The route of administration dictates the immunogenicity of peptide-based cancer vaccines in mice
Vaccines consisting of synthetic peptides representing cytotoxic T-lymphocyte (CTL) epitopes have long been considered as a simple and cost-effective approach to treat cancer. However, the efficacy of these vaccines in the clinic in patients with measurable disease remains questionable. We believe that the poor performance of peptide vaccines is due to their inability to generate sufficiently large CTL responses that are required to have a positive impact against established tumors. Peptide vaccines to elicit CTLs in the clinic have routinely been administered in the same manner as vaccines designed to induce antibody responses: injected subcutaneously and in many instances using Freund’s adjuvant. We report here that peptide vaccines and poly-ICLC adjuvant administered via the unconventional intravenous route of immunization generate substantially higher CTL responses as compared to conventional subcutaneous injections, resulting in more successful antitumor effects in mice. Furthermore, amphiphilic antigen constructs such as palmitoylated peptides were shown to be better immunogens than long peptide constructs, which now are in vogue in the clinic. The present findings if translated into the clinical setting could help dissipate the wide-spread skepticism of whether peptide vaccines will ever work to treat cancer.
KeywordsPeptide vaccines Route of injection CD8 T cells Melanoma
Adoptive cell transfer
Cytotoxic T lymphocyte
Immune checkpoint inhibitors
Incomplete Freund’s adjuvant
Melanoma differentiation-associated protein 5
MHC class I
MHC class II
Poly-IC stabilized with poly-lysine and carboxymethyl cellulose
T-cell receptor for antigen
Toll-like receptor 3
Tyrosinase-related protein 1
HS, TK, TN, and JW performed research and analyzed the data. EC designed, supervised, and analyzed the experiments and wrote the manuscript. AMS provided reagents and discussed results.
This work was supported by National Cancer Institute Grant R01CA157303 and by start-up funds from Augusta University, Georgia Cancer Center and the Georgia Research Alliance (GRA).
Compliance with ethical standards
Conflict of interest
Andres M. Salazar is President and CEO of Oncovir, Inc. and is developing poly-ICLC (Hiltonol ™) for the clinic. Esteban Celis is a consultant for Oncovir, Inc. and has filed patent applications based on the use of synthetic peptides and poly-IC combinatorial vaccines. The rights of the patent applications have been transferred to the Moffitt Cancer Center (Tampa, FL). Other authors declare no conflict of interest.
Animal sources and statement on the welfare of animals
C57BL/6 (WT-B6) and B6-Ly5.1 (CD45.1) mice were purchased from the National Cancer Institute (Wilmington, MA). TnTR1 TCR-transnuclear, pmel-1 and Trp1-KO mice were bred at the Georgia Cancer Center animal facility. All procedures performed in the experiments involving animals were in accordance with the ethical standards of the Augusta University Institutional Animal Care and Use Committee, where all the studies were conducted (Protocol No. 2013-0598, approved on 11/21/2016).
The B16F10 murine melanoma cell line was obtained from the American Type Culture Collection.
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