Therapeutic Area: Oncology

Yu Zhao 1, Bing He 1, Zhimeng Xu 1, Yidan Zhang 1,2, Xuan Zhao 1, Zhi-An Huang 1,3, Fan Yang 1, Liang Wang 1, Lei Duan 2, Jiangning Song 1,4, Jianhua Yao 1; 1 AI Lab, Tencent, Shenzhen, China. 2 School of Computer Science, Sichuan University, Chengdu, China. 3 Center for Computer Science and Information Technology, City University of Hong Kong Dongguan Research Institute, Dongguan, China. 4 Monash Biomedicine Discovery Institute and Monash Data Futures Institute, Monash University, Melbourne, VIC 3800, Australia.

Kyoko Yoshida-Court 1, Tatiana V Karpinets 2, Aparna Mitra 1, Travis N Solley 1, Stephanie Dorta-Estremera 3, Travis T Sims 4, Andrea Y Delgado Medrano 1, Molly B El Alam 1, Mustapha Ahmed-Kaddar 1, Erica J Lynn 1, K Jagannadha Sastry 5, Jianhua Zhang 2, Andrew Futreal 2, Alpa Nick 6,7, Karen Lu 4, Lauren E Colbert 1, Ann H Klopp 1; 1 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. 2 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. 3 Comprehensive Cancer Center, Cancer Biology, Department of Microbiology and Zoology, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico. 4 Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. 5 Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. 6 Saint Thomas Health/Ascension, Nashville, TN, United States of America. 7 Tennessee Oncology, Nashville, Tennessee, United States of America.

Meenal Sinha 1, Courtney Betts 2, Li Zhang 1,3, Madeline J Griffith 1, Isabelle Solman 4, Brandon Chen 1, Eric Liu 1, Whitney Tamaki 1, Jacob Stultz 1, Jaqueline Marquez 1, Shamilene Sivagnanam 2, Alexander Cheung 1, Denise Pener 5, Anne Fahlman 5, Erin Taber 5, Kimberly Lerner 5, Matthew Crocker 5, Kendra Todd 5, Brindha Rajagopalan 5, Clarisha Ware 1, Mark Bridge 1, Johnson Vo 5, Hannah Dragomanovich 1, Julie Sudduth-Klinger 1, Gina Vaccaro 6, Charles D Lopez 2,5, Margaret Tempero 1, Lisa M Coussens # 2, Lawrence Fong # 7,8; 1 Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA. 2 Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, USA. 3 Department of Biostatistics, University of California, San Francisco, California, USA. 4 AbbVie, Irvine, California, USA. 5 Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA. 6 Medical Oncology, Providence Portland Medical Center, Portland, Oregon, USA. 7 Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA lawrence.fong@ucsf.edu. 8 Parker Institute for Cancer Immunotherapy, San Francisco, California, USA. #Contributed equally.

Many acute myeloid leukemia (AML) patients exhibit hallmarks of immune exhaustion, such as increased myeloid-derived suppressor cells, suppressive regulatory T cells and dysfunctional T cells. Similarly, we have identified the same immune-related features, including exhausted CD8+ T cells (TEx) in a mouse model of AML. Here we show that inhibitors that target bromodomain and extra-terminal domain (BET) proteins affect tumor-intrinsic factors but also rescue T cell exhaustion and ICB resistance. Ex vivo treatment of cells from AML mice and AML patients with BET inhibitors (BETi) reversed CD8+ T cell exhaustion by restoring proliferative capacity and expansion of the more functional precursor-exhausted T cells. This reversal was enhanced by combined BETi and anti-PD1 treatment. BETi synergized with anti-PD1 in vivo, resulting in the reduction of circulating leukemia cells, enrichment of CD8+ T cells in the bone marrow, and increase in expression of Tcf7, Slamf6, and Cxcr5 in CD8+ T cells. Finally, we profiled the epigenomes of in vivo JQ1-treated AML-derived CD8+ T cells by single-cell ATAC-seq and found that JQ1 increases Tcf7 accessibility specifically in Tex cells, suggesting that BETi likely acts mechanistically by relieving repression of progenitor programs in Tex CD8+ T cells and maintaining a pool of anti-PD1 responsive CD8+ T cells.

Jara Palomero 1, Carla Panisello 1, Maria Lozano-Rabella 1, Ricky Tirtakasuma 1, Judit Díaz-Gómez 1, Daniela Grases 1, Helena Pasamar 1, Laura Arregui 2, Eduard Dorca Duch 3, Esther Guerra Fernández 3, Ana Vivancos 4, Carlos E de Andrea 5,6, Ignacio Melero 6,7,8, Jordi Ponce 9, August Vidal 3,6, Josep Maria Piulats 10, Xavier Matias-Guiu 3,6,11, Alena Gros 12; 1 Tumor Immunology and Immunotherapy, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. 2 HUB-ICO-IDIBELL Biobank, Bellvitge Institute for Biomedical Research, L'Hospitalet de Llobregat, Spain. 3 Pathology, Bellvitge University Hospital, IDIBELL, L'Hospitalet de Llobregat, Spain. 4 Cancer Genomics, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. 5 Pathology, Clinica Universidad de Navarra, Pamplona, Spain. 6 Centro de Investigación Biomedica en Red de Cáncer (CIBERONC), Madrid, Spain. 7 Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain. 8 Navarra Institute for Health Research IDISNA, Pamplona, Spain. 9 Department of Gynaecology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Spain. 10 Medical Oncology, Catalan Institute of Oncology (ICO), IDIBELL-OncoBell, L'Hospitalet de Llobregat, Spain. 11 Pathology, Arnau de Vilanova University Hospital, University of LLeida, IRBLLEIDA, Lleida, Spain. 12 Tumor Immunology and Immunotherapy, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain agros@vhio.net.

Jani Huuhtanen 1,2,3,4, Henna Kasanen 1,2,4, Katriina Peltola 4,5, Tapio Lönnberg 6, Virpi Glumoff 7, Oscar Brück 1,2,4, Olli Dufva 1,2,4, Karita Peltonen 1,2,4, Johanna Vikkula 3, Emmi Jokinen 1,2,3,4, Mette Ilander 1,2, Moon Hee Lee 1,2,4, Siru Mäkelä 5, Marta Nyakas 8, Bin Li 9, Micaela Hernberg 5, Petri Bono 5, Harri Lähdesmäki 3, Anna Kreutzman 1,2, Satu Mustjoki 1,2,4; 1 Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland. 2 Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland. 3 Department of Computer Science, Aalto University, Espoo, Finland. 4 iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland. 5 Department of Oncology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland. 6 Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland. 7 Research Unit of Biomedicine, Medical Microbiology and Immunology, University of Oulu, Oulu, Finland. 8 Oslo University Hospital-Radiumhospitalet, Oslo, Norway. 9 Bristol Myers Squibb (BMS) Research and Development, Princeton, New Jersey, USA.

Mengyun Hu 1,2 , Samuele Notarbartolo 1,3 , Mathilde Foglierini 1,4 , Sandra Jovic 1 , Federico Mele 1 , David Jarrossay 1 , Antonio Lanzavecchia 5 , Antonino Cassotta 1 , Federica Sallusto 1,6; 1 Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland. 2 Present address: Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA, USA. 3 Present address: National Institute of Molecular Genetics, Milano, Italy. 4 Present address: Service d'immunologie et d'allergie, CHUV, Lausanne, Switzerland. 5 National Institute of Molecular Genetics, Milano, Italy. 6 Institute of Microbiology, ETH Zurich, Zurich, Switzerland.

Mirco J Friedrich 1 , Paola Neri 2 , Niklas Kehl 3 , Julius Michel 3 , Simon Steiger 4 , Michael Kilian 3 , Noémie Leblay 5 , Ranjan Maity 5 , Roman Sankowski 6 , Holly Lee 2 , Elie Barakat 5 , Sungwoo Ahn 5 , Niels Weinhold 7 , Karsten Rippe 8 , Lukas Bunse 3 , Michael Platten 9 , Hartmut Goldschmidt 10 , Carsten Müller-Tidow 10 , Marc-Steffen Raab 11 , Nizar J Bahlis 12; 1 Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: mfriedri@broadinstitute.org. 2 Arnie Charbonneau Cancer Research Institute, University of Calgary, Calgary, Canada; Tom Baker Cancer Center, Department of Hematology and Oncology, Calgary, Canada. 3 Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 4 Division of Chromatin Networks, BioQuant Center & German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. 5 Tom Baker Cancer Center, Department of Hematology and Oncology, Calgary, Canada. 6 Department of Neuropathology, Freiburg University Hospital, Freiburg, Germany. 7 Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany. 8 Division of Chromatin Networks, BioQuant Center & German Cancer Research Center (DKFZ), Heidelberg, Germany. 9 Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Helmholtz Institute of Translational Oncology (HI-TRON), Mainz, Germany; National Center for Tumor Diseases (NCT), Heidelberg, Germany; DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim Germany. 10 Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany; National Center for Tumor Diseases (NCT), Heidelberg, Germany. 11 Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany; Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: marc.raab@med.uni-heidelberg.de. 12 Arnie Charbonneau Cancer Research Institute, University of Calgary, Calgary, Canada; Tom Baker Cancer Center, Department of Hematology and Oncology, Calgary, Canada. Electronic address: nbahlis@ucalgary.ca.