Oncolytic measles vaccines encoding PD-1 and PD-L1 checkpoint blocking antibodies to increase tumor-specific T cell memory

Molecular Therapy: Oncolytics

Christian J. Buchholz¹  Lara M. Jeworowski²  Coline Moulin³  Gemma Pidelaserra-Martí⁴  Rūta Veinalde⁴  Dirk Jäger⁴  Guy Ungerechts⁵  Linda Küther⁵  Christine E. Engeland⁶ 

[1] Ecole Normale Supérieure de Lyon, 15 parvis René Descartes, 69342 Lyon, France;Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany;Faculty of Health, School of Medicine, Center for Biomedical Research and Education, Institute of Virology and Microbiology, Witten/Herdecke University, Stockumer Str. 10, 58453 Witten, Germany;Clinical Cooperation Unit Virotherapy, German Cancer Research Center, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany;Faculty of Health, School of Medicine, Center for Biomedical Research and Education, Institute of Virology and Microbiology, Witten/Herdecke University, Stockumer Str. 10, 58453 Witten, Germany;Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, 63225 Langen, Germany;

关键词: oncolytic virus;    measles virus;    PD-1;    PD-L1;    immune checkpoint;    cancer immunotherapy;   

DOI  :  

来源: DOAJ

【 摘 要 】

PD-1/PD-L1 checkpoint blockade has achieved unprecedented success in cancer immunotherapy. Nevertheless, many immune-excluded tumors are resistant to therapy. Combination with oncolytic virotherapy may overcome resistance by inducing acute inflammation, immune cell recruitment, and remodeling of the tumor immune environment. Here, we assessed the combination of oncolytic measles vaccine (MV) vectors and PD-1/PD-L1 blockade. In the MC38cea model of measles virus oncolysis, MV combined with anti-PD-1 and MV vectors encoding anti-PD-1 or anti-PD-L1 antibodies achieved modest survival benefits compared with control MV or vectors encoding the antibody constant regions only. Analyses of tumor samples and tumor-draining lymph nodes revealed slight increases in intratumoral T cell effector cytokines as well as a shift toward an effector memory phenotype in the T cell compartment. Importantly, increased IFN-γ recall responses were observed in tumor rechallenge experiments with mice in complete tumor remission after treatment with MV encoding anti-PD-1 or anti-PD-L1 compared with control MV. These results prompted us to generate MV encoding the clinically approved agents pembrolizumab and nivolumab. Previously, we have generated MV encoding atezolizumab. We demonstrated the functionality of the novel vectors in vitro. We envision these vectors as therapeutics that induce and support durable anti-tumor immune memory.

【 授权许可】

Unknown