Neoleukin-2 enhances anti-tumour immunity downstream of peptide vaccination targeted by an anti-MHC class II VHH

• Published in: Open biology Vol. 10; no. 2; p. 190235
• Main Authors: Crowley, Stephanie J, Bruck, Patrick T, Bhuiyan, Md Aladdin, Mitchell-Gears, Amelia, Walsh, Michael J, Zhangxu, Kevin, Ali, Lestat R, Jeong, Hee-Jin, Ingram, Jessica R, Knipe, David M, Ploegh, Hidde L, Dougan, Michael, Dougan, Stephanie K
• Format: Journal Article
• Language: English
• Published: England The Royal Society 01.02.2020
• Subjects: alpaca nanobodies; Animals; Antigens, Neoplasm - immunology; Autoantigens - immunology; Camelids, New World - immunology; cancer immunology; cancer vaccines; Cancer Vaccines - administration & dosage; Cancer Vaccines - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; cytokines; Drug Synergism; Histocompatibility Antigens Class II - immunology; Interleukin-2 - administration & dosage; Interleukin-2 - immunology; Melanoma - drug therapy; Melanoma - immunology; Mice; neoantigens; Peptides - administration & dosage; Peptides - immunology; Recombinant Proteins - administration & dosage; Recombinant Proteins - immunology; Single-Domain Antibodies - metabolism; Vaccines, Subunit; vhh; Xenograft Model Antitumor Assays; neoantigens; cytokines; cancer vaccines; alpaca nanobodies; VHH; cancer immunology
• ISSN: 2046-2441; 2046-2441
• DOI: 10.1098/rsob.190235

Cancer-specific mutations can lead to peptides of unique sequence presented on MHC class I to CD8 T cells. These neoantigens can be potent tumour-rejection antigens, appear to be the driving force behind responsiveness to anti-CTLA-4 and anti-PD1/L1-based therapies and have been used to develop personalized vaccines. The platform for delivering neoantigen-based vaccines has varied, and further optimization of both platform and adjuvant will be necessary to achieve scalable vaccine products that are therapeutically effective at a reasonable cost. Here, we developed a platform for testing potential CD8 T cell tumour vaccine candidates. We used a high-affinity alpaca-derived VHH against MHC class II to deliver peptides to professional antigen-presenting cells. We show and that peptides derived from the model antigen ovalbumin are better able to activate naive ovalbumin-specific CD8 T cells when conjugated to an MHC class II-specific VHH when compared with an irrelevant control VHH. We then used the VHH-peptide platform to evaluate a panel of candidate neoantigens in a mouse model of pancreatic cancer. None of the candidate neoantigens tested led to protection from tumour challenge; however, we were able to show vaccine-induced CD8 T cell responses to a melanoma self-antigen that was augmented by combination therapy with the synthetic cytokine mimetic Neo2/15.