SCIB1, a huIgG1 antibody DNA vaccination, combined with PD-1 blockade induced efficient therapy of poorly immunogenic tumors.
OBJECTIVE
We have previously shown that supraoptimal signaling of high avidity T cells leads to high expression of PD-1 and inhibition of proliferation. This study was designed to see if this effect could be mitigated by combining a vaccine that stimulates high avidity T cells with PD-1 blockade.


METHODS
We investigated the anti-tumor effect of a huIgG1 antibody DNA vaccine (SCIB1) and PD-1 blockade.


RESULTS
Vaccination of HLA-DR4 transgenic mice with SCIB1 induced high frequency and avidity T cell responses that resulted in survival (40%) of mice with established B16F1-DR4 tumors. SCIB1 vaccination was associated with increased infiltration of CD4 and CD8 T cells within the tumor but was also associated with upregulation of PD-L1 within the tumor environment. PD-1 blockade also resulted in increased CD8 T cell infiltration and an anti-tumor response with 50% of mice showing long term survival. In line with our hypothesis that PD-1/PD-L1 signaling results in inhibition of proliferation of high avidity T cells at the tumor site, the combination of PD-1 blockade with vaccination, enhanced the number and proliferation of the CD8 tumor infiltrate. This resulted in a potent anti-tumor response with 80% survival of the mice.


CONCLUSIONS
There is a benefit in combining PD-1 blockade with vaccines that induce high avidity T cell responses and in particular with SCIB1.
Scancell Limited, Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, UK.
Wei
W
Xue
Scancell Limited, Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, UK.
Victoria A
VA
Brentville
Scancell Limited, Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, UK.
Peter
P
Symonds
Scancell Limited, Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, UK.
Katherine W
KW
Cook
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
Hideo
H
Yagita
Scancell Limited, Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, UK.
Rachael L
RL
Metheringham
Scancell Limited, Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, UK.|Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Nottingham, UK.
Lindy G
LG
Durrant
D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology*; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D059016:Tumor Microenvironment; D019444:Vaccines, DNA / Q000276:immunology / Q000494:pharmacology
D000074322:Antineoplastic Agents, Immunological; D019496:Cancer Vaccines; D015804:HLA-DR4 Antigen; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D019444:Vaccines, DNA
DNA vaccine; Fc targeting; PD-1 blockade; melanoma; tumor rejection