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1. The bladder cancer immune micro-environment in the context of response to immune checkpoint inhibition

Author

Jeroen van Dorp and Michiel S. van der Heijden

Subjects
bladder cancer, immune checkpoint inhibition, immune micro-environment, tertiary lymphoid structure, PD-1, PD-L1, Immunologic diseases. Allergy, RC581-607
Abstract

Treatment with neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy is the default treatment for muscle-invasive bladder cancer (BC). However, with the encouraging results of immune checkpoint inhibitiors (ICI) directed against PD-1/PD-L1 and CTLA-4 in recent years, the treatment landscape of BC is rapidly changing. In addition, it is becoming clear that the effect of ICI is highly dependent on the interaction between tumor cells and the tumor immune micro-environment (TIME). Different immune cells are involved in an anti-tumor response in BC. Cytotoxic CD8+ T-cells are the main effector cells, aided by other immune cells including other T-cells, B-cells and pro-inflammatory macrophages. As part of the ongoing anti-tumor immune response, lymphocytes aggregate in clusters called tertiary lymphoid structures (TLS). Tumor mutational burden (TMB) and infiltration of immune cells into the tumor are both important factors for establishing an anti-tumor immune response. In contrast, transforming growth factor beta (TGF-β) signaling in cancer-associated fibroblasts (CAFs) prevents infiltration of lymphocytes and potentially has an immunosuppressive effect. In conclusion, the effect of ICI seems to be reliant on a combination of tumor-intrinsic and TIME-related parameters. More research is needed to fully understand the underlying biological mechanisms to further improve patient care.

Published
2023
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2. A kinome-centered CRISPR-Cas9 screen identifies activated BRAF to modulate enzalutamide resistance with potential therapeutic implications in BRAF-mutated prostate cancer

Author

Sander A. L. Palit, Jeroen van Dorp, Daniel Vis, Cor Lieftink, Simon Linder, Roderick Beijersbergen, Andries M. Bergman, Wilbert Zwart, and Michiel S. van der Heijden

Subjects
Medicine, Science
Abstract

Abstract Resistance to drugs targeting the androgen receptor (AR) signaling axis remains an important challenge in the treatment of prostate cancer patients. Activation of alternative growth pathways is one mechanism used by cancer cells to proliferate despite treatment, conferring drug resistance. Through a kinome-centered CRISPR-Cas9 screen in CWR-R1 prostate cancer cells, we identified activated BRAF signaling as a determinant for enzalutamide resistance. Combined pharmaceutical targeting of AR and MAPK signaling resulted in strong synergistic inhibition of cell proliferation. The association between BRAF activation and enzalutamide resistance was confirmed in two metastatic prostate cancer patients harboring activating mutations in the BRAF gene, as both patients were unresponsive to enzalutamide. Our findings suggest that co-targeting of the MAPK and AR pathways may be effective in patients with an activated MAPK pathway, particularly in patients harboring oncogenic BRAF mutations. These results warrant further investigation of the response to AR inhibitors in BRAF-mutated prostate tumors in clinical settings.

Published
2021
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4. Assessment of Predictive Genomic Biomarkers for Response to Cisplatin-based Neoadjuvant Chemotherapy in Bladder Cancer

Author

Alberto Gil-Jimenez, Jeroen van Dorp, Alberto Contreras-Sanz, Kristan van der Vos, Daniel J. Vis, Linde Braaf, Annegien Broeks, Ron Kerkhoven, Kim E.M. van Kessel, María José Ribal, Antonio Alcaraz, Lodewyk F.A. Wessels, Roland Seiler, Jonathan L. Wright, Lourdes Mengual, Joost Boormans, Bas W.G. van Rhijn, Peter C. Black, Michiel S. van der Heijden, and Urology

Subjects
SDG 3 - Good Health and Well-being, Urology, 610 Medicine & health
Abstract

Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy is recommended for patients with muscle-invasive bladder cancer (MIBC). It has been shown that somatic deleterious mutations in ERCC2, gain-of-function mutations in ERBB2, and alterations in ATM, RB1, and FANCC are correlated with pathological response to NAC in MIBC. The objective of this study was to validate these genomic biomarkers in pretreatment transurethral resection material from an independent retrospective cohort of 165 patients with MIBC who subsequently underwent NAC and radical surgery. Patients with ypT0/Tis/Ta/T1N0 disease after surgery were defined as responders. Somatic deleterious mutations in ERCC2 were found in nine of 68 (13%) evaluable responders and two of 95 (2%) evaluable nonresponders (p = 0.009; FDR = 0.03). No correlation was observed between response and alterations in ERBB2 or in ATM, RB1, or FANCC alone or in combination. In an exploratory analysis, no additional genomic alterations discriminated between responders and nonresponders to NAC. No further associations were identified between the aforementioned biomarkers and pathological complete response (ypT0N0) after surgery. In conclusion, we observed a positive association between deleterious mutations in ERCC2 and pathological response to NAC, but not overall survival or recurrence-free survival. Other previously reported genomic biomarkers were not validated. Patient summary: It is currently unknown which patients will respond to chemotherapy before definitive surgery for bladder cancer. Previous studies described several gene mutations in bladder cancer that correlated with chemotherapy response. This study confirmed that patients with bladder cancer with a mutation in the ERCC2 gene often respond to chemotherapy.

Published
2023

5. High- or low-dose preoperative ipilimumab plus nivolumab in stage III urothelial cancer: the phase 1B NABUCCO trial

Author

Jeroen van Dorp, Christodoulos Pipinikas, Britt B. M. Suelmann, Niven Mehra, Nick van Dijk, Giovanni Marsico, Maurits L. van Montfoort, Sophie Hackinger, Linde M. Braaf, Tauanne Amarante, Charlaine van Steenis, Kirsten McLay, Antonios Daletzakis, Daan van den Broek, Maaike W. van de Kamp, Kees Hendricksen, Jeantine M. de Feijter, Thierry N. Boellaard, Richard P. Meijer, Toine G. van der Heijden, Nitzan Rosenfeld, Bas W. G. van Rhijn, Greg Jones, and Michiel S. van der Heijden

Subjects
All institutes and research themes of the Radboud University Medical Center, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15], General Medicine, General Biochemistry, Genetics and Molecular Biology
Abstract

Item does not contain fulltext Cohort 1 of the phase 1B NABUCCO trial showed high pathological complete response (pCR) rates with preoperative ipilimumab plus nivolumab in stage III urothelial cancer (UC). In cohort 2, the aim was dose adjustment to optimize responses. Additionally, we report secondary endpoints, including efficacy and tolerability, in cohort 2 and the association of presurgical absence of circulating tumor DNA (ctDNA) in urine and plasma with clinical outcome in both cohorts. Thirty patients received two cycles of either ipilimumab 3 mg kg(-1) plus nivolumab 1 mg kg(-1) (cohort 2A) or ipilimumab 1 mg kg(-1) plus nivolumab 3 mg kg(-1) (cohort 2B), both followed by nivolumab 3 mg kg(-1). We observed a pCR in six (43%) patients in cohort 2A and a pCR in one (7%) patient in cohort 2B. Absence of urinary ctDNA correlated with pCR in the bladder (ypT0Nx) but not with progression-free survival (PFS). Absence of plasma ctDNA correlated with pCR (odds ratio: 45.0; 95% confidence interval (CI): 4.9-416.5) and PFS (hazard ratio: 10.4; 95% CI: 2.9-37.5). Our data suggest that high-dose ipilimumab plus nivolumab is required in stage III UC and that absence of ctDNA in plasma can predict PFS. ClinicalTrials.gov registration: NCT03387761 .

Published
2023

6. Supplementary Figure from Escherichia coli–Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer

Author

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

Published
2023

7. Data from Escherichia coli–Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer

Author

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

Published
2023

10. Survival after neoadjuvant/induction combination immunotherapy vs combination platinum-based chemotherapy for locally advanced (Stage III) urothelial cancer

Author

Sarah M. H. Einerhand, Nick van Dijk, Jeroen van Dorp, Jeantine M. de Feijter, Maurits L. van Montfoort, Maaike W. van de Kamp, Eva E. Schaake, Thierry N. Boellaard, Kees Hendricksen, Michiel S. van der Heijden, and Bas W. G. van Rhijn

Subjects
Cancer Research, Carcinoma, Transitional Cell, Ipilimumab, Neoadjuvant Therapy, Carboplatin, Nivolumab, Oncology, Urinary Bladder Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Humans, Immunotherapy, Cisplatin, Immune Checkpoint Inhibitors, Platinum
Abstract

Despite treatment with cisplatin-based chemotherapy and surgical resection, clinical outcomes of patients with locally advanced urothelial carcinoma (UC) remain poor. We compared neoadjuvant/induction platinum-based combination chemotherapy (NAIC) with combination immune checkpoint inhibition (cICI). We identified 602 patients who attended our outpatient bladder cancer clinic in 2018 to 2019. Patients were included if they received NAIC or cICI for cT3-4aN0M0 or cT1-4aN1-3M0 UC. NAIC consisted of cisplatin-based chemotherapy or gemcitabine-carboplatin in case of cisplatin-ineligibility. A subset of patients (cisplatin-ineligibility or refusal of NAIC) received ipilimumab plus nivolumab in the NABUCCO-trial (NCT03387761). Treatments were compared using the log-rank test and propensity score-weighted Cox regression models. We included 107 Stage III UC patients treated with NAIC (n = 83) or cICI (n = 24). NAIC was discontinued in 11 patients due to progression (n = 6; 7%) or toxicity (n = 5; 6%), while cICI was discontinued in 6 patients (25%) after 2 cycles due to toxicity (P = .205). After NAIC, patients had surgical resection (n = 50; 60%), chemoradiation (n = 26; 30%), or no consolidating treatment due to progression (n = 5; 6%) or toxicity (n = 2; 2%). After cICI, all patients underwent resection. After resection (n = 74), complete pathological response (ypT0N0) was achieved in 11 (22%) NAIC-patients and 11 (46%) cICI-patients (P = .056). Median (IQR) follow-up was 26 (20-32) months. cICI was associated with superior progression-free survival (P = .003) and overall survival (P = .003) compared to NAIC. Our study showed superior survival in Stage III UC patients pretreated with cICI if compared to NAIC. Our findings provide a strong rationale for validation of cICI for locally advanced UC in a comparative phase-3 trial.

Published
2022

11. Escherichia coli-Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer

Author

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)

Subjects
[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

Published
2022

12. A kinome-centered CRISPR-Cas9 screen identifies activated BRAF to modulate enzalutamide resistance with potential therapeutic implications in BRAF-mutated prostate cancer

Author

Daniel J. Vis, Simon Linder, Sander Palit, Michiel S. van der Heijden, Cor Lieftink, Wilbert Zwart, Roderick L. Beijersbergen, Andries M. Bergman, and Jeroen van Dorp

Subjects
MAPK/ERK pathway, Male, Proto-Oncogene Proteins B-raf, Cell biology, Cancer therapy, Molecular biology, Science, Antineoplastic Agents, Drug resistance, Urological cancer, Pathogenesis, Article, Tumour biomarkers, chemistry.chemical_compound, Prostate cancer, Medical research, Cell Line, Tumor, Nitriles, Phenylthiohydantoin, Genetics, Medicine, Enzalutamide, Humans, Kinome, Cancer genetics, Cancer, Multidisciplinary, Molecular medicine, business.industry, Cell growth, Prostatic Neoplasms, Oncogenes, medicine.disease, Androgen receptor, Enzyme Activation, chemistry, Oncology, Drug Resistance, Neoplasm, Cancer cell, Benzamides, Mutation, Cancer research, CRISPR-Cas Systems, business, Biotechnology
Abstract

Resistance to drugs targeting the androgen receptor (AR) signaling axis remains an important challenge in the treatment of prostate cancer patients. Activation of alternative growth pathways is one mechanism used by cancer cells to proliferate despite treatment, conferring drug resistance. Through a kinome-centered CRISPR-Cas9 screen in CWR-R1 prostate cancer cells, we identified activated BRAF signaling as a determinant for enzalutamide resistance. Combined pharmaceutical targeting of AR and MAPK signaling resulted in strong synergistic inhibition of cell proliferation. The association between BRAF activation and enzalutamide resistance was confirmed in two metastatic prostate cancer patients harboring activating mutations in the BRAF gene, as both patients were unresponsive to enzalutamide. Our findings suggest that co-targeting of the MAPK and AR pathways may be effective in patients with an activated MAPK pathway, particularly in patients harboring oncogenic BRAF mutations. These results warrant further investigation of the response to AR inhibitors in BRAF-mutated prostate tumors in clinical settings.

Published
2021

13. Abstract 1273: Predicting pathological response after ipilimumab plus nivolumab in stage III urothelial cancer by liquid-biopsy assessment of plasma and urine ctDNA using the RaDaR assay

Author

Jeroen van Dorp, Christodoulos Pipinikas, Nick van Dijk, Greg Jones, Alberto Gil-Jimenez, Giovanni Marsico, Maurits L. van Montfoort, Sophie Hackinger, Linde Braaf, Kirsten McLay, Daan van den Broek, Bas W. Van Rhijn, Nitzan Rosenfeld, and Michiel S. van der Heijden

Subjects
Cancer Research, Oncology
Abstract

Patients (pts) with stage III (cT3-4aN0M0 or cT1-4aN1-3M0) urothelial cancer (UC) have a poor prognosis. In NABUCCO cohort 1, 24 stage III UC pts were treated with ipilimumab (ipi) plus nivolumab (nivo) followed by radical surgery (day 1: ipi 3 mg/kg; day 22: ipi 3 mg/kg + nivo 1 mg/kg; day 43: nivo 3 mg/kg). 14/24 (58%) of pts showed a pathological response (ypT0N0 or ypTisN0/ypTaN0). Currently, there are no good biomarkers to assess response before surgery, potentially leading to overtreatment and unnecessary surgical complications. Here, we investigated whether detection of circulating tumor DNA (ctDNA) in plasma and urine by the RaDaR™ personalized liquid biopsy assay was associated with treatment response and outcomes. EDTA-plasma and urine supernatant were collected before start of treatment (day 1; “baseline”), before each subsequent treatment cycle (day 22 and 43) and before radical surgery. WES was performed on tumor FFPE and peripheral blood germline DNA to identify somatic variants for designing patient-specific, multiplex PCR-based NGS RaDaR™ panels. Plasma and urine ctDNA was analyzed using these panels to determine ctDNA detection and its estimated variant allele frequency (eVAF). Tissue somatic variants were detected in all patients, a median of 48 variants was used per RaDaR™ panel (range: 43-51). ctDNA was detected in 50/94 plasma samples (53%) and in 74/93 urine samples (80%). Detection levels were higher in urine with a median eVAF of 1.98% (range: 0.00057%-35.85%) vs. 0.049% (range: 0.00026%-18.94%) in plasma. ctDNA was detected in baseline plasma in 10/14 (71%) responding pts (median eVAF: 0.325%) and in 8/10 (80%) non-responders (median eVAF: 0.107%). Changes in ctDNA levels reflected clinical responses. After treatment with ipi plus nivo, ctDNA was undetectable in 13/14 (93%) responding pts, and in only 4/10 (40%) of non-responders (p=0.0088). Of the 17 pts with undetectable ctDNA before surgery, 13 (76%) had a pathological response and 16/17 (94%) pts remained recurrence-free after a median follow-up of 34 months. Urine ctDNA was detected at baseline in 12/14 (86%) responding pts (median eVAF: 9.634%) and in 8/10 (80%) non-responders (median eVAF: 2%). After treatment with ipi plus nivo, urine ctDNA was detected in 8/14 (57%) responding pts (median eVAF: 0.87%), and in 8/10 (80%) non-responders (median eVAF: 0.162%). No association was observed between urine ctDNA detection and response (p=0.39). Detection of plasma ctDNA by RaDaR™ after neoadjuvant treatment was associated with pathological response and clinical outcome. In contrast, ctDNA detection in urine was not associated with outcomes. Absence of plasma ctDNA pre-surgery may predict complete response to ipi plus nivo at surgery and may be helpful in guiding clinical decisions in stage III UC, in particular to select pts for bladder-sparing strategies. Citation Format: Jeroen van Dorp, Christodoulos Pipinikas, Nick van Dijk, Greg Jones, Alberto Gil-Jimenez, Giovanni Marsico, Maurits L. van Montfoort, Sophie Hackinger, Linde Braaf, Kirsten McLay, Daan van den Broek, Bas W. Van Rhijn, Nitzan Rosenfeld, Michiel S. van der Heijden. Predicting pathological response after ipilimumab plus nivolumab in stage III urothelial cancer by liquid-biopsy assessment of plasma and urine ctDNA using the RaDaR assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1273.

Published
2022

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