Markovic, Svetomir N.

A vaccine that could expand melanoma-specific T cells might reduce the risk of recurrence of resected melanoma and could provide an alternative or adjunct to standard immunotherapy options. We tested the safety and immunogenicity of a vaccine coupling a melanoma-associated peptide with a xenogenic peptide (to promote epitope spreading) and/or resiquimod (to activate antigen-presenting cells). HLA-A2-positive patients with resected stage II, III, and IV melanoma were assigned to treatment on one of three schedules. All patients received three subcutaneous doses of the peptide MART-1a mixed with Montanide. In addition, patients on schedule 1 received the xenoantigen peptide Gag267–274, patients on schedule 2 received topical resiquimod, and patients on schedule 3 received both Gag267–274 and resiquimod. Blood samples were tested for the frequency of antigen-specific T cells by tetramer assay, as well as immune cell subtypes and plasma cytokine levels. Patients enrolled from October 2012 to December 2014, with 10 patients enrolling to each schedule. The most common adverse events were injection site reaction (26 patients) and fatigue (15 patients). Tetramer analysis revealed antigen-specific responses (defined as doubling of MART-1a-specific T cells from pretreatment to post-treatment) in 20, 60, and 40% of patients treated on schedules 1, 2, and 3, respectively. Vaccine treatment consisting of MART-1a peptide, Gag267–274, Montanide, and topical resiquimod was well-tolerated. The addition of the Gag267–274 xenoantigen was not associated with an increase in the response to MART-1a, whereas use of topical resiquimod was associated with a higher frequency of MART-1a-specific T-cell responses that did not meet statistical significance.

Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years.

ObjectiveTo describe the prevalence, clinical presentation, and management of rheumatic immune‐related adverse effects (Rh‐irAEs) from immune checkpoint inhibitor (ICI) therapy.MethodsFrom a database of all patients who received any ICI at the Mayo Clinic Rochester, Minnesota campus between January 1, 2011 and March 1, 2018, we retrospectively identified those with Rh‐irAEs, using diagnostic codes, search terms, and manual chart review.ResultsOf the 1,293 patients who received any ICI, Rh‐irAEs were clinically diagnosed in 43. Eighteen patients with Rh‐irAEs who received ICI therapy elsewhere were also analyzed. Clinical syndromes included inflammatory arthritis (n = 34 [prevalence 2%]), myopathy (n = 10), and other rheumatic syndromes (n = 17). Inflammatory arthritis was most commonly polyarticular, and glucocorticoid treatment was required in 26 patients (76%). The mean ± SD duration of treatment was 18 ± 18 weeks. Five patients (15%) also received disease‐modifying antirheumatic drugs, and ICI therapy had to be discontinued in 3 patients (9%). Myopathy was treated with glucocorticoids in all cases (mean ± SD treatment duration 15 ± 17 weeks) and led to 2 deaths and permanent ICI discontinuation in 9 patients (90%). Other syndromes included connective tissue diseases, vasculitis, polymyalgia rheumatica–like syndrome, and flare of preexisting rheumatic disease. Most (71%) were treated with immunosuppression, with 12% requiring ICI discontinuation.ConclusionThis study represents the largest cohort of patients with Rh‐irAEs reported to date. Most patients received long courses of immunosuppressive treatment, although discontinuation of ICI therapy was required in only a minority.

11534 Background: To date, there are no validated blood-based biomarkers of predicting response to PD-1 blockade. We previously reported that Bim is a downstream signaling molecule of the PD-1 pathway, and that measurement of Bim levels in circulating T-cells may predict and monitor responses to anti–PD-1 therapy in melanoma. We have identified the existence of sPD-L1 in cancer patients and showed that the sPD-L1 is biologically active and capable of triggering apoptosis in activated T-cells. Here we evaluated T cell Bim and sPD-L1 in the peripheral blood (PB) as biomarkers of response in a cohort of patients with metastatic melanoma and lung cancer undergoing anti-PD1 therapy. Methods: 60 pts treated with anti-PD-1 had PB collected at baseline and at radiographic tumor evaluation. Frequencies of Bim+ T cells and Bim median fluorescence intensity (MFI) were measured by flow cytometry in gated tumor-reactive CD11ahighPD1+ CD8+ T cells. We also measured levels of sPD-L1 at baseline and serially during treatment with sPD-L1 ELISA. Baseline Bim and sPD-L1 levels and percent change in Bim levels in patients (pts) who had a radiographic response (CR/PR) were compared to those who had progressive disease (PD) at 12 wks. Results: Similarly to previously reported preliminary data, pts with objective response (CR/PR, 15/60) after 4 cycles of anti-PD1 therapy had higher frequency of Bim T cells at baseline compared to pts with PD (16/60) (mean 43% vs. 30%, P = 0.0484). The frequencies of Bim+ T cells decreased significantly after the first 3 months of treatment in responders compared with progressors (mean -16% vs. + 40% P = 0.0111). High baseline sPD-L1 were associated with progression on anti-PD1 therapy (mean 2.8 ng/mL vs. 0.7 ng/mL, p = 0.07, n = 13) and the levels increased by the first tumor assessment in patients resistant to anti-PD-1. Conclusions: Measurements of Bim and sPD-L1 levels may help to select patients who are likely to benefit from anti-PD1 monotherapy versus combinatorial strategies, and provide a new non-invasive way to monitor response to anti-PD-1 blockade. A larger validation study is underway.

e21057 Background: BRAF, NRAS, CDKN2A and P53 mutations are commonly observed pathogenic mutations in cutaneous melanoma. The influence of mutations such as BRAF, NRAS, CDKN2A and P53 on treatment response in the PD1 inhibitor era has not been well defined. Methods: This study included patients with melanoma with a cutaneous or unknown primary. All patients had genomic profiling with the Mayo Clinic 50-gene solid tumor mutation panel. Treatment response to first line immunotherapy with PD1, CTLA-4, or combination PD1/CTLA-4 inhibitors were assessed by response rate and time-to-progression (TTP) rate at 12 months. Each patient outcome was stratified by non-mutually exclusive gene mutation status into BRAF, NRAS, P53, CDKN2A, or quadruple negative (N4) groups. Results: Genomic profiling was performed on 208 patients, of whom 102 received first line immunotherapy. Most patients received a PD1 inhibitor (n = 62), followed by CTLA-4 inhibitor (n = 34), and combination therapy (n = 6). A trend towards improved outcomes was observed in CDKN2A and BRAF mutated patients with worse outcomes noted in P53, N4, and NRAS patients. The percent without progression at 12 months were BRAF 52.2%, CDKN2A 58.2%, NRAS 30.5%, P53 37.7%, and N4 26.7% (see table below). Response rates were BRAF 46.4%, CDKN2A 38.5%, NRAS 22.2%, P53 40.0%, and N4 33.3%. Conclusions: There is a trend towards improved outcomes with immunotherapy in BRAF and CDKN2A mutated patients while P53, NRAS and N4 patients have inferior outcomes. [Table: see text]