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2. Supplementary Figure from Escherichia coli–Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer
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Yohann Loriot, Laurence Zitvogel, Jean-Yves Scoazec, Guido Kroemer, Miriam Merad, Fabrice Andre, Benjamin Besse, Michiel S. Van Der Heijden, Nick Van Dijk, Jeroen Van Dorp, Aurélien Marabelle, Lisa Derosa, Gwénaël Le Teuff, Florent Ginhoux, Mathieu Rouanne, Jacques Fieschi, Yves Allory, Camelia Radulescu, Etienne Rouleau, Romain Daillere, Adeline Mallet, Maryse Moya-Nilges, Nadège Cayet, Ivo Gomperts Boneca, Shaima Belhechmi, Baptiste Archambaud, Thibault Raoult, Aymeric Silvin, Kevin Mulder, Garett Dunsmore, François-Xavier Danlos, Camille Bleriot, Jacques Bou Khalil, Gabriel Haddad, Caroline Davin, Mounia Filahi, Thomas Sbarrato, Allan Sauvat, Nicolas Signolle, Virginie Marty, Pierre Ly, Caroline Flament, Marine Mazzenga, Agathe Dubuisson, Idir Ouzaid, Evanguelos Xylinas, Morgan Roupret, Luca Campedel, Carole Helissey, Gwenaelle Gravis, Géraldine Pignot, François Audenet, Constance Thibault, Cédric Lebacle, Cassandra Thelemaque, Maxime Descartes Mbogning-Fonkou, Marianne Gazzano, Isabelle Peguillet, Carolina Alves Costa Silva, Leonardo Lordello, and Anne-Gaëlle Goubet
- Abstract
Supplementary Figure from Escherichia coli–Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer
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- 2023
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3. Data from Escherichia coli–Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer
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Yohann Loriot, Laurence Zitvogel, Jean-Yves Scoazec, Guido Kroemer, Miriam Merad, Fabrice Andre, Benjamin Besse, Michiel S. Van Der Heijden, Nick Van Dijk, Jeroen Van Dorp, Aurélien Marabelle, Lisa Derosa, Gwénaël Le Teuff, Florent Ginhoux, Mathieu Rouanne, Jacques Fieschi, Yves Allory, Camelia Radulescu, Etienne Rouleau, Romain Daillere, Adeline Mallet, Maryse Moya-Nilges, Nadège Cayet, Ivo Gomperts Boneca, Shaima Belhechmi, Baptiste Archambaud, Thibault Raoult, Aymeric Silvin, Kevin Mulder, Garett Dunsmore, François-Xavier Danlos, Camille Bleriot, Jacques Bou Khalil, Gabriel Haddad, Caroline Davin, Mounia Filahi, Thomas Sbarrato, Allan Sauvat, Nicolas Signolle, Virginie Marty, Pierre Ly, Caroline Flament, Marine Mazzenga, Agathe Dubuisson, Idir Ouzaid, Evanguelos Xylinas, Morgan Roupret, Luca Campedel, Carole Helissey, Gwenaelle Gravis, Géraldine Pignot, François Audenet, Constance Thibault, Cédric Lebacle, Cassandra Thelemaque, Maxime Descartes Mbogning-Fonkou, Marianne Gazzano, Isabelle Peguillet, Carolina Alves Costa Silva, Leonardo Lordello, and Anne-Gaëlle Goubet
- Abstract
Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale.Significance:In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli–specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies.This article is highlighted in the In This Issue feature, p. 2221
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- 2023
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4. Abstract CT088: Phase I/II study of the PARP inhibitor olaparib in combination with irinotecan in children with advanced malignancies: arm D of the AcSé-ESMART trial
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Susanne A. Gatz, Pablo Berlanga, Baptiste Archambaud, Yassine Bouchoucha, Nicolas André, Nadege Corradini, Windy Rondof, Jonathan Rubino, Souad Nebchi, Antonin Marchais, Estelle Thebaud, Alba Rubio San Simón, Natasha K. van Eijkelenburg, Lynley V. Marshall, Anne-Sophie Defachelles, Adela Canyete, Stephane Ducassou, Guy Makin, Michela Casanova, Emilie De Carli, Arnaud Petit, Gwenael Le Teuff, Xavier Paoletti, Peter G. Mortimer, Gilles Vassal, and Birgit Geoerger
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Cancer Research ,Oncology - Abstract
Background: AcSé-ESMART is a proof-of-concept, phase I/II, platform trial, designed to explore targeted agents in a molecularly enriched relapsed/refractory pediatric population. Arm D was evaluating the PARP inhibitor (PARPi) olaparib (ola) in combination with irinotecan (iri). In contrast to other PARPi/chemotherapy combination studies, we opted for a prolonged course of PARPi and low dose irinotecan as sensitizer. The Phase I part previously established the recommended Phase II dose (RP2D) (Gatz ASCO 2019). This is the report of the Phase II part of the trial assessing the activity in two separate expansion cohorts: cohort 1: homologous recombination repair defect (HRD) and cohort 2: Ewing sarcoma (ES). Methods: Ola was administered orally twice daily at 90 mg/m2 on Days 1 to 10 and iri intravenously at 20 mg/m2 on Days 4 to 8 of a 21-day cycle. Activity assessment followed a Minimax Simon 2-stage design. Each cohort was to progress to the second stage (additional 9 patients) if 2 or more confirmed responses were observed in the first 16 patients. Patients treated in the Phase I part at the RP2D were counting towards the respective expansion cohorts. Results: Seventy patients (median age: 14 years, range 5-23) were included in the whole study, 67 received treatment; 27 patients were treated in the dose escalation part, including 10 at the RP2D (8 in cohort 1 and 2 in cohort 2). Both cohorts passed the 1st stage and a total of 24 and 26 patients were recruited to cohort 1 and 2, respectively. Main diagnoses in cohort 1 were sarcoma (n=10), brain tumor (n=9), neuroblastoma (n=4). In cohort 1, 15 of 24 patients were considered enriched based on molecular alteration at relapse (ATM n=6; BRCA1 n=2; DNA signature 3 n=3; FANCD2, CHEK2, FANCA, ATRX all n=1); all patients in cohort 2 had presence of a ES fusion (ESWR1::FLI1 n=22; EWSR1::ERG n=4). Median number of treatment cycles were 2, range 1;51 in cohort 1 and 1;32+ in cohort 2. In cohort 1, 3 patients had a partial response (PR) (pinealoblastoma, neuroblastoma, choroid plexus carcinoma; treated with 12, 51, 25 cycles), 1 patient an unconfirmed PR (rhabdomyosarcoma, 6 cycles) and 7 patients stable disease (SD) (2 prolonged with 6 and 8 cycles). In cohort 2, 1 patient had a complete response (10 cycles) and 1 a PR (32+ cycles), 7 patients had SD (3 prolonged with 6, 10, 16 cycles). Molecular enrichment did not predict response. Retrospective correlative analysis of the molecular profiling data and tumor tissue expression analysis are ongoing to identify predictive biomarkers for PARPi combination trials and data will be presented. Conclusions: Encouraging clinical benefit was observed with the protracted ola-iri schedule in a subset of patients. Current molecular hypothesis is insufficient for patient selection and better biomarkers are needed. Citation Format: Susanne A. Gatz, Pablo Berlanga, Baptiste Archambaud, Yassine Bouchoucha, Nicolas André, Nadege Corradini, Windy Rondof, Jonathan Rubino, Souad Nebchi, Antonin Marchais, Estelle Thebaud, Alba Rubio San Simón, Natasha K. van Eijkelenburg, Lynley V. Marshall, Anne-Sophie Defachelles, Adela Canyete, Stephane Ducassou, Guy Makin, Michela Casanova, Emilie De Carli, Arnaud Petit, Gwenael Le Teuff, Xavier Paoletti, Peter G. Mortimer, Gilles Vassal, Birgit Geoerger. Phase I/II study of the PARP inhibitor olaparib in combination with irinotecan in children with advanced malignancies: arm D of the AcSé-ESMART trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT088.
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- 2023
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5. Escherichia coli-Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer
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Anne-Gaëlle Goubet, Leonardo Lordello, Carolina Alves Costa Silva, Isabelle Peguillet, Marianne Gazzano, Maxime Descartes Mbogning-Fonkou, Cassandra Thelemaque, Cédric Lebacle, Constance Thibault, François Audenet, Géraldine Pignot, Gwenaelle Gravis, Carole Helissey, Luca Campedel, Morgan Roupret, Evanguelos Xylinas, Idir Ouzaid, Agathe Dubuisson, Marine Mazzenga, Caroline Flament, Pierre Ly, Virginie Marty, Nicolas Signolle, Allan Sauvat, Thomas Sbarrato, Mounia Filahi, Caroline Davin, Gabriel Haddad, Jacques Bou Khalil, Camille Bleriot, François-Xavier Danlos, Garett Dunsmore, Kevin Mulder, Aymeric Silvin, Thibault Raoult, Baptiste Archambaud, Shaima Belhechmi, Ivo Gomperts Boneca, Nadège Cayet, Maryse Moya-Nilges, Adeline Mallet, Romain Daillere, Etienne Rouleau, Camelia Radulescu, Yves Allory, Jacques Fieschi, Mathieu Rouanne, Florent Ginhoux, Gwénaël Le Teuff, Lisa Derosa, Aurélien Marabelle, Jeroen Van Dorp, Nick Van Dijk, Michiel S. Van Der Heijden, Benjamin Besse, Fabrice Andre, Miriam Merad, Guido Kroemer, Jean-Yves Scoazec, Laurence Zitvogel, Yohann Loriot, Université Paris-Saclay, Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, NF-kappaB, Différenciation et Cancer (OncokappaB (URP_7324)), Université Paris Cité (UPCité), Immunologie intégrative des tumeurs et immunothérapie des cancers (INTIM), Institut Curie [Paris], Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Petites Molécules de neuroprotection, neurorégénération et remyélinisation, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital d'Instruction des Armées Begin, Service de Santé des Armées, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Direction de la recherche clinique [Gustave Roussy], Service de biostatistique et d'épidémiologie (SBE), Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Département de médecine oncologique [Gustave Roussy], Département de biologie et pathologie médicales [Gustave Roussy], Oncologie gynécologique, ANR-16-RHUS-0008, ANR-21-RHUS-0017, Bristol-Myers Squibb, BMS, Pfizer, Astellas Pharma US, APUS, AstraZeneca, Genentech, Merck, Roche, Gilead Sciences, Meso Scale Diagnostics, MSD, Janssen Pharmaceuticals, Merck Sharp and Dohme, MSD, Horizon 2020 Framework Programme, H2020: 19-CE15-0029-01, 825410, Clovis Oncology, Seerave Foundation, Fondation Philanthropia, Advanced Accelerator Applications, AAA, Agence Nationale de la Recherche, ANR: ANR-10-LABX-62-IBEID, Fondation pour la Recherche Médicale, FRM, Daiichi-Sankyo, Fondation ARC pour la Recherche sur le Cancer, ARC, Ligue Contre le Cancer, Institut Universitaire de France, IUF, Institut National Du Cancer, INCa, Cancéropôle Ile de France, Association Française d'Urologie, AFU, Labex Immuno-Oncology, The trial was conducted by the French Genitourinary Group (GETUG) and funded by MSD, which provided the drug. This study was approved by the ethics committee CPP Est-III in December 2017 and the French National Agency for the Safety of Medicines and Health Products (ANSM) in November 2017, and was conducted in accordance with the protocols and Good Clinical Practice Guidelines defined by the International Conference for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and the principles of the Declaration of Helsinki., C. Alves Costa Silva reports grants from MSD Avenir Foundation during the conduct of the study. C. Thibault reports personal fees and nonfinancial support from Pfizer, Merck, MSD, Janssen, and Ipsen, grants, personal fees, and nonfinancial support from AstraZeneca, We thank pathologists, nurses, and clinical research associates from Hôpital Européenn George Pompidou, Hôpital Begin, Institut Paoli-Calmettes, Hôpital Bichat, and Hôpital Pitié-Salpétrière for their participation in the PANDORE clinical trial. We are thankful to the flow and mass cytometry facility team of Gustave Roussy (Philippe Rameau and Cyril Catelain). We thank Fluidigm for their support. We are grateful for support for equipment from the French Government Programme Investissements d’Avenir France BioImag-ing (FBI, No. ANR-10-INSB-04-01) and the French Government (Agence Nationale de la Recherche) Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (ANR-10-LABX-62-IBEID). A.-G. Goubet was supported by Fondation pour la Recherche Médicale. C. Alves Costa Silva was supported by MSD Avenir. F.-X. Danlos was supported by Fondation Philantropia. M. Roupret was supported by Fondation Foch and the Association Française d’Urologie (AFU). L. Zitvogel was funded by the RHU Torino Lumière (ANR-16-RHUS-0008). L. Zitvogel and L. Derosa were supported by RHU5 'ANR-21-RHUS-0017' IMMUNOLIFE, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), as well as the SIGN’IT ARC foundation. L. Zitvogel was supported by European Union’s Horizon 2020 research and innovation programme under grant agreement number 825410 [project acronym: ONCOBIOME, project title: Gut OncoMicrobiome Signatures (GOMS) associated with cancer incidence, prognosis, and prediction of treatment response]. L. Zitvogel also received an ANR grant–French-German Ileobiome 19-CE15-0029-01. L. Zitvogel and G. Kroemer received a donation from the Seerave Foundation. L. Zitvogel and G. Kroemer were supported by the Ligue contre le Cancer (équipe labelisée), ANR projets blancs, Cancéropôle Ile-de-France, Fondation pour la Recherche Médicale (FRM), a donation by Elior, Institut National du Cancer (INCa), Inserm (HTE), Institut Universitaire de France, the LabEx Immuno-Oncology, and FHU CARE, Dassault, and Badinter Philantropia. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact., Bristol Myers Squibb, and Sanofi, and personal fees from Astellas and AAA during the conduct of the study, as well as personal fees and nonfinancial support from Pfizer, Merck, MSD, Janssen, and Ipsen, grants, personal fees, and nonfinancial support from AstraZeneca, Bristol Myers Squibb, and Sanofi, and personal fees from Astellas and AAA outside the submitted work. F. Audenet reports personal fees from Astellas, Urodiag, Vitadx, and Bristol Myers Squibb, and nonfinancial support from Ipsen outside the submitted work. G. Gravis reports grants from Bristol Myers Squibb, and other support from MSD, Bristol Myers Squibb, and Merck–Pfizer alliance outside the submitted work. C. Helissey reports personal fees from Janssen-Cilag, Roche, Bayer, AstraZeneca, and Astellas outside the submitted work. L. Cam-pedel reports personal fees from MSD, Pfizer, Bristol Myers Squibb, and Bayer outside the submitted work. T. Sbarrato reports personal fees from Veracyte during the conduct of the study. T. Raoult reports grants, personal fees, and nonfinancial support from Merck Sharp & Dohme during the conduct of the study. E. Rouleau reports grants from AstraZeneca, Roche, Clovis, Bristol Myers Squibb, and MSD outside the submitted work. Y. Allory reports other support from Astra-Zeneca, MSD, and Bristol Myers Squibb outside the submitted work. J. Fieschi reports personal fees from Veracyte during the conduct of the study. A. Marabelle reports grants, personal fees, nonfinancial support, and other support from MSD, Bristol Myers Squibb, and AstraZeneca, and personal fees, nonfinancial support, and other support from Roche/Genentech and Pfizer outside the submitted work. J. Van Dorp reports other support from Bristol Myers Squibb during the conduct of the study. M.S. van der Heijden reports grants from Bristol Myers Squibb during the conduct of the study, as well as grants and personal fees from Bristol Myers Squibb, Roche, and AstraZeneca, grants from 4SC, and personal fees from MSD/Merck, Janssen, Pfizer, and Seagen outside the submitted work. B. Besse reports grants from 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Chu-gai Pharmaceutical, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, Eisai, Genzyme Corporation, GSK, Inivata, Ipsen, Janssen, Onxeo, OSE Immunotherapeutics, Pfizer, Roche/Genentech, Sanofi, Takeda, Tolero Pharmaceuticals, and Turning Point Therapeutics during the conduct of the study. F. Andre reports grants and other support from AstraZeneca and Daiichi Sankyo, grants from Lilly and Sanofi, and other support from Novartis and Relay outside the submitted work. M. Merad reports grants and personal fees from Regeneron, personal fees from Compugen, Morphic Therapeutics, Myeloid Therapeutics, Nirogy, DrenBio, Oncoresponse, Asherbio, Pionyr, Owkin, and Larkspur, other support from Innate Pharma, Genenta, DBV, and OSE Immunotherapeutics, and grants from Boehringer outside the submitted work. G. Kroemer reports grants from Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sotio, Tollys, Vascage, and Vasculox/Tioma, and personal fees from Reithera outside the submitted work, is on the Board of Directors for Bristol Myers Squibb Foundation France, and is a scientific cofounder of EverImmune, Osasuna Therapeutics, Samsara Therapeutics, and Therafast Bio. L. Zitvogel reports grants and personal fees from EverImmune, and grants from 9 Meters and Pileje during the conduct of the study, grants from Daiichi Sankyo outside the submitted work, and a patent for B220028EPA pending. Y. Loriot reports grants from MSD and personal fees from MSD during the conduct of the study, personal fees from Bristol Myers Squibb, Pfizer, Merck Serono, AstraZeneca, Seattle Genetics, Gilead, Taiho, and Astel-las, grants and personal fees from Janssen, and grants from Roche and Celsius outside the submitted work, and a patent for EP2305181.4 pending. No disclosures were reported by the other authors., and FHU CARE, Dassault, and Badinter Philantropia., ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), and ANR-21-RHUS-0017,IMMUNOLIFE,Microbiota-centered interventions to solve antibiotics-induced primary resistance to immune checkpoint inhibitors(2021)
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[SDV]Life Sciences [q-bio] ,Muscles ,Programmed Cell Death 1 Receptor ,T-Lymphocytes, Helper-Inducer ,Chemokine CXCL13 ,B7-H1 Antigen ,Neoadjuvant Therapy ,Treatment Outcome ,Oncology ,Urinary Bladder Neoplasms ,Immunoglobulin G ,Escherichia coli ,Humans ,Immune Checkpoint Inhibitors - Abstract
Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale. Significance: In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli–specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies. This article is highlighted in the In This Issue feature, p. 2221
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- 2022
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6. Doxorubicin plus trabectedin for metastatic or unresectable leiomyosarcoma – Authors' reply
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Patricia, Pautier, Marie-Laure, Tanguy, and Baptiste, Archambaud
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Leiomyosarcoma ,Oncology ,Doxorubicin ,Humans ,Trabectedin - Published
- 2022
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7. Bacteria-specific CXCL13-producing follicular helper T cells are putative prognostic markers to neoadjuvant PD-1 blockade in muscle-invasive urothelial carcinoma
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Anne-Gaëlle Goubet, Carolina Alves Costa Silva, Leonardo Lordello De Melo, Marianne Gazzano, Cédric Lebacle, Constance Thibault, Geraldine Pignot, Carole Helissey, Morgan Roupret, Evanguelos Xylinas, Caroline Flament, Virginie Marty, Nicolas Signolle, Baptiste Archambaud, Shayma Bel-Hechmi, Romain Daillere, Gwénaël Le Teuff, Jean-Yves Scoazec, Laurence Zitvogel, and Yohann Loriot
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Cancer Research ,Oncology - Abstract
535 Background: Immune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1 antibodies, have emerged as a successful immunotherapeutic strategy for advanced and metastatic urothelial cancer (UC). Therapeutic blockade of PD-1 or PD-L1 with monoclonal antibodies leads to durable tumor regressions in up to 25% metastatic muscle invasive UC (MIBC). Neoadjuvant use of ICI also showed remarkable efficacy and represents a unique opportunity to study immunodynamics during PD-1 blockade to decipher functional predictors of response and resistance. Methods: Patients diagnosed with T2-T4aN0M0 MIBC were treated with 3 cycles of neoadjuvant pembrolizumab before cystectomy in the PANDORE trial (NCT03212651). The primary endpoint was pathologic complete response (ypT0N0). Secondary endpoints focused on safety, progression-free survival (PFS) and biomarker analysis. We performed longitudinal analysis of peripheral and tumor infiltrating lymphocytes, tumor microbiome as well as soluble factors using high dimensionnal immune phenotyping by mass cytometry, immuno-fluorescence and -histochemistry and multiplex immunoassays. Humoral and cellular recall immune memory against urinary tract commensals were studied. Results: Thirty-nine patients were enrolled from October 2017 to December 2019. All but 5 (n = 34 patients (87.2%)) proceeded with cystectomy. Ten patients presented with ypT0N0 (29.4%; 95% CI: 15.1 %-47.5 %). Multidimensional biomarkers analysis showed that baseline follicular T helper (Tfh) and post-pembrolizumab tertiary lymphoid structure (TLS) and activated B cells were associated with outcome ( p= 0.005, p= 0.01 and p= 0.04, respectively). Plasma CXCL13 (the prototypic chemokine secreted by Tfh and involved in TLS functions) increased after 1 cycle of PD-1 blockade in responders and patients without progression at 24 months ( p= 0.002 and p= 0.0001, respectively). Focusing on MIBC tumor microbiome, we showed that intracellular Gram negative bacteria and other commensals were more frequent in tumoral than in normal urothelium ( p= 0.04). Interestingly, basal CXCL13-secreting CD4+ T cells and IgG directed against urinary pathobionts such as Escherichia coli predicted prolonged PFS ( p= 0.01 and p= 0.001, respectively). Conclusions: Our results suggest that urothelial commensals could induce specific Tfh and B cell responses that were re-invigorated by PD-1 blockade and associated with clinical benefit to pembrolizumab. Further analyses are needed to validate the predictive value of commensal-specific Tfh in UC and other epithelial cancers that are directly or indirectly exposed to bacteria. Clinical trial information: NCT03212651.
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- 2022
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