Oncoimmunology. 2018 Sep 5;7(12):e1502904. doi: 10.1080/2162402X.2018.1502904. eCollection 2018.
CD27 stimulation unveils the efficacy of linked class I/II peptide vaccines in poorly immunogenic tumors by orchestrating a coordinated CD4/CD8 T cell response.
Riccione KA1,2,3, He LZ4, Fecci PE1,2,5,6, Norberg PK1,2,5, Suryadevara CM1,2,6, Swartz A1,2,6, Healy P7, Reap E1,2,5, Keler T4, Li QJ8, Congdon KL1,2,5, Sanchez-Perez L1,2,5, Sampson JH1,2,5,3,6.
1
Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC.
2
The Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA.
3
Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, USA.
4
Celldex Therapeutics, Hampton, NJ, USA.
5
Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA.
6
Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
7
Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA.
8
Department of Immunology, Duke University School of Medicine, Durham, NC, USA.
Despite their promise, tumor-specific peptide vaccines have limited efficacy. CD27 is a costimulatory molecule expressed on CD4+ and CD8+ T cells that is important in immune activation. Here we determine if a novel CD27 agonist antibody (ahCD27) can enhance the antitumor T cell response and efficacy of peptide vaccines. We evaluated the effects of ahCD27 on the immunogenicity and antitumor efficacy of whole protein, class I-restricted, and class II-restricted peptide vaccines using a transgenic mouse expressing human CD27. We found that ahCD27 preferentially enhances the CD8+ T cell response in the setting of vaccines comprised of linked class I and II ovalbumin epitopes (SIINFEKL and TEWTSSNVMEERKIKV, respectively) compared to a peptide vaccine comprised solely of SIINFEKL, resulting in the antitumor efficacy of adjuvant ahCD27 against intracranial B16.OVA tumors when combined with vaccines containing linked class I/II ovalbumin epitopes. Indeed, we demonstrate that this efficacy is both CD8- and CD4-dependent and ahCD27 activity on ovalbumin-specific CD4+ T cells is necessary for its adjuvant effect. Importantly for clinical translation, a linked universal CD4+ helper epitope (tetanus P30) was sufficient to instill the efficacy of SIINFEKL peptide combined with ahCD27, eliminating the need for a tumor-specific class II-restricted peptide. This approach unveiled the efficacy of a class I-restricted peptide vaccine derived from the tumor-associated Trp2 antigen in mice bearing intracranial B16 tumors. CD27 agonist antibodies combined with peptide vaccines containing linked tumor-specific CD8+ epitopes and tumor-specific or universal CD4+ epitopes enhance the efficacy of active cancer immunotherapy. |
