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Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. An Author Correction to this article was published on 06 March Treatment was well tolerated. Tissue was obtained at multiple time points, allowing analysis of the effects of single-agent anti-programmed cell death ligand 1 PD-L1 and the subsequent combination with chemotherapy on the TME. Twenty of 21 patients underwent surgery and were evaluable for secondary pathologic response and survival endpoints, and 19 were evaluable for exploratory translational analyses. At a median follow-up of 47 months, 13 of 14 responders were alive and disease-free, and five of six nonresponders had died as a result of recurrence. On the basis of these data, FLOT has become standard-of-care. Over the past decade, immune checkpoint blockade ICB has emerged as an effective and promising therapeutic approach in a variety of malignancies. PD-L1, an inhibitory checkpoint molecule, has been shown to be upregulated in gastric cancer 5 , 6 , and its expression negatively correlates with prognosis and survival 7 , 8. Importantly, anti-programmed cell death protein 1 PD-1 has also been shown to improve survival in patients with stage II and III disease in the Checkmate study, in which DFS was significantly higher in patients treated with adjuvant nivolumab compared to placebo in patients undergoing surgery after chemoradiotherapy for esophageal and GEJ adenocarcinoma, regardless of PD-L1 expression Neoadjuvant ICB has been shown to result in remarkable pathologic responses in several tumor types, including melanoma, lung cancer, bladder cancer and colorectal cancer. In addition, pathologic responses to ICB are highly correlated with improved survival 12 , 13 , 14 , 15 , 16 , 17 , The high response rate to neoadjuvant ICB may be attributed to the presence of a larger amount of antigen with which checkpoint inhibition can synergize Also, it may be speculated that, in case of tumor-draining lymph node dissection, ICB before surgery may benefit from the presence of a larger pool of tumor-reactive T cells. These data highlight the importance of predictive markers in personalization of neoadjuvant therapies. Although there is increasing evidence for the immune-potentiating effects of combined ICB plus chemotherapy 21 , 22 , the order in which to administer these therapies to achieve optimal antitumor efficacy remains to be elucidated. In early triple-negative breast cancer, anti-PD-1 monotherapy given before chemotherapy was associated with a higher pCR rate than concomitant anti-PD-1 plus chemotherapy 24 , In the current study, we aimed to evaluate the immune-modulating effects of PD-L1 blockade alone by administering monotherapy atezolizumab before its combination with chemotherapy. Tumor biopsies were obtained through endoscopy at baseline, after monotherapy atezolizumab and after the first combination treatment. Surgery was performed 6—9 weeks after the last treatment cycle, and tissue was obtained from surgical resection specimens Extended Data Fig. The primary objective was safety and feasibility. Secondary objectives included efficacy assessed by histopathologic regression, changes in the TME and clinical outcomes. An important purpose of this study design was to allow separate dissection of the effects of PD-L1 blockade alone and the subsequent combination with chemotherapy on the TME, as well as their association with clinical response. From 12 April to 14 May , a total of 21 patients were enrolled. Baseline patient and tumor characteristics are summarized in Table 1. One patient with a dMMR tumor died shortly after atezolizumab monotherapy because of external factors unrelated to the study treatment. Twenty patients underwent surgery and were evaluable in the per-protocol PP population for safety and secondary efficacy endpoints according to the study protocol Extended Data Fig. Overall, treatment was well tolerated, and the study met its primary endpoint of safety and feasibility. There were no grade 4 or 5 irAEs. In one patient, grade 3 immune-related hepatitis and meningitis were suspected on the basis of elevated liver enzymes and headache following monotherapy atezolizumab. Although liver biopsy and cerebrospinal fluid analysis failed to confirm these diagnoses, high-dose steroids and mycophenolate mofetil were started, with complete resolution of both AEs. Atezolizumab was discontinued, and the patient received all cycles of neoadjuvant chemotherapy. One patient with grade 3 diarrhea had complete resolution of symptoms within 1 week with supportive treatment. Finally, one patient who was excluded from the PP population experienced grade 3 fatigue after monotherapy atezolizumab, and steroid treatment was initiated. This AE could not be followed up because of study unrelated death. Chemotherapy was administered to all 20 patients. Twenty patients underwent surgery, all without treatment-related delays. One patient chose to postpone surgery for personal reasons. The median interval between the last study treatment and surgery was 6 weeks range 5—13 weeks. Thirteen patients underwent transhiatal esophagectomy with gastric tube reconstruction and cervical anastomosis, six patients a total gastrectomy with Roux-and-Y reconstruction and one patient subtotal gastrectomy with Billroth II reconstruction. One patient undergoing total gastrectomy for linitis plastica with a tumor-positive distal resection margin underwent adjuvant chemoradiotherapy. No unexpected surgical complications were observed, and there were no intraoperative complications or surgery-related deaths. Left, some preexistent lymphoid tissue arrowheads and complete tumor regression characterized by cholesterol clefts circle. Right, multinucleated giant cells arrowheads. Tumor regression was characterized histologically by fibrosis, neuronal hyperplasia, influx of immune cells, acellular mucin pools and regional necrosis Fig. Notably, resection specimens from multiple patients contained lymph nodes with evidence of histologic regression, including a patient with pretreatment clinical N3 stage whose resection specimen contained eight tumor-regressed lymph nodes without viable tumor cells Fig. Pathologically assessed downstaging was evident in 13 of 20 patients. Therefore, response assessment was mostly descriptive. Of the 13 pathologic responders who underwent preoperative CT scans, 11 patients were described as having a decrease in tumor size, yet none of the nine patients with a pCR were radiographically assessed as complete responders. Although ten of 12 pathologic responders were evaluated as near- complete responders, the remaining two responders both pCR in the primary tumor were assessed as partial responder and stable disease. These data are in line with the previously described underestimation of response to neoadjuvant immunotherapy by radiographic assessment across tumor types, highlighting the need for more accurate methods of response evaluation 17 , 29 , 30 , Disease recurrences in nonresponders occurred after a median follow-up of 10 months range 5—29 after surgery, and nonresponding patients with disease recurrence died with a median survival after recurrence of 10 months range 2— One responder with a cT3N3 tumor at baseline who had a pCR developed recurrent disease in the brain at 38 months after surgery. A solitary brain lesion was resected and confirmed clonal relatedness to the primary tumor. The patient died 4 months after diagnosis of metastatic disease as a result of rapidly progressive brain metastases. These data indicate an association between ctDNA and pathologic response to neoadjuvant treatment. Although ctDNA positivity and nonclearance at the presurgery time point were associated with an inferior DFS, this was not significant, probably because of the small sample size Extended Data Fig. Box plots represent the median, 25th and 75th percentiles; the whiskers extend from the hinge to the largest value no farther than 1. For comparison between nonresponders red and responders green , significance was tested using a two-sided Wilcoxon rank-sum test. P values were calculated using the two-sided log-rank test. One patient who discontinued atezolizumab after the first cycle was excluded from exploratory translational analyses because this TME was not considered representative for a response to the study treatment. An overview of samples used for translational analyses is provided in Supplementary Fig. Dots represent individual patients. The difference between R and NR was tested using a two-sided Wilcoxon rank-sum test. CXCL13 h. PD-1 i. PD-L1 j. FOXP3 k. CD45 l. Eosinophil signature m. Differences between R and NR were tested using a two-sided Wilcoxon rank-sum test. Differences between time points in R and NR separately were tested using a two-sided Wilcoxon signed-rank test. Only significant P values are shown; colors indicate a significant increase or decrease in responders green or a significant difference between responders and nonresponders black. RPM, reads per million. Importantly, and in contrast to findings in metastatic disease, where efficacy of immunotherapy is primarily observed in PD-L1 CPS-positive tumors, CPS was not predictive of response at cut-offs of 1, 5 or 10 Supplementary Table 2. These analyses did not show significant baseline differences between responders and nonresponders Fig. Boxplots represent the median, 25th and 75th percentiles; whiskers extend from the hinge to the largest value below 1. Blue stars indicate patients with dMMR tumors. Box plots represent the median, 25th and 75th percentiles; whiskers extend from the hinge to the largest value below 1. The difference between NR and R was tested using a two-sided Wilcoxon rank-sum test. Patients x axis were ordered on the basis of hierarchical clustering upper dendrogram. The association of signature expression with response is shown on the right as a lollipop plot of signed, two-sided Wilcoxon rank-sum test-based P values unadjusted for multiple hypothesis testing; x axis on log 10 scale. Deconvolution of RNA sequencing data indicated no other significant associations between pathologic response and relative cell type compositions Fig. Genomic analyses showed that the genetic makeup of our cohort was representative of this patient population Fig. Furthermore, these analyses did not show any significant associations between pathologic response and alterations of driver genes Fig. Notably, pathologic responses were observed despite a low pretreatment tumor mutational burden TMB , and TMB was not significantly different between responders and nonresponders, with a median of 4. A challenge in clinical immune-oncology studies that evaluate combination therapies has been to assign treatment-induced alterations of the TME to individual drugs or their combination. To understand whether therapy-induced TME alterations induced by the atezolizumab-chemotherapy combination are substantially different from the effects of atezolizumab monotherapy, we compared changes in the TME after the initial cycle of atezolizumab monotherapy to those observed on subsequent combination therapy. IMC was performed to further characterize tumor-infiltrating immune cells in a subset of pMMR tumors, including nonresponders and responders with a pCR Supplementary Fig. Because there is increasing evidence that the spatial proximity of immune cells to tumor cells may be predictive for response to ICB 42 , IMC data were also used to explore the spatial distribution of cells in the TME. Increased immune infiltration was also evident from transcriptomic data, showing increases in CD45 and eosinophil signature expression Fig. After exclusion of dMMR tumors, the observed higher immune activation in responders after monotherapy atezolizumab generally held true, although to a slightly lesser extent Supplementary Fig. With the availability of biopsies at different time points per patient, we were also able to assess the dynamics of immune cell subsets after the subsequent addition of chemotherapy to atezolizumab. As a control, transcriptomic analysis of samples at surgery showed that expression levels of above-mentioned immune-related genes remained relatively stable, with no significant changes relative to the samples obtained after the first combination cycle in either responders or nonresponders Fig. Importantly, pathologic response showed an excellent correlation with survival, with 13 of 14 responders without disease recurrence after a median follow-up of 47 months, whereas five of six nonresponders had a recurrence and died of their disease. In line with prior research in colorectal cancer and esophagogastric tumors 47 , 48 , we observed an association between ctDNA and recurrence risk. In addition, presurgical ctDNA status was associated with pathologic response, highlighting potential clinical utility. Despite the limitations of cross-trial comparisons and our small patient cohort, these findings warrant validation in larger cohorts. Albeit in a small cohort, these pathologic responses compare favorably to historical data in similar patient populations. Altogether, our results indicate that adding atezolizumab to neoadjuvant chemotherapy may lead to a higher pathologic response rate than expected with chemotherapy alone. Although a higher pathologic response rate is also observed in similar studies of ICB plus chemotherapy 49 , 50 , 52 , 53 , 54 , 55 , 56 , 57 , the seemingly higher responses achieved in our study may be attributed to differences in study design including induction treatment with atezolizumab monotherapy and total neoadjuvant treatment instead of perioperative treatment. Second, and most importantly, our study design included a cycle of monotherapy atezolizumab before combination with chemotherapy, providing the opportunity to specifically capture the contribution of anti-PD-L1 and the subsequent combination with chemotherapy. Nevertheless, it should be noted that a single dose of chemotherapy before the introduction of anti-PD-1 in gastric cancer patients has led to similar signs of immune activation Therefore, although our findings are consistent with ICB potentially priming the TME, a randomized comparison is warranted to clarify these data. These findings indicate that after chemotherapy, an immunosuppressive TME with high T reg cell infiltration potentially contributes to ICB treatment failure and thus provides a topic for future investigation that may help unravel mechanisms underlying nonresponse to ICB Limitations of our study include the small number of patients and the single-arm design, making this a proof-of-concept study. Regardless, immune activation on atezolizumab monotherapy was unambiguous and most prominent in responding patients. Furthermore, the observed high T reg cell infiltration in nonresponders, together with emerging evidence that T reg cell-targeted approaches may enhance neoadjuvant ICB efficacy, prompt further exploration in future studies In addition to next-generation anti-CTLA-4, which has been shown to improve T reg cell depletion 64 , 65 , antibodies targeting CCR8, a chemokine receptor selectively expressed on immunosuppressive T reg cells in the TME, are being developed and may provide new avenues 66 , Additionally, on the basis of the observation that atezolizumab monotherapy leads to prominent changes in the TME, the question of whether selective absence of chemotherapy during the first treatment cycle is causally related to the observed high response rate may be explored. Eligible patients were 18 years of age or older and had previously untreated, histologically confirmed gastric or GEJ adenocarcinoma that was deemed resectable and showed no signs of distant metastases. Full inclusion and exclusion criteria were as follows. Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days before initiation of study treatment:. For diffuse-type gastric cancers, diagnostic laparoscopy should be performed and show no signs of peritoneal metastases. Patients must be willing to undergo esophagogastroduodenoscopy and biopsies before start of treatment and during treatment at defined time points. Men receiving atezolizumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. Women who are not of childbearing potential that is, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception. Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only for example, patients with psoriatic arthritis are excluded are eligible for the study provided all of the following conditions are met:. No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors or high-potency or oral corticosteroids in the previous 12 months. History of idiopathic pulmonary fibrosis, organizing pneumonia for example, bronchiolitis obliterans , drug-induced pneumonitis or idiopathic pneumonitis or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field fibrosis is permitted. Significant cardiovascular disease such as New York Heart Association Class II or greater cardiac disease, myocardial infarction or cerebrovascular accident within 3 months before initiation of study treatment, unstable arrhythmia or unstable angina. Major surgical procedure other than diagnostic laparoscopy within 4 weeks before initiation of study treatment or anticipation of need for a major surgical procedure, other than for this diagnosis, during the study. Severe infection within 4 weeks before initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia or severe pneumonia. Any other disease, metabolic dysfunction, physical examination finding or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results or may render the patient at high risk from treatment complications. Treatment with a live, attenuated vaccine within 4 weeks before initiation of study treatment or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab. Treatment with systemic immunostimulatory agents including, but not limited to, interferon and interleukin 2 IL-2 within 4 weeks or 5 half-lives of the drug whichever is longer before initiation of study treatment. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins. Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation. Intercurrent illnesses, including, but not limited to, infections, that are determined incompatible with the study treatment and protocol by the study team. Underlying medical conditions that will make the administration of the study drug hazardous or obscure the interpretation of toxicity determination of AEs. Positive test for hepatitis B surface antigen or hepatitis C virus ribonucleic acid HCV antibody indicating acute or chronic infection. History of testing positive human immunodeficiency virus or known acquired immunodeficiency syndrome AIDS. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. Pregnancy or breastfeeding or intention of becoming pregnant during study treatment or within months after the last dose of study treatment. Because of the exploratory nature of this study, no formal sample size calculation was performed. The present study aimed to include a total of 20 patients Extended Data Fig. Patients were consulted in the outpatient clinic of the Netherlands Cancer Institute. Long-term follow-up was performed either at the outpatient clinic, by telephone or through telemedicine. All treatment cycles were given preoperatively, and patients received no standard adjuvant treatment. Surgery was scheduled 6—9 weeks after the start of the last treatment cycle. The type of surgical procedure was determined predominantly on the basis of tumor location. Patients underwent a transhiatal esophagectomy with gastric tube reconstruction and cervical anastomosis or either subtotal gastrectomy with Billroth II reconstruction or total gastrectomy with Roux-and-Y reconstruction. In all patients, a formal lymphadenectomy was performed. The surgical approach was open or minimally invasive. Primary endpoints were safety and feasibility. Safety analyses were performed in the PP population defined as all patients who received at least one dose of the study drugs atezolizumab, docetaxel, oxaliplatin and capecitabine. Patients were monitored for S AEs until days after the last dose of study treatment, and events were scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v. Feasibility was determined by adherence to the timeline according to the study protocol. Secondary and translational endpoints were analyzed in the PP population and included DFS calculated from the date of surgery, OS calculated from the date of enrollment, radiologic tumor regression assessed before cycle 4 of combination treatment, efficacy evaluated by histopathological response to treatment and associations between pathologic response and genomics, transcriptomics, IHC and IMC findings and ctDNA, including the TMB, gene expression signatures and TCI. In absence of measurable lesions, considering that the primary tumor in a hollow organ cannot be assessed according to RECIST 1. Before the start of treatment, clinical stage was assessed by physical examination, esophagoduodenoscopy with representative biopsies from tumor and normal tissue, blood tests and CT scan of thorax and abdomen. For cT3 and cT4 gastric cancers, diagnostic laparoscopy was performed to exclude signs of peritoneal metastases according to national guidelines. Baseline clinical staging of primary tumors and lymph nodes was done according to the 8 th edition of the AJCC Cancer Staging Manual Blood samples, including peripheral blood mononuclear cells PBMCs , were obtained before each treatment cycle, before surgery and during follow-up. On-treatment endoscopy with biopsies was performed after the initial cycle of atezolizumab monotherapy and again after the first cycle of DOC-A combination treatment. Posttreatment tissue was obtained by surgical resection. All tissue samples were directly frozen or formalin-fixed and embedded in paraffin. Baseline characteristics are presented for the intention-to-treat population defined as all patients enrolled in the study. Categorical variables are summarized as absolute numbers and percentages and continuous variables with medians and interquartile ranges. The Kaplan—Meier method was used to analyze time-to-event endpoints. A log-rank test was used to compare DFS and OS curves between responders and nonresponders; for comparison of the OS curves, landmark analysis was performed with a landmark at the date of surgery. Median follow-up time from enrollment was calculated using the reverse Kaplan—Meier method. Analyses were performed using R v. Experiments performed on patient-derived material were not repeated. All patients provided written informed consent before enrollment. There was no Data Safety Monitoring Board. Formalin-fixed, paraffin-embedded FFPE sections were obtained from biopsies taken before and during treatment as well as from resection specimens. Two experienced gastrointestinal pathologists performed histopathologic examination of biopsies and resection specimens. Digital imaging analysis was performed using HALO imaging analysis software v. Tumor areas were manually annotated by an experienced pathologist. Results presented here were obtained by measuring the entire tumor area followed by quantification of stained cells in these areas. IMC was performed on biopsies obtained at baseline and after monotherapy atezolizumab from a subset of patients with pMMR tumors, including nonresponders and responders with a pCR. In short, tissue sections were deparaffinized by consecutive incubations in Xylol and ethanol, followed by heat-mediated antigen retrieval in high-pH Antigen Retrieval Solution eBioscience, Thermo Fisher Scientific. All antibodies were previously tested for optimal incubation temperature. Data quality was visually inspected using the Fluidigm MCD viewer v. Images were normalized by rescaling all images and markers between 0 and 1 followed by a two-step denoising where first a minimal signal threshold of 0. Cell segmentation masks were generated from the normalized images using CellProfiler v. First nuclei were defined using the DNA images to which membranes were added using keratin, vimentin and CD45 images. Single-cell marker expression flow cytometry standard files were generated by combining the normalized images with cell segmentation masks in ImaCytE 77 , and after dimensionality reduction, cells were clustered by mean-shift clustering in Cytosplore v. Clusters were mapped back on the images and visually confirmed by comparison with raw images in the MCD viewer. Finally, cluster abundances per image were combined per sample and visualized as cells per mm 2. Because of low abundance of CD and Granzyme B, no distinct clusters were formed, and thus their presence was determined by counting the number of cells with a marker expression above 0. To account for random localization of highly abundant cells, a iteration permutation test was used in which all cells were randomly distributed throughout the image. All interactions with a Z -score greater than 2 were considered specific. Data were combined and visualized in RStudio R v. RNA was isolated from tumor samples taken pre-, on- and posttreatment to determine expression of various individual genes as well as immune-related gene signatures. During library amplification, four PCR cycles were performed to obtain enough yield for exome capture. The pool was captured with an xGen Exome V2. After paired-end adapter trimming using SeqPurge v. BaseRecalibrator Genome Analysis Toolkit pipeline, v. To characterize the mutational driver landscape of the cohort, we considered all nonsynonymous mutations affecting oncogenes and tumor suppressors in the cancer-driver catalog, as previously defined Strand synthesis was performed using Polymerase I and RNaseH, replacing deoxythymidine triphosphate with deoxyuridine triphosphate. The hybridized target regions were captured using streptavidin magnetic beads and subjected to two stringency washes, an elution step and a second round of enrichment followed by cleanup using AMPure XP beads Beckman, A and PCR amplification of ten cycles. The target-enriched pools were analyzed on a Bioanalyzer using a chip Agilent , diluted and subsequently pooled equimolar into a multiplex sequencing pool. Then, samples were aligned to the human reference genome GRCh38 using hisat2 v. The expression of specific marker gene sets was calculated as the mean log 2 reads per million expression of the genes in the gene set Supplementary Table 4 and refs. This method allows for filtering out putative germline and clonal hematopoiesis of indeterminate potential mutations. A prioritized list of up to 16 somatic single-nucleotide variants were selected, for which PCR amplicons were designed and applied to cfDNA of all patients A median of The ctDNA concentration was measured and reported as mean tumor molecules per milliliter of plasma Survival analyses were carried out with R software v. The Kaplan—Meier method was used to estimate the survival distribution. Differences between groups were tested using the log-rank test. To account for immortal time bias, a landmark analysis was performed at 12 weeks after surgery, whereby DFS was measured starting from day Analysis of ctDNA concentration between responders and nonresponders at a post-neoadjuvant time point was performed using the ggplot2 package v. Box plots were generated using the ggplot2 package v. Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. The researcher will need to sign a data access agreement with the NKI after approval. 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Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria irPRC. Vos, J. Imaging 49 , — Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial. Rozeman, E. Cascone, T. Gros, A. Hummelink, K. Cancer Res. Thommen, D. Duhen, T. Ayers, M. Schumacher, T. Tertiary lymphoid structures in cancer. Science , eabf Siddiqui, I. Immunity 50 , — Zhao, X. TCF1 in T cell immunity: a broadened frontier. Krystel-Whittemore, M. Mast cell: a multi-functional master cell. Front Immunol. PubMed Google Scholar. Network, C. Comprehensive molecular characterization of gastric adenocarcinoma. Nature , — Chen, Y. Predicting response to immunotherapy in gastric cancer via multi-dimensional analyses of the tumour immune microenvironment. Basham, T. Blomberg, O. Cancer Cell 41 , — Cunningham, D. 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ImaCytE: visual exploration of cellular micro-environments for imaging mass cytometry data. IEEE Trans. Forum 35 , — Priestley, P. Pan-cancer whole-genome analyses of metastatic solid tumours. Alexandrov, L. The repertoire of mutational signatures in human cancer. Nature , 94— Danaher, P. Gene expression markers of tumor infiltrating leukocytes. Cancer 5 , 18 Reinert, T. JAMA Oncol. Download references. We thank Hoffman-La Roche for funding this study. We thank all the patients and their families for participating in the present study. Broeks, S. Cornelissen and M. Alkemade, for their support in processing samples and performing immunohistochemistry; M. Nieuwland, R. Kluin, A. Velds and the Genomics Core Facility for their support with sequencing; I. Harkes and Y. Al-van Wijck and M. Brandhorst for facilitating sample acquisition and processing; T. Korse, M. Lucas and E. Hilhorst and M. We would also like to acknowledge M. Liu and G. Laliotis from Natera for their supervision and critical review of the ctDNA analysis. The funding source had no role in design and execution of the study, data analysis or writing of the manuscript. Yara L. Verschoor, Jolanda M. Vollebergh, Peggy den Hartog, Monique E. Joris van de Haar, Ton N. Johanna W. Marieke E. Marieke A. Vollebergh, John B. You can also search for this author in PubMed Google Scholar. All authors reviewed, edited and approved the manuscript and vouch for the accuracy of the data reported and adherence to the protocol. Correspondence to Myriam Chalabi. All grants were paid to the institution s. All grants were paid to the institutions. Nature Medicine thanks Anwaar Saeed and the other, anonymous, reviewer s for their contribution to the peer review of this work. Representative biopsies from tumor and normal tissue were obtained after monotherapy atezolizumab and after the first combination cycle. Surgery was performed 6—9 weeks after the last treatment cycle and tissue was obtained from surgical resection specimens. The intention-to-treat ITT population was defined as all patients enrolled in the study. The per-protocol PP population was defined as all patients who received at least one dose of the study drugs atezolizumab, docetaxel, oxaliplatin and capecitabine. Patients are ordered by decreasing clinical follow-up. Significance was calculated using the two-sided log-rank test. Significance was calculated using a two-sided log-rank test. Reprints and permissions. Verschoor, Y. Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial. Nat Med 30 , — Download citation. Received : 12 May Accepted : 07 December Published : 08 January Issue Date : February Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly. Skip to main content Thank you for visiting nature. Download PDF. This article has been updated. Neoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer Article Open access 03 January Results Patient characteristics From 12 April to 14 May , a total of 21 patients were enrolled. Table 1 Baseline patient and tumor characteristics Full size table. Full size image. Methods Patient population Eligible patients were 18 years of age or older and had previously untreated, histologically confirmed gastric or GEJ adenocarcinoma that was deemed resectable and showed no signs of distant metastases. Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation Intercurrent illnesses, including, but not limited to, infections, that are determined incompatible with the study treatment and protocol by the study team Underlying medical conditions that will make the administration of the study drug hazardous or obscure the interpretation of toxicity determination of AEs Positive test for hepatitis B surface antigen or hepatitis C virus ribonucleic acid HCV antibody indicating acute or chronic infection History of testing positive human immunodeficiency virus or known acquired immunodeficiency syndrome AIDS History of uncontrolled medical or psychiatric illness. Endpoints and statistics Primary endpoints were safety and feasibility. Pathology assessments and IHC analyses Formalin-fixed, paraffin-embedded FFPE sections were obtained from biopsies taken before and during treatment as well as from resection specimens. Reporting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. References Sung, H. Article Google Scholar Bailly, C. Article Google Scholar Gordon, A. Article Google Scholar van Hagen, P. Article Google Scholar van der Werf, L. Article Google Scholar Priestley, P. Acknowledgements We thank Hoffman-La Roche for funding this study. Schumacher Authors Yara L. Verschoor View author publications. View author publications. Ethics declarations Competing interests Y. Peer review Peer review information Nature Medicine thanks Anwaar Saeed and the other, anonymous, reviewer s for their contribution to the peer review of this work. Extended data. Extended Data Fig. Extended Data Table 5 Pathologic response rate Full size table. Supplementary information Supplementary Information Supplementary Figs. Reporting Summary. About this article. Cite this article Verschoor, Y. Copy to clipboard. Isaeva Marleen Kok Nature Medicine Search Search articles by subject, keyword or author. Show results from All journals This journal. Advanced search. Close banner Close. Email address Sign up. Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer.

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