufficient lymphocyte reconstitution (\>200 lymphocytes/microliter) has occurred and approximately 4-6 weeks after infusion. * Up to 20 patients may be enrolled over 20-24 months.