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.

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.

Introduction:  Stimulation of the occipital nerves is becoming more widely accepted in the treatment of occipital neuritis and migraine disorders. Objective:  Presently, equipment available for spinal cord stimulation is adapted for insertion into the subcutaneous space over the occipital nerves. Many technical factors need to be reassessed to optimize the therapy. Methods:  We performed a retrospective review of patients implanted from 2003 to 2007 at a single center. We aimed to analyze the rate of surgical complications related to implantation technique. A total of 28 patients were present for analysis. Patients were followed up to 60 months with a mean follow‐up of 21 months. Results:  There is a 32% revision rate for electrode migration or displacement, 3.6% removal rate for infection, and a 21% removal rate for lack of efficacy. Although not well studied secondary to small patient populations, this was consistent with a review of the literature which demonstrated a 10–60% revision rate. Other factors such as anchoring strategy, strain relief, and battery location were all considered in the analysis and will be presented. A major determination was that use of a second incision with an additional strain relief loop had only a 10% revision rate of the lead while those without this additional strain relief loop had a 62.5% revision rate. Conclusion:  Many technical factors need to be addressed for optimization of occipital nerve stimulation.

#09-C-0079; Results.

IntroductionHereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with variants in E-cadherin (CDH1), diffuse gastric cancer and lobular breast cancer. There is considerable heterogeneity in its clinical manifestations. This study aimed to determine associations between CDH1 germline variant status and clinical phenotypes of HDGC.MethodsOne hundred and fifty-two HDGC families, including six previously unreported families, were identified. CDH1 gene-specific guidelines released by the Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel were applied for pathogenicity classification of truncating, missense and splice site CDH1 germline variants. We evaluated ORs between location of truncating variants of CDH1 and incidence of colorectal cancer, breast cancer and cancer at young age (gastric cancer at <40 or breast cancer <50 years of age).ResultsFrequency of truncating germline CDH1 variants varied across functional domains of the E-cadherin receptor gene and was highest in linker (0.05785 counts/base pair; p=0.0111) and PRE regions (0.10000; p=0.0059). Families with truncating CDH1 germline variants located in the PRE-PRO region were six times more likely to have family members affected by colorectal cancer (OR 6.20, 95% CI 1.79 to 21.48; p=0.004) compared with germline variants in other regions. Variants in the intracellular E-cadherin region were protective for cancer at young age (OR 0.2, 95% CI 0.06 to 0.64; p=0.0071) and in the linker regions for breast cancer (OR 0.35, 95% CI 0.12 to 0.99; p=0.0493). Different CDH1 genotypes were associated with different intracellular signalling activation levels including different p-ERK, p-mTOR and β-catenin levels in early submucosal T1a lesions of HDGC families with different CDH1 variants.ConclusionType and location of CDH1 germline variants may help to identify families at increased risk for concomitant cancers that might benefit from individualised surveillance and intervention strategies.

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