Activating NRAS mutations are found in 15-20% of melanomas. Immune therapies have become a mainstay in advanced melanoma treatment. We sought to evaluate whether tumor genotype (e.g. NRAS mutations) correlate with benefit from immune therapy in melanoma. We identified 229 melanoma patients treated with immune therapies (interleukin-2, ipilimumab, or anti-programmed cell-death-1/ligand-1 (PD-1/PD-L1)) at three centers, and compared clinical outcomes following immune therapy for patients with or without NRAS mutations. Of the 229 melanoma patients, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF WT. The NRAS-mutant cohort had superior or a trend to superior outcomes compared to the other cohorts in terms of response to first-line immune therapy (28% vs. 16%, p=0.04), response to any line of immune therapy (32% vs. 20%, p=0.07), clinical benefit (response + stable disease lasting ≥24 weeks; 50% vs. 31%, p<0.01), and progression-free survival (median 4.1 vs. 2.9 months, p=0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort (clinical benefit rate 73% vs. 35%). In an independent group of patient samples, NRAS-mutant melanoma had higher PD-L1 expression (although not statistically significant) compared to other genotypes (8/12 vs. 9/20 samples with ≥1% expression; 6/12 vs 6/20 samples with ≥5% expression), suggesting a potential mechanism for the clinical results. This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared to other genetic subtypes. If confirmed by prospective studies, this may be explained in part by high rates of PD-L1 expression.

While advanced stage melanoma patients have a median survival of less than a year, adoptive T cell therapy can induce durable clinical responses in some patients. Successful adoptive T cell therapy to treat cancer requires engraftment of anti-tumor T lymphocytes that not only retain specificity and function in vivo but also display an intrinsic capacity to survive. To date, adoptively transferred anti-tumor CD8+ T lymphocytes (CTL) have had limited life spans unless the host has been manipulated. To generate CTL that possess an intrinsic capacity to persist in vivo, we developed a human artificial antigen presenting cell system that can educate anti-tumor CTL to acquire both a central memory and effector memory phenotype as well as the capacity to survive in culture for prolonged periods of time. In the present report, we examined whether anti-tumor CTL generated using this system could function and persist in patients. Here, we showed that MART1-specific CTL, educated and expanded using our artificial antigen presenting cell system, could survive for prolonged periods in advanced stage melanoma patients without previous conditioning or cytokine treatment. Moreover, these CTL trafficked to the tumor, mediated biological and clinical responses, and established anti-tumor immunologic memory. Therefore, this approach may broaden the availability of adoptive cell therapy to patients both alone and in combination with other therapeutic modalities.

Purpose Ipilimumab was the first FDA-approved agent for advanced melanoma to improve survival and represents a paradigm shift in melanoma and cancer treatment. Its unique toxicity profile and kinetics of treatment response raise novel patient education challenges. We assessed patient perceptions of ipilimumab therapy across the treatment trajectory. Methods Four patient cohorts were assessed at different time points relative to treatment initiation: (1) prior to initiation of ipilimumab (n = 10), (2) at weeks 10–12 before restaging studies (n = 11), (3) at week 12 following restaging studies indicating progression of disease (n = 10), and (4) at week 12 following restaging studies indicating either a radiographic response or disease stability (n = 10). Patients participated in a semistructured qualitative interview to assess their experiences with ipilimumab. Quality of life was assessed via the Functional Assessment of Cancer Therapy-General and its Melanoma-specific module. Results Perceived quality of life was comparable across cohorts, and a majority of the sample understood side effects from ipilimumab and the potential for a delayed treatment response. Patients without progression of disease following restaging studies at week 12 held more positive views regarding ipilimumab compared to patients who had progressed. Conclusion Patients generally regarded ipilimumab positively despite the risk of unique toxicities and potential for delayed therapeutic responses; however, those with progression expressed uncertainty regarding whether taking ipilimumab was worthwhile. Physician communication practices and patient education regarding realistic expectations for therapeutic benefit as well as unique toxicities associated with ipilimumab should be developed so that patients can better understand the possible outcomes from treatment.

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