Abstract BRAF mutations are identified in 40–50% of patients with melanoma. Treatment of these patients with either of two BRAF inhibitors (vemurafenib, dabrafenib) or the MEK inhibitor trametinib is ...associated with improved clinical benefit (response rate, progression free survival, and overall survival) compared with treatment with chemotherapy in three phase III trials. Unfortunately, most patients, including those who experience initial, profound tumour regression, have evidence of disease progression within 6–8 months after commencing therapy with one of these agents. The mechanisms of resistance are varied and include activation of alternative signalling pathways as well as reactivating the MAP kinase pathway through alternative means. This review describes relevant aspects of MAP kinase pathway signalling, summarises the clinical data with BRAF and MEK inhibitors, presents the known resistance mechanisms to BRAF inhibitor therapy, and provides some strategies for how resistance may be overcome.
Checkpoint blockade with antibodies specific for the PD-1 and CTLA-4 inhibitory receptors can induce durable responses in a wide range of human cancers. However, the immunological mechanisms ...responsible for severe inflammatory side effects remain poorly understood. Here we report a comprehensive single-cell analysis of immune cell populations in colitis, a common and severe side effect of checkpoint blockade. We observed a striking accumulation of CD8 T cells with highly cytotoxic and proliferative states and no evidence of regulatory T cell depletion. T cell receptor (TCR) sequence analysis demonstrated that a substantial fraction of colitis-associated CD8 T cells originated from tissue-resident populations, explaining the frequently early onset of colitis symptoms following treatment initiation. Our analysis also identified cytokines, chemokines, and surface receptors that could serve as therapeutic targets for colitis and potentially other inflammatory side effects of checkpoint blockade.
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•Mechanisms of inflammatory adverse events induced by checkpoint blockade•Colitis-associated differentiation of CD8 Trm cells to cytotoxic effector cells•Persistence and expansion of CTLA-4+ Treg cells•Inflammatory pathways provide opportunities for therapeutic intervention
Single-cell analyses of immune checkpoint blockade-associated colitis patient samples reveal enrichment of regulatory T cells in colitic lesions and nominate inflammatory pathways for potential therapeutic intervention.
Homogeneous catalysis has provided chemists with numerous transformations to enable rapid construction of organic molecules. However, these reactions are complex, requiring multiple ...substrate‐dependent mechanistic steps to operate in harmony under a single set of experimental conditions. As a consequence, synthetic chemists often carry out laborious, empirical screening to identify suitable catalysts, solvents, and additives to achieve high yields and selectivity. In this Minireview, recently developed tools, technologies, and strategies will be described that improve this development process. In particular, the application of high throughput techniques to run more experiments, experimental design principles to access better data, and statistical tools to provide predictive models will be discussed.
Catalytic reactions can be challenging to develop and implement because of unforeseen interactions between reaction components. As a consequence, chemists rely on laborious screening. This review describes strategies to improve the way that catalytic experiments are designed, implemented, analyzed, and interpreted.
With the identification of activating mutations in BRAF across a wide variety of malignancies, substantial effort was placed in designing safe and effective therapeutic strategies to target BRAF. ...These efforts have led to the development and regulatory approval of three BRAF inhibitors as well as five combinations of a BRAF inhibitor plus an additional agent(s) to manage cancer such as melanoma, non-small cell lung cancer, anaplastic thyroid cancer, and colorectal cancer. To date, each regimen is effective only in patients with tumors harboring BRAFV600 mutations and the duration of benefit is often short-lived. Further limitations preventing optimal management of BRAF-mutant malignancies are that treatments of non-V600 BRAF mutations have been less profound and combination therapy is likely necessary to overcome resistance mechanisms, but multi-drug regimens are often too toxic. With the emergence of a deeper understanding of how BRAF mutations signal through the RAS/MAPK pathway, newer RAF inhibitors are being developed that may be more effective and potentially safer and more rational combination therapies are being tested in the clinic. In this review, we identify the mechanics of RAF signaling through the RAS/MAPK pathway, present existing data on single-agent and combination RAF targeting efforts, describe emerging combinations, summarize the toxicity of the various agents in clinical testing, and speculate as to where the field may be headed.
Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to ...these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.
BACKGROUND
It remains unclear whether high doses of glucocorticoids have a negative impact on the efficacy of checkpoint inhibitors. To control for the potential association between immune‐related ...adverse events (irAEs) and improved survival, this study examined a unique cohort of patients who had the same irAE treated with varying glucocorticoid doses.
METHODS
In total, 98 patients with melanoma who had ipilimumab‐induced hypophysitis were identified retrospectively in the Partners Healthcare system using an automated electronic medical record query tool. Patients with melanoma who received ipilimumab at Massachusetts General Hospital without developing hypophysitis were listed in an actively maintained institutional patient database. Glucocorticoid doses for patients with hypophysitis were categorized as low dose (LD) or high dose (HD). Survival analyses were performed for patients who received ipilimumab monotherapy.
RESULTS
Both overall survival (OS) and the time to treatment failure were significantly longer in the LD group compared with the HD group (hazard ratio, 0.24; P = .002 and 0.28, P = .001, respectively). Median OS and the time to treatment failure were not reached in the LD group and were 23.3 and 14.5 months, respectively, in the HD group. All patients who had hypophysitis had improved OS compared with patients who did not have hypophysitis (median, 28.2 vs 9.5 months; P = .0003). This advantage was maintained in the HD group versus the nonhypophysitis group (P = .02). Radiologic and endocrinologic outcomes and symptom resolution did not differ in the LD group versus the HD group.
CONCLUSIONS
Among patients with melanoma who had ipilimumab‐induced hypophysitis, those who received higher doses of glucocorticoids had reduced survival. This is the first study to demonstrate a potential negative effect of high glucocorticoid doses on the efficacy of checkpoint inhibitors after an irAE. These findings have potential implications for the management of other irAEs.
This study is the first analysis of the effects of differing glucocorticoid doses on the antitumor efficacy of checkpoint inhibitors after the development of an immune‐related adverse event. The results demonstrate that high dosages of glucocorticoids may have a negative impact on the antitumor efficacy of checkpoint inhibitors and do not improve other outcomes for patients with hypophysitis.
The development of highly effective BRAF‐targeted therapy and immune checkpoint inhibition for patients with advanced metastatic melanoma has transformed the treatment of this disease. More recently, ...these advances have moved into the resected, high‐risk stage II and III settings. For patients with resected, BRAF‐mutant stage III melanoma, there are no head‐to‐head data to support the use of BRAF‐targeted therapy (specifically the combination of dabrafenib and trametinib) with either single‐agent nivolumab or pembrolizumab. Because the relapse‐free and distant metastasis–free survivals are similar in a cross‐trial comparison, it is not clear what the best option for these patients is. In this piece, the authors argue on behalf of and against both approaches.
Plain Language Summary
Two types of therapy exist for patients diagnosed with melanoma who have completed surgery and remain at high risk for tumor recurrence: (1) drugs that target the BRAF mutation (found in ∼50% of patients) and (2) immunotherapy.
There are no data showing that either approach is better than the other, so the choice of which therapy is best for an individual patient can be challenging.
In this article, we make arguments for and against each option.
Highly effective BRAF‐targeted therapy and anti–programmed death receptor 1 therapy are approved in the adjuvant setting to treat resected, high‐risk melanoma. Arguments for and against each approach are made in this Insight From the Experts piece.
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