Marta Español-Rego1, Carlos Fernández-Martos2, Elena Elez3, Carles Foguet4, Leire Pedrosa5, Nuria Rodríguez6, Ana Ruiz-Casado7, Estela Pineda5, Joan Cid8, Raquel Cabezón1, Helena Oliveres5, Miquel Lozano8, Angels Ginés9,10, Angeles García-Criado11, Juan Ramon Ayuso11, Mario Pagés11, Miriam Cuatrecasas12,10, Ferràn Torres13, Timothy Thomson14,10,15, Marta Cascante4,10, Daniel Benítez-Ribas16, Joan Maurel17,18. 1. Immunology Department, Hospital Clínic, Barcelona, Spain. 2. Medical Oncology Department, Instituto Valenciano de Oncología, Valencia, Spain. 3. Medical Oncology Department, Vall d'Hebrón Barcelona Hospital Campus, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain. 4. Department of Biochemistry and Molecular Medicine, Universitat de Barcelona, Barcelona, Spain. 5. Translational Genomics and Targeted Therapeutics in Solid Tumors Group, Medical Oncology Department, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, C. Villarroel, 170. 08036, Barcelona, Spain. 6. Medical Oncology Department, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. 7. Medical Oncology Department, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain. 8. Apheresis & Cellular Therapy Unit, Department of Hemotherapy and Hemostasis, IDIBAPS, Hospital Clínic, Barcelona, Spain. 9. Endoscopic Unit, Gastrointestinal Service, Hospital Clínic Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain. 10. Networked Center for Hepatic and Digestive Diseases (CIBER-EHD), Instituto Nacional de La Salud Carlos III, Madrid, Spain. 11. Radiology Department, Hospital Clínic Barcelona, Barcelona, Spain. 12. Pathology Department, Hospital Clínic de Barcelona, Barcelona, Spain. 13. Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona, Barcelona, Spain. 14. Barcelona Institute for Molecular Biology, National Science Council (IBMB-CSIC), Barcelona, Spain. 15. Universidad Peruana Cayetano Heredia, Lima, Peru. 16. Immunology Department, Hospital Clínic, Barcelona, Spain. DBENITEZR@clinic.cat. 17. Translational Genomics and Targeted Therapeutics in Solid Tumors Group, Medical Oncology Department, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, C. Villarroel, 170. 08036, Barcelona, Spain. JMAUREL@clinic.cat. 18. Networked Center for Hepatic and Digestive Diseases (CIBER-EHD), Instituto Nacional de La Salud Carlos III, Madrid, Spain. JMAUREL@clinic.cat.
Abstract
BACKGROUND: Immune check-point blockade (ICB) has shown clinical benefit in mismatch repair-deficient/microsatellite instability high metastatic colorectal cancer (mCRC) but not in mismatch repair-proficient/microsatellite stable patients. Cancer vaccines with autologous dendritic cells (ADC) could be a complementary therapeutic approach to ICB as this combination has the potential to achieve synergistic effects. METHODS: This was a Phase I/II multicentric study with translational sub-studies, to evaluate the safety, pharmacodynamics and anti-tumor effects of Avelumab plus ADC vaccine in heavily pre-treated MSS mCRC patients. Primary objective was to determine the maximum tolerated dose and the efficacy of the combination. The primary end-point was 40% progression-free survival at 6 months with a 2 Simon Stage. RESULTS: A total of 28 patients were screened and 19 pts were included. Combined therapy was safe and well tolerated. An interim analysis (Simon design first-stage) recommended early termination because only 2/19 (11%) patients were disease free at 6 months. Median PFS was 3.1 months [2.1-5.3 months] and overall survival was 12.2 months [3.2-23.2 months]. Stimulation of immune system was observed in vitro but not clinically. The evaluation of basal RNA-seq noted significant changes between pre and post-therapy liver biopsies related to lipid metabolism and transport, inflammation and oxidative stress pathways. CONCLUSIONS: The combination of Avelumab plus ADC vaccine is safe and well tolerated but exhibited modest clinical activity. Our study describes, for the first-time, a de novo post-therapy metabolic rewiring, that could represent novel immunotherapy-induced tumor vulnerabilities.
BACKGROUND: Immune check-point blockade (ICB) has shown clinical benefit in mismatch repair-deficient/microsatellite instability high metastatic colorectal cancer (mCRC) but not in mismatch repair-proficient/microsatellite stable patients. Cancer vaccines with autologous dendritic cells (ADC) could be a complementary therapeutic approach to ICB as this combination has the potential to achieve synergistic effects. METHODS: This was a Phase I/II multicentric study with translational sub-studies, to evaluate the safety, pharmacodynamics and anti-tumor effects of Avelumab plus ADC vaccine in heavily pre-treated MSS mCRC patients. Primary objective was to determine the maximum tolerated dose and the efficacy of the combination. The primary end-point was 40% progression-free survival at 6 months with a 2 Simon Stage. RESULTS: A total of 28 patients were screened and 19 pts were included. Combined therapy was safe and well tolerated. An interim analysis (Simon design first-stage) recommended early termination because only 2/19 (11%) patients were disease free at 6 months. Median PFS was 3.1 months [2.1-5.3 months] and overall survival was 12.2 months [3.2-23.2 months]. Stimulation of immune system was observed in vitro but not clinically. The evaluation of basal RNA-seq noted significant changes between pre and post-therapy liver biopsies related to lipid metabolism and transport, inflammation and oxidative stress pathways. CONCLUSIONS: The combination of Avelumab plus ADC vaccine is safe and well tolerated but exhibited modest clinical activity. Our study describes, for the first-time, a de novo post-therapy metabolic rewiring, that could represent novel immunotherapy-induced tumor vulnerabilities.
Authors: Dung T Le; Jennifer N Uram; Hao Wang; Bjarne R Bartlett; Holly Kemberling; Aleksandra D Eyring; Andrew D Skora; Brandon S Luber; Nilofer S Azad; Dan Laheru; Barbara Biedrzycki; Ross C Donehower; Atif Zaheer; George A Fisher; Todd S Crocenzi; James J Lee; Steven M Duffy; Richard M Goldberg; Albert de la Chapelle; Minori Koshiji; Feriyl Bhaijee; Thomas Huebner; Ralph H Hruban; Laura D Wood; Nathan Cuka; Drew M Pardoll; Nickolas Papadopoulos; Kenneth W Kinzler; Shibin Zhou; Toby C Cornish; Janis M Taube; Robert A Anders; James R Eshleman; Bert Vogelstein; Luis A Diaz Journal: N Engl J Med Date: 2015-05-30 Impact factor: 91.245
Authors: Roy S Herbst; Jean-Charles Soria; Marcin Kowanetz; Gregg D Fine; Omid Hamid; Michael S Gordon; Jeffery A Sosman; David F McDermott; John D Powderly; Scott N Gettinger; Holbrook E K Kohrt; Leora Horn; Donald P Lawrence; Sandra Rost; Maya Leabman; Yuanyuan Xiao; Ahmad Mokatrin; Hartmut Koeppen; Priti S Hegde; Ira Mellman; Daniel S Chen; F Stephen Hodi Journal: Nature Date: 2014-11-27 Impact factor: 49.962
Authors: Isabelle Soubeyran; Alban Bessede; Sophie Cousin; Coralie Cantarel; Jean-Philippe Guegan; Carlos Gomez-Roca; Jean-Philippe Metges; Antoine Adenis; Simon Pernot; Carine Bellera; Michèle Kind; Céline Auzanneau; François Le Loarer; Antoine Italiano Journal: Clin Cancer Res Date: 2021-01-25 Impact factor: 12.531