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Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8+T cells from systemic circulation. Within the liver, activated antigen-specific Fas+CD8+T cells undergo apoptosis following their interaction with FasL+CD11b+F4/80+monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.

BACKGROUND:Kim et al. report two patients with melanoma metastases to the brain that responded to treatment with RRx-001 and whole brain radiotherapy (WBRT) without neurologic or systemic toxicity in the context of a phase I/II clinical trial. RRx-001 is an reactive oxygen and reactive nitrogen species (ROS/RNS)-dependent systemically nontoxic hypoxic cell radiosensitizer with vascular normalizing properties under investigation in patients with various solid tumors including those with brain metastases. SIGNIFICANCE:Metastatic melanoma to the brain is historically associated with poor outcomes and a median survival of 4 to 5 months. WBRT is a mainstay of treatment for patients with multiple brain metastases, but no significant therapeutic advances for these patients have been described in the literature. To date, candidate radiosensitizing agents have failed to demonstrate a survival benefit in patients with brain metastases, and in particular, no agent has demonstrated improved outcome in patients with metastatic melanoma. Kim et al. report two patients with melanoma metastases to the brain that responded to treatment with novel radiosensitizing agent RRx-001 and WBRT without neurologic or systemic toxicity in the context of a phase I/II clinical trial.

Introduction:Immune checkpoint inhibitors (ICIs) are associated with myocarditis; however, there is no consensus on strategies to identify or monitor for myocarditis. We sought to characterize longitudinal biomarkers in patients receiving ICIs.Methods:We conducted an observational cohort study of adult (≥18 years) patients who had received at least one dose of single or dual ICI at Michigan Medicine between June 2014 - December 2021. Patients were identified as having myocarditis if a clinical diagnosis was noted in the medical record by the cardiovascular consult team. Laboratory values (i.e., high-sensitivity troponin-T [hsTnT], aspartate transaminase [AST], alanine transaminase [ALT], lactate dehydrogenase [LDH], and creatinine phosphokinase [CPK]) were collected from medical records for 12 months after beginning ICI.Results:In 2,606 patients (mean (SD) age 64 (13) years; 60.8% male), 27 (1.0%) developed myocarditis at a median (IQR) time of 28 (18,40) days after starting ICIs. At diagnosis, most patients with myocarditis had a non-cardiac immune-related adverse event (88.9%) and an elevated ALT (88.9%), AST (85.2%), CPK (88.9%), and LDH (92.6%). All patients with myocarditis had an elevated hsTnT. Compared to patients without myocarditis, patients with myocarditis had significant elevations in ALT, AST, CPK, and LDH after starting ICIs (all P<0.001) (Figure). In patients with myocarditis, average concentrations of AST and ALT remained elevated at 12 months, whereas CPK peaked at 1 month then rapidly declined. Average concentrations of all biomarkers in patients without myocarditis were in the normal range. CPK values greater than the upper limit of normal had a sensitivity and specificity of detecting myocarditis of 99% and 23%, respectively.Conclusions:Myocarditis rarely occurs in the absence of other immune-related adverse events. Elevated AST, ALT and CPK should prompt measuring hs-TnT and initiating further evaluation for ICI myocarditis.

IMPORTANCE: The anti–PD-1 therapeutic antibody, nivolumab, has demonstrated clinical activity in patients with advanced melanoma. The activity of nivolumab in subgroups of patients with tumors which have wild-type BRAF kinase vs patients with tumors having mutant BRAF has not systematically been explored in a large dataset. OBJECTIVE: To evaluate the efficacy and safety of nivolumab in patients with wild-type BRAF and mutant BRAF metastatic melanoma. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective analysis of data pooled from 4 clinical trials of nivolumab in 440 adult patients with unresectable stage III or stage IV melanoma, who had been tested for BRAF mutational status while participating in one of the studies. INTERVENTION: The investigational drug, nivolumab, was administered intravenously to study participants over a 60-minute period, at doses of 0.1, 0.3, 1.0, 3.0, or 10.0 mg/kg every 2 weeks until disease progression, discontinuation owing to adverse events, withdrawal, or end of study. Most patients (83%) received nivolumab at a dosage of 3 mg/kg. MAIN OUTCOME AND MEASURE: Best overall response by modified World Health Organization or Response Evaluation Criteria In Solid Tumors criteria and safety profile. RESULTS: Of a total of 440 patients from 4 nivolumab clinical trials included in the analysis, 334 were BRAF wild-type and 106 were positive for BRAF V600 mutation. With the exception of prior BRAF inhibitor therapy, the demographics were well balanced between the 2 cohorts. In patients evaluable for response, the objective response rates were 34.6% (95% CI, 28.3-41.3) for the 217 patients with wild-type BRAF status and 29.7% (95% CI, 19.7-41.5) for the 74 with mutant BRAF status. The objective response rates did not seem to be affected by prior BRAF inhibitor therapy, prior ipilimumab therapy, or PD-L1 status of the tumor. The median duration of objective response was 14.8 months (95% CI, 11.1-24.0 months) for wild-type BRAF and 11.2 months (95% CI, 7.3-22.9 months) for mutant BRAF. Median time to objective response was 2.2 months in both patient groups. The incidence of treatment-related adverse events of any grade was 68.3% in the wild-type BRAF group and 58.5% in the mutant BRAF group, with grade 3 or 4 adverse events in 11.7% and 2.8% of patients, respectively. Treatment-related AEs of any grade that occurred in at least 5% of patients in either group were fatigue, pruritus, rash, and diarrhea. CONCLUSIONS AND RELEVANCE: The results of this retrospective analysis suggest that nivolumab has similar efficacy and safety outcomes in patients with wild-type or mutant BRAF, regardless of prior BRAF inhibitor or ipilimumab treatment.

Dysplasia in Barrett esophagus is a premalignant condition that is associated with an increased risk of developing esophageal adenocarcinoma. Unfortunately, clinical investigation aimed at prevention of progression to malignant disease has been hampered by the variable prevalence of dysplasia reported in the literature. The objective of the current study was to more accurately determine the prevalence of dysplasia among individuals with Barrett esophagus who would be available for enrollment in a chemoprevention trial. The pathology archives of 3 institutions were reviewed over a 5-year period for all reports of diagnoses of Barrett esophagus. Surgical cases, malignancies, and duplicate or referral cases were excluded from the analysis. A total of 790 cases of Barrett esophagus were identified. Of these, 37 (4.7%) were cases of low-grade dysplasia (LGD), and 20 (2.5%) were cases of high-grade dysplasia. The University of Michigan Medical Center (Ann Arbor, MI) diagnosed 18 cases of LGD, Henry Ford Hospital (Detroit, MI) diagnosed 15 cases of LGD, and Brigham and Women's Hospital (Boston, MA) diagnosed 4 cases of LGD in patients with Barrett esophagus over the 5-year study period. The confirmed low prevalence of cases of LGD will affect the design of future clinical trials of chemopreventive interventions for Barrett esophagus. Cancer 2004. © 2004 American Cancer Society.

L’essai de phase 3 CheckMate 067 a montré un bénéfice clinique durable et prolongé avec l’association nivolumab (NIVO)+ipilimumab (IPI) et avec NIVO seul vs IPI sur une période de suivi de 5 ans (taux de survie globale [SG] et de survie sans progression [SSP] : 52 %, 44 %, 26 % et 36 %, 29 %, 8 %, respectivement). Sont présentées ici les données d’efficacité et de tolérance à 6,5 ans.

Immune checkpoint inhibitors (ICIs) have been a transformational advance in cancer therapy in the past decade. However, ICIs can produce immune-related adverse effects (irAEs), which can lead to both morbidity and premature termination of therapy. Recent studies suggest that the gut microbiota and its metabolites affect ICI efficacy and toxicity. Herein, we review such evidence in the context of ICI-induced colitis. In particular, the short-chain fatty acid butyrate, a microbial metabolite, has known protective effects on the intestine. We discuss how the use of dietary prebiotics, which can be metabolized by bacteria to produce butyrate, can be an intriguing new investigational approach to prevent ICI-associated colitis and lead to improved patient outcomes.

The mutations present in advanced cancers can be identified by integrative high-throughput sequencing to enable biomarker-driven clinical trials and, ultimately, treatment.