Background Uveal melanoma is a rare tumor with no established treatments once metastases develop. Although a variety of immune based therapies have demonstrated efficacy in metastatic cutaneous melanoma, their use in ocular variants has been disappointing. Recently, adoptive T cell therapy has shown salvage responses in multiple refractory solid tumors. Thus, we sought to determine if adoptive transfer of autologous tumor infiltrating lymphocytes (TIL) could mediate regression of metastatic uveal melanoma. Methods In this ongoing single-center, two-stage phase 2, single-arm trial, patients with histologically confirmed metastatic ocular melanoma (aged ≥ 16 years) were enrolled. Key eligibility criteria were an ECOG performance status of 0 or 1, progressive metastatic disease, and adequate hematological, renal, and hepatic function. Metastasectomy operations were performed to procure tumor tissue to generate autologous TIL cultures, which then underwent large scale ex vivo expansion. Patients were treated with lymphodepleting conditioning chemotherapy followed by intravenous infusion of autologous TIL and high-dose interleukin-2. The primary end-point was objective tumor response in evaluable patients per protocol using Response to Evaluation Criteria in Solid Tumors (RECIST), version 1.0. An interim analysis of this ongoing trial is currently being reported. The trial is registered with ClinicalTrials.gov as NCT01814046. Findings From the completed first stage and ongoing expansion stage of this trial, a total of twenty-one consecutive metastatic uveal melanoma patients were enrolled and received TIL therapy. Seven of 20 evaluable patients demonstrated objective tumor regression (35%; 95% CI: 16%-59%). Among the responders, six patients achieved partial response (PR), two of which are ongoing and have not reached maximum response. One patient achieved complete response (CR) of numerous hepatic metastases currently ongoing at 21 months post therapy. Three of the responders were refractory to prior immune checkpoint blockade. Common grade 3 or more toxic effects were related to the lymphodepleting chemotherapy regimen and included lymphopenia, neutropenia, and thrombocytopenia (21 [100%] of patients for each toxicity); anemia (14 [67%] of patients); infection (6 [29%] of patients). There was one treatment-related mortality secondary to sepsis induced multi-organ failure. Interpretation To our knowledge, this is the first report describing the ability of adoptive transfer of autologous TIL to mediate objective tumor regression in patients with metastatic uveal melanoma. These initial results challenge the belief that metastatic uveal melanoma is immunotherapy resistant and support the further investigation of immune based therapies for this cancer. Refinement of this T cell therapy is critical to improve the frequency of clinical responses and the general applicability of this treatment modality. This research was fully supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research.

Therapeutic subunit vaccines based on tumor-associated antigens (TAA) represent an attractive approach for the treatment of cancer. However, poor immunogenicity of TAAs requires potent adjuvants for therapeutic efficacy. We recently proposed the tumor necrosis factor family costimulatory ligands as potential adjuvants for therapeutic vaccines and, hence, generated a soluble form of 4-1BBL chimeric with streptavidin (SA-4-1BBL) that has pleiotropic effects on cells of innate, adaptive, and regulatory immunity. We herein tested whether these effects can translate into effective cancer immunotherapy when SA-4-1BBL was also used as a vehicle to deliver TAAs in vivo to dendritic cells (DCs) constitutively expressing the 4-1BB receptor. SA-4-1BBL was internalized by DCs upon receptor binding and immunization with biotinylated antigens conjugated to SA-4-1BBL resulted in increased antigen uptake and cross-presentation by DCs, leading to the generation of effective T-cell immune responses. Conjugate vaccines containing human papillomavirus 16 E7 oncoprotein or survivin as a self-TAA had potent therapeutic efficacy against TC-1 cervical and 3LL lung carcinoma tumors, respectively. Therapeutic efficacy of the vaccines was associated with increased CD4 + T and CD8 + T-cell effector and memory responses and

Purpose Uveal melanoma (UM) is a rare melanoma variant with no effective therapies once metastases develop. Although durable cancer regression can be achieved in metastatic cutaneous melanoma (CM) with immunotherapies that augment naturally existing anti-tumor T cell responses, the role of these treatments for metastatic UM remains unclear. We sought to define the relative immunogenicity of these two melanoma variants and determine whether endogenous anti-tumor immune responses exist against UM. Experimental Design We surgically procured liver metastases from UM (n=16) and CM (n=35) patients and compared the attributes of their respective tumor cell populations and their infiltrating T cells (TIL) using clinical radiology, histopathology, immune assays and whole exomic sequencing. Results Despite having common melanocytic lineage, UM and CM metastases differed in their melanin content, tumor differentiation antigen expression, and somatic mutational profile. Immunologic analysis of TIL cultures expanded from these divergent forms of melanoma revealed CM TIL were predominantly composed of CD8+ T cells, while UM TIL were CD4+ dominant. Reactivity against autologous tumor was significantly greater in CM TIL compared to UM TIL. However, we identified TIL from a subset of UM patients which had robust anti-tumor reactivity comparable in magnitude to CM TIL. Interestingly, the absence of melanin pigmentation in the parental tumor strongly correlated with the generation of highly reactive UM TIL. Conclusions The discovery of this immunogenic group of UM metastases should prompt clinical efforts to determine whether patients who harbor these unique tumors can benefit from immunotherapies that exploit endogenous anti-tumor T cell populations.