Precision Oncology in Melanoma: Changing Practices.

Over the last 2 decades, significant progress has been made in our understanding of the genomics, tumor immune microenvironment, and immunogenicity of malignant melanoma. Historically, the prognosis for metastatic melanoma was poor because of limited treatment options. However, after multiple landmark clinical trials displaying the efficacy of combined inhibition for -mutant melanoma and the application of immune checkpoint inhibitors targeting the programmed death-1, cytotoxic T-lymphocyte antigen-4, and lymphocyte activation gene-3 molecules, overall survival rates have dramatically improved.

Comparing the rate of immunotherapy treatment change due to toxicity by sex.

Background: Immuno-oncology therapy (IO) is associated with a variety of treatment-related toxicities. However, the impact of toxicity on the treatment discontinuation rate between males and females is unknown. We hypothesized that immune-related adverse events would lead to more frequent treatment changes in females since autoimmune diseases occur more frequently in females.

Case Report: Dynamic overlap of melanoma, sarcoidosis, and targeted therapy for -mutant melanoma.

Targeted therapies, including BRAF and MEK inhibitors, are valuable treatment options for patients with unresectable or metastatic BRAF V600-mutant melanoma. With the improvement in survival seen with modern melanoma therapeutics, clinicians are learning the variable patterns associated with extended clinical courses. Sarcoidosis is characterized by non-caseating granulomatous inflammation of unknown etiology, often presenting with cutaneous, lung, or lymph node involvement.

Relevance of the Updated Recursive Partitioning Analysis (U-RPA) Classification in the Contemporary Care of Patients with Brain Metastases.

Patients with brain metastases (BMETS) need information about the prognosis and potential value of treatment options to make informed therapeutic decisions, but tools to predict survival in contemporary practice are scarce. We propose an Updated Recursive Partitioning Analysis (U-RPA) instrument to predict survival and benefit from brain-directed treatment (BDT) of contemporary patients. This was a retrospective analysis of patients with BMETS treated between 2017 and 2019.

PD-L1 and MHC Class I Expression in High-grade Ovarian Cancers, Including Platinum-resistant Recurrences Treated With Checkpoint Inhibitor Therapy.

Immune-modulating therapies targeting the programmed cell death-1/programmed cell death ligand-1 (PD-L1) immunosuppressive system have been used successfully in many solid tumor types. There is evidence that biomarkers such as PD-L1 and major histocompatibility complex (MHC) class I help identify candidates for anti-programmed cell death-1/PD-L1 checkpoint inhibition, though the evidence is limited in ovarian malignancies. PD-L1 and MHC Class I immunostaining was performed on pretreatment whole tissue sections in 30 cases of high-grade ovarian carcinoma.

Phase I/II clinical trial of a helper peptide vaccine plus PD-1 blockade in PD-1 antibody-naïve and PD-1 antibody-experienced patients with melanoma (MEL64).

Background: A vaccine containing 6 melanoma-associated peptides to stimulate helper T cells (6MHP) is safe, immunogenic, and clinically active. A phase I/II trial was designed to evaluate safety and immunogenicity of 6MHP vaccines plus programmed death 1 (PD-1) blockade.

Participants And Methods: Participants with advanced melanoma received 6MHP vaccines in an incomplete Freund's adjuvant (6 vaccines over 12 weeks).

Multicenter Experience with Neoadjuvant Therapy in Melanoma Highlights Heterogeneity in Contemporary Practice.

Objective: To determine the feasibility and impact of neoadjuvant therapy (NT) in patients who present with advanced melanoma amenable to surgical resection.

Summary Background Data: Given current effective systemic therapy for melanoma, the use of NT is being explored in patients with advanced melanoma with disease amenable to surgical resection.

Methods: Prospective data from 3 institutions was obtained in patients with clinically evident Stage III/IV melanoma who underwent NT.

Outcomes From Cytotoxic Chemotherapy Following Progression on Immunotherapy in Metastatic Melanoma: An Institutional Case-Series.

Introduction: The role of chemotherapy in the management of advanced melanoma is limited due to low response rates and short survival. Improved outcomes to chemotherapy administered after immunotherapy for metastatic melanoma and other solid tumors have been reported. We studied the outcomes of subjects treated at the University of Virginia (UVA) with chemotherapy following progression on prior systemic immunotherapy and compared the results with the existing literature.

Multiple evanescent white dot syndrome-like reaction associated with ipilimumab and nivolumab immune checkpoint inhibitor therapy for metastasis of choroidal melanoma.

Purpose: To present a rare case of multiple evanescent white dot syndrome (MEWDS)-like presentation associated with immune checkpoint inhibitor therapy for metastatic choroidal melanoma.

Observations: A 67-year-old non-myopic Caucasian female presented with bilateral worsening vision, flashes, and floaters after receiving two doses of ipilimumab and nivolumab for metastatic class 2 peripheral choroidal melanoma. Fundus imaging of the right eye revealed hypopigmented, extra-foveal scattered chorioretinal lesions with foveal granularity.

Phase I/II trial of a long peptide vaccine (LPV7) plus toll-like receptor (TLR) agonists with or without incomplete Freund's adjuvant (IFA) for resected high-risk melanoma.

Background: We performed a clinical trial to evaluate safety and immunogenicity of a novel long peptide vaccine administered in combinations of incomplete Freund's adjuvant (IFA) and agonists for TLR3 (polyICLC) and TLR7/8 (resiquimod). We hypothesized that T cell responses to minimal epitope peptides (MEPs) within the long peptides would be enhanced compared with prior vaccines with MEP themselves and that T cell responses would be enhanced with TLR agonists, compared with IFA alone.

Methods: Participants with resected stage IIB-IV melanoma were vaccinated with seven long melanoma peptides (LPV7) from tyrosinase, gp100, MAGE-A1, MAGE-A10, and NY-ESO-1, each containing a known MEP for CD8 T cells, plus a tetanus helper peptide (Tet) restricted by Class II MHC.

A phase 1 study of NY-ESO-1 vaccine + anti-CTLA4 antibody Ipilimumab (IPI) in patients with unresectable or metastatic melanoma.

Ipilimumab (IPI) can enhance immunity to the cancer-testis antigen NY-ESO-1. A clinical trial was designed to assess safety, immunogenicity, and clinical responses with IPI + NY-ESO-1 vaccines and effects on the tumor microenvironment (TME). Patients with measurable NY-ESO-1 tumors were enrolled among three arms: A) IPI + NY-ESO-1 protein + poly-ICLC (pICLC) + incomplete Freund's adjuvant (IFA); B) IPI + NY-ESO-1 overlapping long peptides (OLP) + pICLC + IFA; and C) IPI + NY-ESO-1 OLP + pICLC.

Trial to evaluate the immunogenicity and safety of a melanoma helper peptide vaccine plus incomplete Freund's adjuvant, cyclophosphamide, and polyICLC (Mel63).

Background: Peptide vaccines designed to stimulate melanoma-reactive CD4 T cells can induce T cell and antibody (Ab) responses, associated with enhanced overall survival. We hypothesized that adding toll-like receptor 3 agonist polyICLC to an incomplete Freund's adjuvant (IFA) would be safe and would support strong, durable CD4 T cell and Ab responses. We also hypothesized that oral low-dose metronomic cyclophosphamide (mCy) would be safe, would reduce circulating regulatory T cells (T-regs) and would further enhance immunogenicity.

Severe combined cardiac and neuromuscular toxicity from immune checkpoint blockade: an institutional case series.

Background: Immune checkpoint inhibition is part of standard systemic management for many advanced malignancies. Toxicities from this treatment approach are unpredictable, though usually reversible with management per established guidelines. Some patients suffer major morbidity and treatment-related mortality from these agents in an unpredictable manner.

Genesis of Quality Measurements to Improve the Care Delivered to Patients With Brain Metastases.

Purpose: High-value and high-quality health care requires outcome measurements to inform treatment decisions, but, to our knowledge, no standardized measurements exist to evaluate brain metastases (BMs) care. We propose a set of measurements and report on their implementation in the care of patients with BMs.

Methods: On the basis of a stakeholders' needs assessment and review of the literature, we identified outcome and process measurements to assess the care of patients with BMs according to treatment modality.

MHC-restricted phosphopeptide antigens: preclinical validation and first-in-humans clinical trial in participants with high-risk melanoma.

Background: Phosphorylated peptides presented by MHC molecules represent a new class of neoantigens expressed on cancer cells and recognized by CD8 T-cells. These peptides are promising targets for cancer immunotherapy. Previous work identified an HLA-A*0201-restricted phosphopeptide from insulin receptor substrate 2 (pIRS2) as one such target.

A multipeptide vaccine plus toll-like receptor agonists LPS or polyICLC in combination with incomplete Freund's adjuvant in melanoma patients.

Background: Cancer vaccines require adjuvants to induce effective immune responses; however, there is no consensus on optimal adjuvants. We hypothesized that toll-like receptor (TLR)3 agonist polyICLC or TLR4 agonist lipopolysaccharide (LPS), combined with CD4 T cell activation, would support strong and durable CD8 T cell responses, whereas addition of an incomplete Freund's adjuvant (IFA) would reduce magnitude and persistence of immune responses.

Patients And Methods: Participants with resected stage IIB-IV melanoma received a vaccine comprised of 12 melanoma peptides restricted by Class I MHC (12MP), plus a tetanus helper peptide (Tet).

Quantitative Spatial Profiling of PD-1/PD-L1 Interaction and HLA-DR/IDO-1 Predicts Improved Outcomes of Anti-PD-1 Therapies in Metastatic Melanoma.

PD-1/L1 axis-directed therapies produce clinical responses in a subset of patients; therefore, biomarkers of response are needed. We hypothesized that quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti-PD-1 response. Pretreatment tumor biopsies from 166 patients treated with anti-PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery ( = 24) and validation ( = 142) cohorts.

Regression of an intramedullary spinal cord metastasis with a checkpoint inhibitor: a case report.

Intramedullary spinal cord metastasis is an increasingly common diagnosis in patients with cancer largely owing to new imaging techniques and the increase lifespan of patients with malignant tumors. The diagnosis confers significant morbidity and a poor prognosis. Mainstay palliative treatment options include corticosteroids, fractionated radiotherapy and surgery in select cases.

Primary Cutaneous Small/Medium CD4+ T-CELL Lymphoproliferative Disorder Occurring in a Patient With Metastatic Melanoma.

Therapeutic agents designed to stimulate the immune system are now cornerstones in the treatment of metastatic melanoma. These drugs promote lymphocyte growth and survival, which could plausibly result in clinical lymphoproliferative disorders. We report the case of a 62-year-old female with metastatic melanoma who developed primary cutaneous small/medium CD4 T-cell lymphoproliferative disorder (PC-SMTCL) after treatment with vemurafenib and recombinant high-dose interleukin-2 (IL-2).

Sarcoidosis in the setting of combination ipilimumab and nivolumab immunotherapy: a case report & review of the literature.

Background: We report a case of sarcoidosis in a patient with metastatic melanoma managed with combination ipilimumab/nivolumab. Sarcoid development has been linked with single agent immunotherapy but, to our knowledge, it has not been reported with combination ipilimumab/nivolumab treatment. This case raises unique management challenges for both the melanoma and the immunotherapy-related toxicity.

Beyond melanoma: inhibiting the PD-1/PD-L1 pathway in solid tumors.

Immune checkpoint inhibitors have been identified as breakthrough treatment in melanoma given its dramatic response to PD-1/PD-L1 blockade. This is likely to extend to many other cancers as hundreds of clinical trials are being conducted or proposed using this exciting modality of therapy in a variety of malignancies. While immune checkpoint inhibitors have been extensively studied in melanoma and more recently in lung cancer, little is known regarding immune checkpoint blockade in other cancers.