Taking advantage of the antigen (Ag)-specific T cell induction of a protein vaccine (containing a cell-penetrating peptide, Ag, and a peptide TLR4 agonist) and the powerful innate-adaptive stimulation by a VSV oncolytic virus (OV) carrying the same Ag, Das and Belnoue et al. demonstrated that s.c. protein vaccine priming followed by i.v. OV boosting led to the optimal Ag-specific CD8+ T cell responses (number and quality), resulting in significant TME remodeling and tumor control in multiple models. Resistance to complete tumor control was associated with the presence of early exhausted T cells, and addition of anti-PD-1 axis therapy led to more CRs.
Contributed by Ed Fritsch
ABSTRACT: Functional tumor-specific cytotoxic T cells elicited by therapeutic cancer vaccination in combination with oncolytic viruses offer opportunities to address resistance to checkpoint blockade therapy. Two cancer vaccines, the self-adjuvanting protein vaccine KISIMA, and the recombinant oncolytic vesicular stomatitis virus pseudotyped with LCMV-GP expressing tumor-associated antigens, termed VSV-GP-TAA, both show promise as a single agent. Here we find that, when given in a heterologous prime-boost regimen with an optimized schedule and route of administration, combining KISIMA and VSV-GP-TAA vaccinations induces better cancer immunity than individually. Using several mouse tumor models with varying degrees of susceptibility for viral replication, we find that priming with KISIMA-TAA followed by VSV-GP-TAA boost causes profound changes in the tumor microenvironment, and induces a large pool of poly-functional and persistent antigen-specific cytotoxic T cells in the periphery. Combining this heterologous vaccination with checkpoint blockade further improves therapeutic efficacy with long-term survival in the spectrum. Overall, heterologous vaccination with KISIMA and VSV-GP-TAA could sensitize non-inflamed tumors to checkpoint blockade therapy.
Author Info: (1) Christian Doppler Laboratory for Viral Immunotherapy of Cancer, Medical University of Innsbruck, Innsbruck, Austria. Institute of Virology, Medical University of Innsbruck, Inn
Author Info: (1) Christian Doppler Laboratory for Viral Immunotherapy of Cancer, Medical University of Innsbruck, Innsbruck, Austria. Institute of Virology, Medical University of Innsbruck, Innsbruck, Austria. (2) AMAL Therapeutics, Geneva, Switzerland. Boehringer Ingelheim International GmbH, Ingelheim, Germany. (3) AMAL Therapeutics, Geneva, Switzerland. Boehringer Ingelheim International GmbH, Ingelheim, Germany. (4) Christian Doppler Laboratory for Viral Immunotherapy of Cancer, Medical University of Innsbruck, Innsbruck, Austria. Institute of Virology, Medical University of Innsbruck, Innsbruck, Austria. (5) Christian Doppler Laboratory for Viral Immunotherapy of Cancer, Medical University of Innsbruck, Innsbruck, Austria. Institute of Virology, Medical University of Innsbruck, Innsbruck, Austria. (6) Boehringer Ingelheim International GmbH, Ingelheim, Germany. ViraTherapeutics GmbH, Innsbruck, Austria. (7) Christian Doppler Laboratory for Viral Immunotherapy of Cancer, Medical University of Innsbruck, Innsbruck, Austria. Institute of Virology, Medical University of Innsbruck, Innsbruck, Austria. (8) Christian Doppler Laboratory for Viral Immunotherapy of Cancer, Medical University of Innsbruck, Innsbruck, Austria. Institute of Virology, Medical University of Innsbruck, Innsbruck, Austria. (9) Institute of Virology, Medical University of Innsbruck, Innsbruck, Austria. (10) Unit of Laboratory Animal Pathology, Institute of Pathology, University of Veterinary Medicine Vienna, Vienna, Austria. (11) Boehringer Ingelheim International GmbH, Ingelheim, Germany. ViraTherapeutics GmbH, Innsbruck, Austria. (12) Unit of Laboratory Animal Pathology, Institute of Pathology, University of Veterinary Medicine Vienna, Vienna, Austria. Department of Experimental Pathology, Medical University of Vienna, Vienna, Austria. (13) Institute of Virology, Medical University of Innsbruck, Innsbruck, Austria. (14) Boehringer Ingelheim International GmbH, Ingelheim, Germany. ViraTherapeutics GmbH, Innsbruck, Austria. (15) AMAL Therapeutics, Geneva, Switzerland. madiha.derouazi@boehringer-ingelheim.com. Boehringer Ingelheim International GmbH, Ingelheim, Germany. madiha.derouazi@boehringer-ingelheim.com. (16) Christian Doppler Laboratory for Viral Immunotherapy of Cancer, Medical University of Innsbruck, Innsbruck, Austria. guido.wollmann@i-med.ac.at. Institute of Virology, Medical University of Innsbruck, Innsbruck, Austria. guido.wollmann@i-med.ac.at.
