Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma.

PD-1 immune checkpoint blockade provides significant clinical benefits for melanoma patients. We analyzed the somatic mutanomes and transcriptomes of pretreatment melanoma biopsies to identify factors that may influence innate sensitivity or resistance to anti-PD-1 therapy. We find that overall high mutational loads associate with improved survival, and tumors from responding patients are enriched for mutations in the DNA repair gene BRCA2. Innately resistant tumors display a transcriptional signature (referred to as the IPRES, or innate anti-PD-1 resistance), indicating concurrent up-expression of genes involved in the regulation of mesenchymal transition, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing. Notably, mitogen-activated protein kinase (MAPK)-targeted therapy (MAPK inhibitor) induces similar signatures in melanoma, suggesting that a non-genomic form of MAPK inhibitor resistance mediates cross-resistance to anti-PD-1 therapy. Validation of the IPRES in other independent tumor cohorts defines a transcriptomic subset across distinct types of advanced cancer. These findings suggest that attenuating the biological processes that underlie IPRES may improve anti-PD-1 response in melanoma and other cancer types.

Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance.

Clinically acquired resistance to MAPK inhibitor (MAPKi) therapies for melanoma cannot be fully explained by genomic mechanisms and may be accompanied by co-evolution of intra-tumoral immunity. We sought to discover non-genomic mechanisms of acquired resistance and dynamic immune compositions by a comparative, transcriptomic-methylomic analysis of patient-matched melanoma tumors biopsied before therapy and during disease progression. Transcriptomic alterations across resistant tumors were highly recurrent, in contrast to mutations, and were frequently correlated with differential methylation of tumor cell-intrinsic CpG sites. We identified in the tumor cell compartment supra-physiologic c-MET up-expression, infra-physiologic LEF1 down-expression and YAP1 signature enrichment as drivers of acquired resistance. Importantly, high intra-tumoral cytolytic T cell inflammation prior to MAPKi therapy preceded CD8 T cell deficiency/exhaustion and loss of antigen presentation in half of disease-progressive melanomas, suggesting cross-resistance to salvage anti-PD-1/PD-L1 immunotherapy. Thus, melanoma acquires MAPKi resistance with highly dynamic and recurrent non-genomic alterations and co-evolving intra-tumoral immunity.

T cells specific for α-myosin drive immunotherapy-related myocarditis.

Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy1. The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1-/-Ctla4+/- mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration2. Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1-/-Ctla4+/- mice, we identify clonal effector CD8+ T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1-/-Ctla4+/- mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, which required CD8+ T cells. The cardiac-specific protein α-myosin, which is absent from the thymus3,4, was identified as the cognate antigen source for three major histocompatibility complex class I-restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from three patients with ICI-MC were expanded by α-myosin peptides. Moreover, these α-myosin-expanded T cells shared TCR clonotypes with diseased heart and skeletal muscle, which indicates that α-myosin may be a clinically important autoantigen in ICI-MC. These studies underscore the crucial role for cytotoxic CD8+ T cells, identify a candidate autoantigen in ICI-MC and yield new insights into the pathogenesis of ICI toxicity.

Biomarkers of immune checkpoint inhibitor response and toxicity: Challenges and opportunities.

Immune checkpoint inhibitors have transformed cancer therapy, but their optimal use is still constrained by lack of response and toxicity. Biomarkers of response may facilitate drug development by allowing appropriate therapy selection and focusing clinical trial enrollment. However, aside from PD-L1 staining in a subset of tumors and rarely mismatch repair deficiency, no biomarkers are routinely used in the clinic. In addition, severe toxicities may cause severe morbidity, therapy discontinuation, and even death. Here, we review the state of the field with a focus on our research in therapeutic biomarkers and toxicities from immune checkpoint inhibitors.

Clinical Pharmacology and Interplay of Immune Checkpoint Agents: A Yin-Yang Balance.

T cells have a central role in immune system balance. When activated, they may lead to autoimmune diseases. When too anergic, they contribute to infection spread and cancer proliferation. Immune checkpoint proteins regulate T cell function, including cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) and its ligand (PD-L1). These nodes of self-tolerance may be exploited pharmacologically to downregulate (CTLA-4 agonists) and activate [CTLA-4 and PD-1/PD-L1 antagonists, also called immune checkpoint inhibitors (ICIs)] the immune system.CTLA-4 agonists are used to treat rheumatologic immune disorders and graft rejection. CTLA-4, PD-1, and PD-L1 antagonists are approved for multiple cancer types and are being investigated for chronic viral infections. Notably, ICIs may be associated with immune-related adverse events (irAEs), which can be highly morbid or fatal. CTLA-4 agonism has been a promising method to reverse such life-threatening irAEs. Herein, we review the clinical pharmacology of these immune checkpoint agents with a focus on their interplay in human diseases.

Interactive network-based clustering and investigation of multimorbidity association matrices with associationSubgraphs.

MOTIVATION: Making sense of networked multivariate association patterns is vitally important to many areas of high-dimensional analysis. Unfortunately, as the data-space dimensions grow, the number of association pairs increases in O(n2); this means that traditional visualizations such as heatmaps quickly become too complicated to parse effectively. RESULTS: Here, we present associationSubgraphs: a new interactive visualization method to quickly and intuitively explore high-dimensional association datasets using network percolation and clustering. The goal is to provide an efficient investigation of association subgraphs, each containing a subset of variables with stronger and more frequent associations among themselves than the remaining variables outside the subset, by showing the entire clustering dynamics and providing subgraphs under all possible cutoff values at once. Particularly, we apply associationSubgraphs to a phenome-wide multimorbidity association matrix generated from an electronic health record and provide an online, interactive demonstration for exploring multimorbidity subgraphs. AVAILABILITY AND IMPLEMENTATION: An R package implementing both the algorithm and visualization components of associationSubgraphs is available at https://github.com/tbilab/associationsubgraphs. Online documentation is available at https://prod.tbilab.org/associationsubgraphs_info/. A demo using a multimorbidity association matrix is available at https://prod.tbilab.org/associationsubgraphs-example/.

Novel endoscopic scoring system for immune mediated colitis: a multicenter retrospective study of 674 patients.

BACKGROUND AND AIMS: No endoscopic scoring system has been established for immune-mediated colitis (IMC). This study aimed to establish such a system for IMC and explore its utility in guiding future selective immunosuppressive therapy (SIT) use compared to clinical symptoms. METHODS: This retrospective, international, 14-center study included 674 patients who developed IMC after immunotherapy and underwent endoscopic evaluation. Ten endoscopic features were selected by group consensus and assigned 1 point each to calculate an IMC endoscopic score (IMCES). IMCES cutoffs were chosen to maximize specificity for SIT use. This specificity was compared between IMCESs, and clinical symptoms were graded according to a standardized instrument. RESULTS: A total of 309 (45.8%) patients received SIT. IMCES specificity for SIT use was 82.8% with a cutoff of 4. The inclusion of ulceration as a mandatory criterion resulted in higher specificity (85.0% for a cutoff of 4). In comparison, the specificity of a Mayo endoscopic subscore of 3 was 74.6%, and the specificity of clinical symptom grading was much lower at 27.4% and 12.3%, respectively. Early endoscopy was associated with timely SIT use (P < .001; r = 0.4084). CONCLUSIONS: This is the largest multicenter study to devise an endoscopic scoring system to guide IMC management. An IMCES cutoff of 4 has a higher specificity for SIT use than clinical symptoms, supporting early endoscopic evaluation for IMC.

High response rate to PD-1 blockade in desmoplastic melanomas.

Desmoplastic melanoma is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, and is highly associated with ultraviolet light-induced DNA damage. We analysed sixty patients with advanced desmoplastic melanoma who had been treated with antibodies to block programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1). Objective tumour responses were observed in forty-two of the sixty patients (70%; 95% confidence interval 57-81%), including nineteen patients (32%) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF1 mutations (fourteen out of seventeen cases) in these tumours. Immunohistochemistry analysis from nineteen desmoplastic melanomas and thirteen non-desmoplastic melanomas revealed a higher percentage of PD-L1-positive cells in the tumour parenchyma in desmoplastic melanomas (P = 0.04); these cells were highly associated with increased CD8 density and PD-L1 expression in the tumour invasive margin. Therefore, patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.

Therapeutic Responses to Combination Nivolumab and Temozolomide as Salvage Therapy for Metastatic Melanoma: A Case Series.

The management of metastatic melanoma patients that fail multiple lines of systemic therapy remains a significant challenge. There is limited literature regarding combination of anti-PD-1 and temozolomide, or of other chemotherapy agents, in melanoma. Here, we present a series of 3 patients with metastatic melanoma and their responses to nivolumab and temozolomide combination therapy after progression on several local/regional therapies, combination immune checkpoint inhibitors, and/or targeted therapies. The novel combinatory strategy led to remarkable responses in all 3 patients shortly after initiating treatment with tumor remission and symptomatic improvement. The first patient has had ongoing response 15 months after initiating treatment, although he has since discontinued temozolomide due to intolerance. The remaining 2 patients show ongoing response after 4 months, with good tolerability. This case series suggests that nivolumab and temozolomide may be a promising option in the setting of advanced melanoma refractory to standard treatments, and warrants further investigation in larger series.

Prognostic Risk Stratification and End-of-Life Care Outcomes in Patients With Metastatic Melanoma Treated With Immune Checkpoint Inhibitors.

INTRODUCTION: The emergence of immune checkpoint inhibitors (ICIs) has improved survival outcomes in patients with metastatic melanoma, while potentially increasing the use of systemic therapy near the end of life (EOL). Yet, less is known on how to facilitate treatment decision making and identify patients who might benefit from early palliative care comanagement. MATERIALS AND METHODS: We determined baseline clinical and laboratory factors that are associated with poor prognosis for patients with advanced melanoma treated with ICIs. We subsequently identified prognostic subgroups to evaluate association with EOL outcomes and determine if EOL care varied across prognostic strata. RESULTS: Our cohort included 398 patients with metastatic melanoma treated with ICIs. Factors associated with overall survival (OS) included: lactate dehydrogenase, neutrophil/lymphocyte ratio, performance status, prior therapies, liver metastases, and lung metastases. Patients were stratified by risk of death using risk scores developed from multivariable analyses. A total of 205 patients died: 45/133 (34%) low-risk, 63/133 (47%) medium-risk, and 97/132 (73%) of high-risk patients. Among those who died, higher risk patients were more likely to receive ICIs within 14, 30, and 90 days of death. We found no association between risk group and hospice referrals or location of death. CONCLUSION: Patients with metastatic melanoma at highest risk of death as defined by our model were more likely than lower-risk patients to receive ICIs near the EOL. Prognostic risk stratification may guide early palliative care interventions to appropriately utilize ICIs and optimize EOL care.

Perspectives in Immunotherapy: meeting report from Immunotherapy Bridge (Naples, November 30th-December 1st, 2022).

The discovery and development of novel treatments that harness the patient's immune system and prevent immune escape has dramatically improved outcomes for patients across cancer types. However, not all patients respond to immunotherapy, acquired resistance remains a challenge, and responses are poor in certain tumors which are considered to be immunologically cold. This has led to the need for new immunotherapy-based approaches, including adoptive cell transfer (ACT), therapeutic vaccines, and novel immune checkpoint inhibitors. These new approaches are focused on patients with an inadequate response to current treatments, with emerging evidence of improved responses in various cancers with new immunotherapy agents, often in combinations with existing agents. The use of cell therapies, drivers of immune response, and trends in immunotherapy were the focus of the Immunotherapy Bridge (November 30th-December 1st, 2022), organized by the Fondazione Melanoma Onlus, Naples, Italy, in collaboration with the Society for Immunotherapy of Cancer.

Impact of COVID-19 in patients on active melanoma therapy and with history of melanoma.

INTRODUCTION: COVID-19 particularly impacted patients with co-morbid conditions, including cancer. Patients with melanoma have not been specifically studied in large numbers. Here, we sought to identify factors that associated with COVID-19 severity among patients with melanoma, particularly assessing outcomes of patients on active targeted or immune therapy. METHODS: Using the COVID-19 and Cancer Consortium (CCC19) registry, we identified 307 patients with melanoma diagnosed with COVID-19. We used multivariable models to assess demographic, cancer-related, and treatment-related factors associated with COVID-19 severity on a 6-level ordinal severity scale. We assessed whether treatment was associated with increased cardiac or pulmonary dysfunction among hospitalized patients and assessed mortality among patients with a history of melanoma compared with other cancer survivors. RESULTS: Of 307 patients, 52 received immunotherapy (17%), and 32 targeted therapy (10%) in the previous 3 months. Using multivariable analyses, these treatments were not associated with COVID-19 severity (immunotherapy OR 0.51, 95% CI 0.19 - 1.39; targeted therapy OR 1.89, 95% CI 0.64 - 5.55). Among hospitalized patients, no signals of increased cardiac or pulmonary organ dysfunction, as measured by troponin, brain natriuretic peptide, and oxygenation were noted. Patients with a history of melanoma had similar 90-day mortality compared with other cancer survivors (OR 1.21, 95% CI 0.62 - 2.35). CONCLUSIONS: Melanoma therapies did not appear to be associated with increased severity of COVID-19 or worsening organ dysfunction. Patients with history of melanoma had similar 90-day survival following COVID-19 compared with other cancer survivors.

Mechanisms of Cardiovascular Toxicities Associated With Immunotherapies.

Immune-based therapies have revolutionized cancer treatments. Cardiovascular sequelae from these treatments, however, have emerged as critical complications, representing new challenges in cardio-oncology. Immune therapies include a broad range of novel drugs, from antibodies and other biologics, including immune checkpoint inhibitors and bispecific T-cell engagers, to cell-based therapies, such as chimeric-antigen receptor T-cell therapies. The recognition of immunotherapy-associated cardiovascular side effects has also catapulted new research questions revolving around the interactions between the immune and cardiovascular systems, and the signaling cascades affected by T cell activation, cytokine release, and immune system dysregulation. Here, we review the specific mechanisms of immune activation from immunotherapies and the resulting cardiovascular toxicities associated with immune activation and excess cytokine production.

Clinical and genomic correlates of imatinib response in melanomas with KIT alterations.

BACKGROUND: Imatinib is an active agent for some patients with melanoma harbouring c-KIT alterations. However, the genetic and clinical features that correlate with imatinib sensitivity are not well-defined. METHODS: We retrospectively evaluated 38 KIT-altered melanoma patients from five medical centres who received imatinib, and pooled data from prospective studies of imatinib in 92 KIT-altered melanoma patients. Baseline patient and disease characteristics, and clinical outcomes were assessed. RESULTS: In the pooled analysis (N = 130), alterations in exons 11/13 had the highest response rates (38% and 33%); L576P (N = 23) and K642E (N = 12) mutations had ORR of 52% and 42%, respectively. ORR was 38% (mucosal), 25% (acral), and 8% (unknown-primary). PFS appeared longer in exon 11/13 vs. exon 17 alterations (median 4.3 and 4.5 vs. 1.1 months; p = 0.19), with similar superiority in OS (median 19.7 and 15.4 vs. 12.1 months; p = 0.20). By histology, median PFS was 4.5 months (mucosal), 2.7 (acral), and 5.0 (unknown-primary) [p = 0.36]. Median OS was 18.0 months (mucosal), 21.8 (acral), 11.5 (unknown-primary) [p = 0.26]. In multivariate analyses, mucosal melanoma was associated with higher PFS and exon 17 mutations were associated with reduced PFS. CONCLUSION: This multicenter study highlights KIT-alterations sensitive to imatinib and augments evidence for imatinib in subsets of KIT-altered melanoma.

Management of Acral and Mucosal Melanoma: Medical Oncology Perspective.

Acral and mucosal melanomas (MM) are rare subtypes of melanoma that are biologically and clinically distinct from cutaneous melanoma. Despite the progress in the treatment of cutaneous melanomas with the development of targeted and immune therapies, the therapeutic options for these less common subtypes remain limited. Difficulties in early diagnosis, the aggressive nature of the disease, and the frequently occult sites of origin have also contributed to the poor prognosis associated with acral and MM, with substantially worse long-term prognosis. The rarity of these subtypes has posed significant barriers to better understanding their biological features and investigating novel therapies. Consequently, establishing standardized treatment guidelines has been a challenge. In this review, we provide a brief overview of the current knowledge regarding acral and MM, focusing on their epidemiology, genetic backgrounds, and unique clinical characteristics. Further discussion centers around the management of primary and advanced disease and the role of emerging targeted and immune therapies for these subtypes, specifically focusing on issues relevant to medical oncologists.

Recurrence of Hypophysitis After Immune Checkpoint Inhibitor Rechallenge.

Immune checkpoint inhibitor (ICI)-induced hypophysitis is an immune-mediated pituitary inflammation that tends to cause long-term pituitary deficiency. Management of ICI-induced hypophysitis includes corticosteroids for acute inflammation and long-term hormone replacement due to irreversible pituitary cell damage. We report a case of recurrent hypophysitis following ICI rechallenge for metastatic melanoma. A 33-year-old woman with recurrent metastatic melanoma with adrenal, pelvic, and inguinal metastases developed recurrent hypophysitis during treatment with ipilimumab and nivolumab which recurred with rechallenge >5 years later. In both cases, headache was the most notable symptom and brain MRI showed pituitary enlargement and edema without evidence of metastases. Central adrenal insufficiency and symptoms caused by mass effect were treated with acute high-dose corticosteroids and long-term replacement corticosteroids. Based on recurrence and failure of symptomatic treatment with continued steroid treatment, ICI was discontinued. This case illustrates that hypophysitis may recur with ICI rechallenge, challenging traditional assumptions that chronic, irreversible irAEs are unlikely to recur or flare. The regenerative potential of pituitary cells after ICI-induced damage or additional damage to previously unaffected cells may be more conceivable than previously realized. Additional research on the potential for recurrent ICI-induced endocrinopathies are needed.

Immune Checkpoint Inhibitors: The Unexplored Landscape of Geriatric Oncology.

Cancer is classically considered a disease of aging, with over half of all new cancer diagnoses occurring in patients over the age of 65 years. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet the participation of older adults with cancer in ICI trials has been suboptimal, particularly at the extremes of age. Despite significant improvement in treatment response and an improved toxicity profile when compared with conventional cytotoxic chemotherapies, many cancers develop resistance to ICIs, and these drugs are not free of toxicities. This becomes particularly important in the setting of older adults with cancer, who are generally frailer and harbor more comorbidities than do their younger counterparts. Immunosenescence, a concept involving age-related changes in immune function, may also play a role in differential responses to ICI treatment in older patients. Data on ICI treatment response in older adult with cancers remains inconclusive, with multiple studies revealing conflicting results. The molecular mechanisms underlying response to ICIs in older cancer patients are poorly understood, and predictors of response that can delineate responders from non-responders remain to be elucidated. In this review, we explore the unique geriatric oncology population by analyzing existing retrospective datasets, and we also sought to highlight potential cellular, inflammatory, and molecular changes associated with aging as potential biomarkers for response to ICIs.

Targeting wild-type TP53 using AMG 232 in combination with MAPK inhibition in Metastatic Melanoma; a phase 1 study.

BACKGROUND: Targeting the MDM2-p53 interaction using AMG 232 is synergistic with MAPK inhibitors (MAPKi) in preclinical melanoma models. We postulated that AMG 232 plus MAPKi is safe and more effective than MAPKi alone in TP53-wild type, MAPKi-naïve metastatic melanoma. METHODS: Patients were treated with increasing (120 mg, 180 mg, 240 mg) oral doses of AMG 232 (seven-days-on, 15-days-off, 21-day cycle) plus dabrafenib (D) and trametinib (T) (Arm 1, BRAFV600-mutant) or T alone (Arm 2, BRAFV600-wild type). Patients were treated for seven days with AMG 232 alone before adding T±D. Safety and efficacy were assessed using CTCAE v4.0 and RECIST v1.1 criteria, respectively. Pharmacokinetic (PK) analysis was performed at baseline and steady-state levels for AMG 232. RESULTS: 31 patients were enrolled. Ten and 21 patients were enrolled in Arm 1 and Arm 2, respectively. The most common AMG 232-related adverse events (AEs) were nausea (87%), diarrhea (77%), and fatigue (74%). Seven patients (23%) were withdrawn from the study due to AMG 232-related AEs. Three dose-limiting AEs occurred (Arm 1, 180 mg, nausea; Arm 2, 240 mg, grade 3 pulmonary embolism; Arm 2, 180 mg, grade 4 thrombocytopenia). AMG 232 PK exposures were not altered when AMG 232 was combined with T±D. Objective responses were seen in 8/10 (Arm 1) and 3/20 (Arm 2) evaluable patients. The median progression-free survival for Arm 1 and Arm 2 was 19.0 months-not reached and 2.8 months, respectively. CONCLUSION: The maximum tolerated dose of AMG 232 for both arms was 120 mg. AMG 232 plus T±D exhibited a favorable PK profile. Although objective responses occurred in both arms, adding AMG 232 to T±D did not confer additional clinical benefit.

Immune checkpoint inhibitors and their impact on liver enzymes and attenuation.

BACKGROUND: Immune related adverse events impacting the liver are common from immune checkpoint inhibitor (ICI) therapy; however, there is little data regarding the subclinical impact of ICIs on liver inflammation. The study aims to determine whether ICI therapy affects liver attenuation and liver enzymes in melanoma patients with and without hepatic steatosis. METHODS: A retrospective, cohort study was conducted of patients with advanced melanoma treated with ICI therapy who received serial PET-CT scans at the Vanderbilt University Medical Center (VUMC). Primary outcomes included: liver attenuation measured by PET-CT/non-contrast CT and liver enzymes. Hepatic steatosis was diagnosed by radiologists on clinical imaging. RESULTS: Among 839 patients with advanced melanoma treated with ICIs, 81 had serial PET-CT scans approximately 12 months apart and long-term survival; of these 11 patients had pre-existing steatosis/steatohepatitis. Overall, ICI was not associated with significant increases in liver enzymes in all patients; modest decreases in liver enzymes were observed in patients with pre-existing steatosis/steatohepatitis. Similarly, liver attenuation did not change from baseline to post-treatment (58.44 vs 60.60 HU, + 2.17, p = 0.055). CONCLUSIONS: ICIs may not chronically affect liver enzymes or liver attenuation, a non-invasive measure of liver fat content and inflammation, in the general population or in those with pre-existing steatosis/steatohepatitis.