Combination Immunotherapy with Vaccine and Oncolytic HSV Virotherapy Is Time Dependent

Author:

Totsch Stacie K.1ORCID,Ishizuka Andrew S.23ORCID,Kang Kyung-Don14ORCID,Gary Sam E.15ORCID,Rocco Abbey1ORCID,Fan Aaron E.14ORCID,Zhou Li4ORCID,Valdes Pablo A.6ORCID,Lee SeungHo7ORCID,Li Jason7ORCID,Peruzzotti-Jametti Luca89ORCID,Blitz Sarah10ORCID,Garliss Christopher M.2ORCID,Johnston James M.11ORCID,Markert James M.11ORCID,Lynn Geoffrey M.2ORCID,Bernstock Joshua D.710ORCID,Friedman Gregory K.14ORCID

Affiliation:

1. Division of Pediatric Hematology and Oncology, Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, Alabama. 1

2. Barinthus Biotherapeutics, Inc., Germantown, Maryland. 2

3. Boston Children’s Hospital, Boston, Massachusetts. 3

4. Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas. 4

5. Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, Alabama. 5

6. Department of Neurosurgery, University of Texas Medical Branch, Galveston, Texas. 6

7. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts. 7

8. Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom. 8

9. Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom. 9

10. Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. 10

11. Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama. 11

Abstract

Abstract Oncolytic virotherapy or immunovirotherapy is a strategy that utilizes viruses to selectively infect and kill tumor cells while also stimulating an immune response against the tumor. Early clinical trials in both pediatric and adult patients using oncolytic herpes simplex viruses (oHSV) have demonstrated safety and promising efficacy; however, combinatorial strategies designed to enhance oncolysis while also promoting durable T-cell responses for sustaining disease remission are likely required. We hypothesized that combining the direct tumor cell killing and innate immune stimulation by oHSV with a vaccine that promotes T cell–mediated immunity may lead to more durable tumor regression. To this end, we investigated the preclinical efficacy and potential synergy of combining oHSV with a self-assembling nanoparticle vaccine codelivering peptide antigens and Toll-like receptor 7 and 8 agonists (referred to as SNAPvax),which induces robust tumor-specific T-cell immunity. We then assessed how timing of the treatments (i.e., vaccine before or after oHSV) impacts T-cell responses, viral replication, and preclinical efficacy. The sequence of treatments was critical, as survival was significantly enhanced when the SNAPvax vaccine was given prior to oHSV. Increased clinical efficacy was associated with reduced tumor volume and increases in virus replication and tumor antigen–specific CD8+ T cells. These findings substantiate the criticality of combination immunotherapy timing and provide preclinical support for combining SNAPvax with oHSV as a promising treatment approach for both pediatric and adult tumors.

Funder

U.S. Food and Drug Administration

Publisher

American Association for Cancer Research (AACR)

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