Lucy Boyce Kennedy

Background: Melanoma brain metastases (MBM) have a unique molecular profile compared to extracranial metastases (ECM). Description of the biological features and clinical outcomes of MBM will facilitate the design of rational therapies. Methods: We examined the mutational landscape and gene expression profiles of MBM (74 patients) and ECM (34 patients) in paired patient samples from a previously published dataset with whole-exome sequencing (WES) and RNA sequencing (RNAseq) data from MD Anderson Cancer Center (MDACC). We also present findings from MBM from a new cohort of 14 patients from Duke University to strengthen investigation of somatic mutations and gene expression profiles. Gene Set Enrichment Analysis (GSEA) was used to compare paired MBM versus lymph node (LN) metastases and skin metastases. Relative immune cell abundance was inferred using deconvolution methods. Survival outcomes from craniotomy and associations with biological features, BRAF mutation status, and PTEN expression were assessed. Results: GSEA found that autophagy signaling pathways are enriched in MBM versus LN and skin metastases. BRAF was the most frequently mutated clinically relevant gene in MBM and ECM, with NRAS and PTEN also frequently altered in MBM. The most strongly upregulated genes in autophagy pathways were glial fibrillary acidic protein (GFAP) and hemoglobin beta (HBB). An increased proportion of immune-suppressive M2 compared to tumor-suppressive M1 macrophages in MBM and ECM was identified. There was not sufficient evidence for an association between BRAF V600 mutation status or expression and overall survival (OS) from craniotomy. Conclusions: The mutational landscape and gene expression of MBM from the Duke cohort resembled those previously reported in the MDACC cohort. Upregulation of autophagy pathways was observed in patient-matched MBM versus LN and skin metastases due to upregulation of two genes, GFAP and HBB. In MBM, higher M2:M1 ratio may contribute to a therapeutically relevant immune-suppressive tumor microenvironment (TME).

Aim: This study determined the characteristics of patients with early-stage melanoma (IA-IIA) who later had stage IV recurrence.

Immunotherapy has revolutionized the treatment of melanoma, but its limitations due to resistance and variable patient responses have become apparent. The microbiota, which refers to the complex ecosystem of microorganisms that inhabit the human body, has emerged as a promising area of research for its potential role in melanoma development and treatment response. Recent studies have highlighted the role of microbiota in influencing the immune system and its response to melanoma, as well as its influence on the development of immune-related adverse events associated with immunotherapy. In this article, we discuss the complex multifactorial mechanisms through which skin and gut microbiota can affect the development of melanoma including microbial metabolites, intra-tumor microbes, UV light, and the immune system. In addition, we will discuss the pre-clinical and clinical studies that have demonstrated the influence of different microbial profiles on response to immunotherapy. Additionally, we will explore the role of microbiota in the development of immune-mediated adverse events.

E14008 Background: For patients with melanoma brain metastasis (MBM) treated with stereotactic radiosurgery (SRS), 5-6.5% develop radiation necrosis of the brain (RNB), which is commonly treated with corticosteroids (CS). Nonetheless, high-dose CS may reduce efficacy of immunotherapy (IO). Bevacizumab (BV) has been shown to reduce symptoms and peritumoral edema associated with RNB. However, data on the efficacy and toxicity of BV in patients with MBM who also receive IO is limited. We aimed to describe clinical features and outcomes of patients with MBM who received BV and were also treated with IO. Methods: Under an IRB-approved protocol, patients with MBM who developed RNB or steroid-refractory edema (SRE) and were treated with BV were identified. The selection criteria were as follows: (1) one or more MBM; (2) prior SRS for MBM; (3) development of RNB or SRE detected radiographically or based on expert opinion; (4) treatment with one or more cycles of BV; (5) treatment with IO for metastatic melanoma. Results: In this single-center retrospective series, 8 patients received IO and BV: 4 concurrently and 4 patients received IO immediately prior to or after BV. IO therapy included ipilimumab-nivolumab, nivolumab alone or pembrolizumab. Median number of MBM was 3.6 (range, 1-8) and median number of RNB/SRE foci were 1.125 (range, 1-2). Median time from diagnosis of RNB/SRE to initiation of BV was 1.4 months (range, 0.5-3 months). BV dosing regimen was 5 mg/kg every 2 weeks, 7.5 mg/kg every 3 weeks or 10 mg/kg every 2 weeks. 71% (5 of 7) patients who required CS for RNB/peritumoral edema symptoms at the time of starting BV were able to taper CS after receiving BV or stop CS completely. This allowed for 4 of these patients to subsequently start or resume IO. 28% (2 of 7) patients had increasing neurological symptoms during CS taper and required an increase in CS dosing. Only 1 patient was not on CS at the time of BV initiation. 75% (6 of 8) cases attained intracranial radiologic response, with documented decreased edema or tumor size, or resolution of enhancement on MRI; 1 patient had stable disease after BV; and 1 patient had continued clinical deterioration despite BV. 62.5% (5 of 8) patients had no adverse events from BV, but 37.5% (3 of 8) had DVT/PE, 1 requiring a thrombectomy, and 1 additionally had perforated diverticulitis. Median follow-up time from BV administration was 17.94 months (range, 1-58 months), with 75% (6 of 8) patients with survival > 10 months. Conclusions: Treatment of RNB/SRE with BV in patients with MBM receiving IO appears to be effective and relatively well tolerated, though with occasional serious adverse events. BV led to improvement of symptoms and allowed for CS taper in a substantial proportion of patients. By reducing CS requirement, BV may permit continuation of IO, which leads to durable survival in a large proportion of patients.

Cancer immunotherapies, including checkpoint inhibitors and adoptive cell therapy, manipulate the immune system to recognize and attack cancer cells. These therapies have the potential to induce durable responses in multiple solid and hematologic malignancies and thus have transformed treatment algorithms for numerous tumor types. Cancer immunotherapies lead to unique toxicity profiles distinct from the toxicities of other cancer therapies, depending on their mechanism of action. These toxicities often require specific management, which can include steroids and immune‐modulating therapy and for which consensus guidelines have been published. This review will focus on the toxicities of checkpoint inhibitors and chimeric antigen receptor T cells, including pathophysiology, diagnosis, and management.