Therapeutic efficacy of PD1/PDL1 blockade in B16 melanoma is greatly enhanced by immunization with dendritic cell-targeting lentiviral vector and protein vaccine

• Published in: Vaccine Vol. 38; no. 17; pp. 3369 - 3377
• Main Authors: Albershardt, Tina Chang, Parsons, Andrea Jean, Reeves, Rebecca Susan, Flynn, Patrick Alexander, Campbell, David James, ter Meulen, Jan, Berglund, Peter
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 09.04.2020; Elsevier Limited
• Subjects: Animals; Antibodies; Anticancer properties; Antigen (tumor-associated); Antigens; Antigens, Neoplasm - immunology; Autoantigens; B7-H1 Antigen - antagonists & inhibitors; Cancer; Cancer Vaccines - immunology; CTLA-4 protein; Cytokines; Dendritic cells; Dendritic Cells - immunology; Exhaustion; Flow cytometry; Genetic Vectors; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immunization; Immunological tolerance; Immunotherapy; Lentiviral vector; Lentivirus; Lymphocytes; Lymphocytes T; Melanoma; Melanoma, Experimental - therapy; Membrane Glycoproteins - immunology; Membrane Proteins - immunology; Mice; Oxidoreductases - immunology; PD-1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Proteins; Solid tumors; Synergism; T cell receptors; TLR4 agonist; Tumors; Tyrosinase; Tyrosinase-related protein 1; Vaccination; Vaccines; Lentiviral vector; Immune checkpoint inhibitors; TLR4 agonist
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2020.02.034

While immune checkpoint inhibition is rapidly becoming standard of care in many solid tumors, immune checkpoint inhibitors (ICIs) fail to induce clinical responses in many patients, presumably due to insufficient numbers of tumor-specific T cells in the tumor milieu. To this end, immunization protocols using viral vectors expressing tumor-associated antigens are being explored to induce T cell responses that synergize with ICIs. However, the optimal combination of vaccine and immune checkpoint regimen remains undefined. Here, a dendritic cell-targeting lentiviral vector (ZVex®) expressing the endogenous murine tyrosinase-related protein 1 (mTRP1), or the human tumor antigen NY-ESO-1, was explored as monotherapy or heterologous prime-boost (HPB) vaccine regimen together with recombinant tumor antigen in the murine B16 melanoma model. PD1/PDL1 blockade significantly enhanced ZVex/mTRP1, but not ZVex/NY-ESO-1, induced immune responses in mice, whereas the opposite effect was observed with anti-CTLA4 antibody. Anti-tumor efficacy of anti-PD1, but not anti-PDL1 or anti-CTLA4, was significantly enhanced by ZVex/mTRP1 and HPB vaccination. These results suggest mechanistic differences in the effect of checkpoint blockade on vaccine-induced immune and anti-tumor responses against self versus non-self tumor antigens, possibly due to tolerance and state of exhaustion of anti-tumor T cells.