The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, ...modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment.
Immunotherapy has revolutionized cancer treatment, yet most patients do not respond. Here, we investigated mechanisms of response by profiling the proteome of clinical samples from advanced stage ...melanoma patients undergoing either tumor infiltrating lymphocyte (TIL)-based or anti- programmed death 1 (PD1) immunotherapy. Using high-resolution mass spectrometry, we quantified over 10,300 proteins in total and ∼4,500 proteins across most samples in each dataset. Statistical analyses revealed higher oxidative phosphorylation and lipid metabolism in responders than in non-responders in both treatments. To elucidate the effects of the metabolic state on the immune response, we examined melanoma cells upon metabolic perturbations or CRISPR-Cas9 knockouts. These experiments indicated lipid metabolism as a regulatory mechanism that increases melanoma immunogenicity by elevating antigen presentation, thereby increasing sensitivity to T cell mediated killing both in vitro and in vivo. Altogether, our proteomic analyses revealed association between the melanoma metabolic state and the response to immunotherapy, which can be the basis for future improvement of therapeutic response.
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•Proteomics of 116 melanoma tumors shows the landscapes of response to immunotherapy•Immunotherapy response was associated with enriched mitochondrial lipid metabolism•High mitochondrial metabolism led to higher antigen presentation and IFN signaling•Knockout of beta-oxidation genes reduced melanoma sensitivity to T cell killing
Proteomic profiling of melanomas from patients undergoing immunotherapy reveals key mediators of tumor immunogenicity.
Purpose of Review
While immune checkpoint inhibitor (ICI) therapy has improved melanoma patient outcomes, it has also resulted in the rise of unique immune-related adverse events (irAEs). Here, we ...review and synthesize irAE management recommendations from several oncological societies into a streamlined format to aid in diagnosis and management. We also include clinical pearls highlighting several recent research studies in this field.
Recent Findings
Knowledge of immunotherapy toxicity has continually evolved, and several major oncologic societies have recently released new or updated guidelines.
Summary
Keeping up with the evolving field of immunotherapy and related toxicities is crucial, because ICI use, in combination with other agents, will only continue to increase and likely result in new and different patterns of irAEs. Providing clear and concise references for clinicians will help ensure proper irAE evaluation and management going forward. We present one such reference here, covering management of common and/or serious irAEs.
Gut bacteria modulate the response to immune checkpoint blockade (ICB) treatment in cancer, but the effect of diet and supplements on this interaction is not well studied. We assessed fecal ...microbiota profiles, dietary habits, and commercially available probiotic supplement use in melanoma patients and performed parallel preclinical studies. Higher dietary fiber was associated with significantly improved progression-free survival in 128 patients on ICB, with the most pronounced benefit observed in patients with sufficient dietary fiber intake and no probiotic use. Findings were recapitulated in preclinical models, which demonstrated impaired treatment response to anti–programmed cell death 1 (anti–PD-1)–based therapy in mice receiving a low-fiber diet or probiotics, with a lower frequency of interferon-γ–positive cytotoxic T cells in the tumor microenvironment. Together, these data have clinical implications for patients receiving ICB for cancer.
BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) are among the cornerstones of metastatic melanoma therapy demonstrating excellent response rates with duration of 7–12 m.
Long-term benefit from ...these agents was reported in patients with normal lactate dehydrogenase (LDH) and less than three disease sites. However, a treatment-dependent marker for long-term efficacy is lacking. Data suggest that immune-related adverse events (irAEs) are associated with clinical benefit in patients treated with immunotherapy and that response to BRAF/MEK therapy may have an underlying immune mechanism. We hypothesised that AEs with an underlying immune mechanism may be associated with a durable response to targeted therapy.
We retrospectively identified a cohort of 78 BRAF V600–mutant metastatic melanoma patients treated with BRAFi or BRAFi + MEKi between November 2010 and November 2013. Four treatment-related AEs including vitiligo, uveitis, erythema nodosum and keratitis sicca were defined as irAEs of interest. Retrospective analysis of AEs in relationship to progression-free survival (PFS), disease burden and LDH levels was performed.
Median PFS (mPFS) for all patients was 7.5 months with responses ongoing in eight patients as of April 2017. Ten patients were identified with the AEs defined previously. Cox regression analysis revealed a very strong association between those AEs and PFS; mPFS was 42.8 m in patients with at least one AE versus 6.1 m in those without an AE (hazard ratio HR 0.22, p = 0.002). This association was independent of LDH levels and disease burden (HR 0.24, p = 0.035).
This analysis demonstrates a strong association between immune AEs and durable response to targeted therapy and may provide a treatment-related biomarker to estimate the outcome of therapy.
•Targeted therapy in metastatic melanoma may cause immune-related adverse events (irAEs).•Patients with irAEs secondary to BRAF inhibitors show very durable responses.•IrAEs may serve as a predictive marker in targeted therapy in metastatic melanoma.
Hemorrhage is a leading cause of preventable death on the battlefield. Timely tourniquet application to massively bleeding extremity wounds is critical for casualty survival albeit with reported ...adverse effects to extremity integrity. The aim of this study was to describe the immediate- and short-term outcomes of point of injury (POI) tourniquet applications during "Operation Protective Edge" (OPE).
A case series study regarding tourniquet application at the POI during OPE was collected. The data gathered included reports by medical providers at the POI, aerial and land evacuation vehicles, and receiving hospitals. Variables collected included, the number of tourniquet applications, caregiver level, tourniquet type, limb characters, tourniquet effectiveness, in-hospital procedures, complications, and short-term limb outcome.
During OPE, the Israeli Defense Forces Medical Corps treated 704 casualties. Of these, 90 casualties were treated with 119 tourniquets of which 79 survived. Penetrating trauma was the mechanism of injury in 97.8% (88 of 90) of the casualties. Injuries sustained from improvised explosive devices and shrapnel were related to the use of more than one tourniquet per casualty and per limb (p = 0.034). The success rate of the first tourniquet was reported to be 70% (84 of 119), regardless of caregiver level (p = 0.56), tourniquet type (p = 0.16), or limb characters (p = 0.48). Twenty-seven (25.7%) of 105 of the tourniquets were converted to direct pressure dressings enroute to receiving hospitals two of the conversions failed and thus a new tourniquet was applied. Fasciotomy was performed on eight casualties (a single limb in each). Vascular injury was presumed to be the indication for fasciotomy in three of these cases, in the other five limbs (6%, 5 of 85), no vascular involvement was discovered during surgery, and the fasciotomy is suspected as tourniquet related. 7%) 6 of 85) suffered from neurological sequela that could not be explained by their primary injury. Total complication rate was 11.7% (10 of 85) (one patient had both fasciotomy and neural complication without vascular injury).
Tourniquet use on the battlefield is a simple method of eliminating preventable death, we believe that clinical practice guidelines should promote liberal use of tourniquets by trained combatants and medical personnel with abilities to convert to direct pressure hemorrhage control when possible since an unjustified tourniquet application risks low rates minor morbidity, whereas a justifiable tourniquet not applied may be lethal.
Epidemiologic study, level III; Therapeutic study, level IV.
Immunotherapy with checkpoint inhibitors revolutionized melanoma treatment in both the adjuvant and metastatic setting, yet not all metastatic patients respond, and metastatic disease still often ...recurs among immunotherapy-treated patients with locally advanced disease. TNFSF4 is a co-stimulatory checkpoint protein expressed by several types of immune and non-immune cells, and was shown in the past to enhance the anti-neoplastic activity of T cells. Here, we assessed its expression in melanoma and its association with outcome in locally advanced and metastatic disease. We used publicly available data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), and RNA sequencing data from anti-PD1-treated patients at Sheba medical center. TNFSF4 mRNA is expressed in melanoma cell lines and melanoma samples, including those with low lymphocytic infiltrates, and is not associated with the ulceration status of the primary tumor. Low expression of TNFSF4 mRNA is associated with worse prognosis in all melanoma patients and in the cohorts of stage III and stage IIIc–IV patients. Low expression of TNFSF4 mRNAs is also associated with worse prognosis in the subgroup of patients with low lymphocytic infiltrates, suggesting that tumoral TNFSF4 is associated with outcome. TNFSF4 expression was not correlated with the expression of other known checkpoint mRNAs. Last, metastatic patients with TNFSF4 mRNA expression within the lowest quartile have significantly worse outcome on anti-PD1 treatment, and a significantly lower response rate to these agents. Our current work points to TNFSF4 expression in melanoma as a potential determinant of prognosis, and warrants further translational and clinical research.
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