Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of melanoma, version 3.0.

Since the first approval for immune checkpoint inhibitors (ICIs) for the treatment of cutaneous melanoma more than a decade ago, immunotherapy has completely transformed the treatment landscape of this chemotherapy-resistant disease. Combination regimens including ICIs directed against programmed cell death protein 1 (PD-1) with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) agents or, more recently, anti-lymphocyte-activation gene 3 (LAG-3) agents, have gained regulatory approvals for the treatment of metastatic cutaneous melanoma, with long-term follow-up data suggesting the possibility of cure for some patients with advanced disease. In the resectable setting, adjuvant ICIs prolong recurrence-free survival, and neoadjuvant strategies are an active area of investigation. Other immunotherapy strategies, such as oncolytic virotherapy for injectable cutaneous melanoma and bispecific T-cell engager therapy for HLA-A*02:01 genotype-positive uveal melanoma, are also available to patients. Despite the remarkable efficacy of these regimens for many patients with cutaneous melanoma, traditional immunotherapy biomarkers (ie, programmed death-ligand 1 expression, tumor mutational burden, T-cell infiltrate and/or microsatellite stability) have failed to reliably predict response. Furthermore, ICIs are associated with unique toxicity profiles, particularly for the highly active combination of anti-PD-1 plus anti-CTLA-4 agents. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of melanoma, including rare subtypes of the disease (eg, uveal, mucosal), with the goal of improving patient care by providing guidance to the oncology community. Drawing from published data and clinical experience, the Expert Panel developed evidence- and consensus-based recommendations for healthcare professionals using immunotherapy to treat melanoma, with topics including therapy selection in the advanced and perioperative settings, intratumoral immunotherapy, when to use immunotherapy for patients with BRAFV600-mutated disease, management of patients with brain metastases, evaluation of treatment response, special patient populations, patient education, quality of life, and survivorship, among others.

Phase I trial of intratumoral PVSRIPO in patients with unresectable, treatment-refractory melanoma.

BACKGROUND: While programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) antagonists have improved the prognosis for many patients with melanoma, around 60% fail therapy. PVSRIPO is a non-neurovirulent rhinovirus:poliovirus chimera that facilitates an antitumor immune response following cell entry via the poliovirus receptor CD155, which is expressed on tumor and antigen-presenting cells. Preclinical studies show that oncolytic virus plus anti-PD-1 therapy leads to a greater antitumor response than either agent alone, warranting clinical investigation. METHODS: An open-label phase I trial of intratumoral PVSRIPO in patients with unresectable melanoma (American Joint Committee on Cancer V.7 stage IIIB, IIIC, or IV) was performed. Eligible patients had disease progression on anti-PD-1 and V-raf murine sarcoma viral oncogene homolog B (BRAF)/mitogen activated protein kinase kinase (MEK) inhibitors (if BRAF mutant). The primary objective was to characterize the safety and tolerability of PVSRIPO. Twelve patients in four cohorts received a total of 1, 2 or 3 injections of PVSRIPO monotherapy, with 21 days between injections. RESULTS: PVSRIPO injections were well tolerated with no serious adverse events (SAEs) or dose-limiting toxicities (DLTs) reported. All adverse events (AEs) were grade (G) 1 or G2 (G1 pruritus most common at 58%); all but two PVSRIPO-treatment related AEs were localized to the injected or adjacent lesions (n=1 G1 hot flash, n=1 G1 fatigue). Four out of 12 patients (33%) achieved an objective response per immune-related response criteria (two observations, 4 weeks apart), including 4/6 (67%) who received three injections. In the four patients with in-transit disease, a pathological complete response (pCR) was observed in two (50%) patients. Following study completion, 11/12 patients (92%) reinitiated immune checkpoint inhibitor-based therapy, and 6/12 patients (50%) remained without progression at a median follow-up time of 18 months. CONCLUSION: Intratumoral PVSRIPO was well tolerated. Despite the limited number of PVSRIPO treatments relative to the overall lesion burden (67% patients>5 lesions), intratumoral PVSRIPO showed promising antitumor activity, with pCR in injected as well as non-injected lesions in select patients. TRIAL REGISTRATION NUMBER: NCT03712358.

A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy.

An in-depth understanding of immune escape mechanisms in cancer is likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and how they impact immunotherapy resistance. Using several preclinical tumor models as well as clinical specimens, we identified a mechanism whereby CD8+ T cell activation in response to programmed cell death 1 (PD-1) blockade induced a programmed death ligand 1/NOD-, LRR-, and pyrin domain-containing protein 3 (PD-L1/NLRP3) inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting antitumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti-PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic mechanism of adaptive resistance to anti-PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.

First-line treatment of metastatic melanoma: role of nivolumab.

Historically, the median overall survival of metastatic melanoma patients was less than 1 year and long-term survivors were rare. Recent advances in therapies have dramatically shifted this landscape with increased survival rates and the real possibility that long-term disease control is achievable. Advances in immune modulators, including cytotoxic T-lymphocyte antigen-4 and programmed death-1 based treatments, have been an integral part of this success. In this article, we review previous and recent therapeutic developments for metastatic melanoma patients. We discuss advances in immunotherapy while focusing on the use of nivolumab alone and in combination with other agents, including ipilimumab in advanced melanoma. One major goal in melanoma research is to optimize combination strategies allowing for more patients to experience benefit while minimizing toxicity. A better understanding of the optimal sequencing, combinations, and mechanisms underlying the development of resistance may provide evidence for rational clinical trial designs of novel immunotherapy strategies in melanoma and other cancer subtypes.

Outcomes and toxicity of stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab.

PURPOSE: Patients with melanoma treated with ipilimumab and radiosurgery (stereotactic radiosurgery [SRS]) were reviewed for efficacy/safety. METHODS: Patients who received ipilimumab and SRS for brain metastases were analyzed for control of SRS-treated metastasis and overall survival. RESULTS: We identified 27 patients, 26 were assessable for outcomes. Median time-to-treated metastasis progression was 6.3 months (95% CI: 3.1-12.2). Overall survival was 23.4 months (95% CI: 5.7-not estimable) for SRS prior to/during ipilimumab (n = 14), and 10.4 months (95% CI: 1.9-not estimable) for SRS after ipilimumab (n = 12). Overall, no unexpected toxicities were seen: 11% of patients experienced grade 3 CNS toxicity and 7% developed radionecrosis. CONCLUSION: SRS for melanoma brain metastases with ipilimumab was well-tolerated. There may be improved survival for patients receiving SRS prior to/during ipilimumab.

Copper suppression as cancer therapy: the rationale for copper chelating agents in BRAFV600 mutated melanoma.

The successful targeting of oncogenic BRAFV600 represents one of the landmark breakthroughs in therapy for advanced melanoma. While the initial clinical benefit can be dramatic, resistance is common due to a number of mechanisms, including MAPK pathway reactivation. Recent data have revealed a novel role for copper (Cu) in BRAF signaling with potential clinical implications. The history, preclinical data and efficacy of Cu chelating agents in cancer, specifically tetrathiomolybdate, will be reviewed with a focus on the rationale for targeting the MAPK cascade in melanoma through novel combination strategies.

Clinical applications of PD-1-based therapy: a focus on pembrolizumab (MK-3475) in the management of melanoma and other tumor types.

Preclinical work has led to an increased understanding of the immunomodulatory mechanisms involved in the regulation of the antitumor response in a variety of tumor types. PD-1 (programmed death 1) appears to be a key checkpoint involved in immune suppression in the tumor microenvironment, even in diseases not previously thought to be sensitive to immune manipulation. More recently, the subsequent clinical development of PD-1-based therapy has resulted in a major breakthrough in the field of oncology. Pembrolizumab, a humanized highly selective IgG4 anti-PD-1 monoclonal antibody, was recently approved for the treatment of advanced melanoma based on promising early-phase clinical data. Encouraging results have also been seen in other malignancies, and PD-1-targeted therapies are likely to markedly change the treatment landscape. Future work will center on rationally designed combination strategies in order to potentiate the antitumor immune response and overcome mechanisms of resistance.

Report of ipilimumab in a heart transplant patient with metastatic melanoma on tacrolimus.

Ipilimumab is the first immunotherapy shown to increase overall survival in patients with metastatic melanoma. Currently, there are no accepted guidelines for use of ipilimumab in organ transplant patients. There is only one report in the literature on successful administration of ipilimumab in two kidney transplant recipients. In this report, a heart transplant patient with metastatic melanoma was successfully treated with ipilimumab. He experienced no adverse drug reactions. However, after standard treatment with regimen of four doses at 3 mg/kg, he experienced disease progression. Here, we address concerns of organ rejection or ineffective treatment when using ipilimumab or other immune checkpoint inhibitors in patients who are chronically immunosuppressed.