Purpose: The CROSS trial established neoadjuvant chemoradiotherapy (nCRT) for patients with resectable esophageal adenocarcinoma (rEAC). In the PERFECT trial, we investigated the feasibility and efficacy of nCRT combined with programmed-death ligand-1 (PD-L1) inhibition for rEAC. Patients and Methods: Patients with rEAC received nCRT according to the CROSS regimen combined with five cycles of atezolizumab (1,200 mg). The primary endpoint was the feasibility of administering five cycles of atezolizumab in ≥75% patients. A propensity score–matched nCRT cohort was used to compare pathologic response, overall survival, and progression-free survival. Exploratory biomarker analysis was performed on repeated tumor biopsies. Results: We enrolled 40 patients of whom 85% received all cycles of atezolizumab. Immune-related adverse events of any grade were observed in 6 patients. In total, 83% proceeded to surgery. Reasons for not undergoing surgery were progression (n = 4), patient choice (n = 2), and death (n = 1). The pathologic complete response rate was 25% (10/40). No statistically significant difference in response or survival was found between the PERFECT and the nCRT cohort. Baseline expression of an established IFNγ signature was higher in responders compared with nonresponders (P = 0.043). On-treatment nonresponders showed either a high number of cytotoxic lymphocytes (CTL) with a transcriptional signature consistent with expression of immune checkpoints, or a low number of CTLs. Conclusions: Combining nCRT with atezolizumab is feasible in patients with rEAC. On the basis of our exploratory biomarker study, future studies are necessary to elucidate the potential of neoadjuvant immunotherapy in patient subgroups. See related commentary by Catenacci, p. 3269

Chemotherapy (CT), radiotherapy (RT), and chemoradiotherapy (CRT) are able to alter the composition of the tumor immune microenvironment (TIME). Understanding the effect of these modalities on the TIME could aid in the development of improved treatment strategies. Our aim was to systematically review studies investigating the influence of CT, RT or CRT on different TIME markers. The EMBASE (Ovid) and PubMed databases were searched until January 2019 for prospective or retrospective studies investigating the dynamics of the local TIME in cancer patients (pts) treated with CT, RT or CRT, with or without targeted agents. Studies could either compare baseline and follow-up specimens - before and after treatment - or a treated versus an untreated cohort. Studies were included if they used immunohistochemistry and/or flow cytometry to assess the TIME. In total we included 110 studies (n = 8850 pts), of which n = 89 (n = 6295 pts) compared pre-treatment to post-treatment specimens and n = 25 (n = 2555 pts) a treated versus an untreated cohort (4 studies conducted both comparisons). For several tumor types (among others; breast, cervical, esophageal, ovarian, rectal, lung mesothelioma and pancreatic cancer) remodeling of the TIME was observed, leading to a potentially more immunologically active microenvironment, including one or more of the following: an increase in CD3 or CD8 lymphocytes, a decrease in FOXP3 Tregs and increased PD-L1 expression. Both CT and CRT were able to immunologically alter the TIME. The TIME of several tumor types is significantly altered after conventional therapy creating opportunities for concurrent or sequential immunotherapy.

Purpose: Cachexia is a multifactorial syndrome, associated with poor survival in patients with cancer, and is influenced by the gut microbiota. We investigated the effects of fecal microbiota transplantation (FMT) on cachexia and treatment response in patients with advanced gastroesophageal cancer. Experimental Design: In a double-blind randomized placebo-controlled trial performed in the Amsterdam University Medical Center, we assigned 24 cachectic patients with metastatic HER2-negative gastroesophageal cancer to either allogenic FMT (healthy obese donor) or autologous FMT, prior to palliative chemotherapy (capecitabine and oxaliplatin). Primary objective was to assess the effect of allogenic FMT on satiety. Secondary outcomes were other features of cachexia, along with disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and toxicity. Finally, exploratory analyses were performed on the effect of FMT on gut microbiota composition (metagenomic sequencing) and metabolites (untargeted metabolomics). Results: Allogenic FMT did not improve any of the cachexia outcomes. Patients in the allogenic group (n = 12) had a higher DCR at 12 weeks (P = 0.035) compared with the autologous group (n = 12), longer median OS of 365 versus 227 days [HR = 0.38; 95% confidence interval (CI), 0.14–1.05; P = 0.057] and PFS of 204 versus 93 days (HR = 0.50; 95% CI, 0.21–1.20; P = 0.092). Patients in the allogenic group showed a significant shift in fecal microbiota composition after FMT (P = 0.010) indicating proper engraftment of the donor microbiota. Conclusions: FMT from a healthy obese donor prior to first-line chemotherapy did not affect cachexia, but may have improved response and survival in patients with metastatic gastroesophageal cancer. These results provide a rational for larger FMT trials.

Background: Dynamic alterations of the tumor immune microenvironment in esophageal squamous cell carcinoma (ESCC) after different neoadjuvant therapies were understudied. Methods: We used mass cytometry with a 42-antibody panel for 6 adjacent normal esophageal mucosa and 26 tumor samples (treatment-naïve, n=12; postneoadjuvant, n=14) from patients with ESCC. Single-cell RNA sequencing of previous studies and bulk RNA sequencing from The Cancer Genome Atlas were analyzed, flow cytometry, immunohistochemistry, and immunofluorescence analyses were performed. Results: Poor tumor regression was observed in the neoadjuvant chemotherapy group. Radiotherapy-based regimens enhanced CD8⁺ T cells but diminished regulatory T cells and promoted the ratio of effector memory to central memory T cells. Immune checkpoint blockade augmented NK cell activation and cytotoxicity by increasing the frequency of CD16⁺ NK cells. We discovered a novel CCR4⁺CCR6⁺ macrophage subset that correlated with the enrichment of corresponding chemokines (CCL3/CCL5/CCL17/CCL20/CCL22). We established a CCR4/CCR6 chemokine-based model that stratified ESCC patients with differential overall survival and responsiveness to neoadjuvant chemoradiotherapy combined with immunotherapy, which was validated in two independent cohorts of esophageal cancer with neoadjuvant treatment. Conclusions: This work reveals that neoadjuvant therapy significantly regulates the cellular composition of the tumor immune microenvironment in ESCC and proposes a potential model of CCR4/CCR6 system to predict the benefits from neoadjuvant chemoradiotherapy combined with immunotherapy.

Idiopathic pulmonary fibrosis is a rare, progressive and fatal lung disease which affects approximately 5 million persons worldwide. Although pirfenidone and/or nintedanib treatment improves patients’ wellbeing, the prognosis of IPF remains poor with 5-year mortality rates still ranging from 70 to 80%. The promise of the anti-cancer agent nintedanib in IPF, in combination with the recent notion that IPF shares several pathogenic pathways with cancer, raised hope that immune checkpoint inhibitors, the novel revolutionary anticancer agents, could also be the eagerly awaited ground-breaking and unconventional novel treatment modality limiting IPF-related morbidity/mortality. In the current review, we analyse the available literature on immune checkpoint proteins in IPF to explore whether immune checkpoint inhibition may be as promising in IPF as it is in cancer. We conclude that despite several promising papers showing that inhibiting specific immune checkpoint proteins limits pulmonary fibrosis, overall the data seem to argue against a general role of immune checkpoint inhibition in IPF and suggest that only PD-1/PD-L1 inhibition may be beneficial.

Background: Alternatives in treatment-strategies exist for resectable gastric cancer. Our aims were: (1) to assess the benefit of perioperative, neoadjuvant and adjuvant treatment-strategies and (2) to determine the optimal adjuvant regimen for gastric cancer treated with curative intent. Methods: PubMed, EMBASE, CENTRAL, and ASCO/ESMO conferences were searched up to August 2017 for randomized-controlled-trials on the curative treatment of resectable gastric cancer. We performed two network-meta-analyses (NMA). NMA-1 compared perioperative, neoadjuvant and adjuvant strategies only if there was a direct comparison. NMA-2 compared different adjuvant chemo(radio)therapy regimens, after curative resection. Overall-survival (OS) and disease-free-survival (DFS) were analyzed using random-effects NMA on the hazard ratio (HR)-scale and calculated as combined HRs and 95% credible intervals (95% CrIs). Results: NMA-1 consisted of 9 direct comparisons between strategies for OS (14 studies, n = 4187 patients). NMA-2 consisted of 16 direct comparisons between adjuvant chemotherapy/chemoradiotherapy regimens for OS (37 studies, n = 10,761) and 14 for DFS (30 studies, n = 9714 patients). Compared to taxane-based-perioperative-chemotherapy, surgery-alone (HR = 0.58, 95% CrI = 0.38–0.91) and perioperative-chemotherapy regimens without a taxane (HR = 0.79, 95% CrI = 0.58–1.15) were inferior in OS. After curative-resection, the doublet oxaliplatin-fluoropyrimidine (for one-year) was the most efficacious adjuvant regimen in OS (HR = 0.47, 95% CrI = 0.28–0.80). Conclusions: For resectable gastric cancer, (1) taxane-based perioperative-chemotherapy was the most promising treatment strategy; and (2) adjuvant oxaliplatin-fluoropyrimidine was the most promising regimen after curative resection. More research is warranted to confirm or reproach these findings.