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

Abstract

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 in vitro and in vivo 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 vivo 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.

Radiation combines with immune checkpoint blockade to enhance T cell priming in a murine model of poorly immunogenic pancreatic cancer

“…Not only do our data correspond with a T cell-mediated mechanism of tumour control, but they also generally corroborate data indicating that combining radiation with anti-PD-L1 or with checkpoint blockade and anti-CD40 therapy slows tumour growth in a KPC model of pancreatic cancer [ 43 , 44 , 50 ]. Other attempts at T cell priming using peptide-based vaccines or other T cell-directed therapies that do not induce tumour cell death have been less effective, suggesting that release of tumour antigens from dying malignant cells is a critical component of successful immunotherapy in PDAC [ 23 , 51 ].…”

Anti-CTLA-4 nanobody as a promising approach in cancer immunotherapy

“…The anti-CD11b nanobody produced the most significant activation of CD8 + T cells [ 103 ]. Crowley et al also created nanobody-conjugated peptide vaccines that targeted MHC-II for APC delivery and showed improved vaccine-mediated CD8 + T cell activation [ 104 ]. In addition, many nanobodies target APCs whose antigens have yet to be discovered, such as DC1.8, DC2.1, and R3_13 nanobodies [ 105 , 106 ].…”

Nanobodies: Next Generation of Cancer Diagnostics and Therapeutics

“…Nanobody-LVs have shown specific DC transduction ( 135 ) in vitro , but a subsequent study suggested that broad tropism LVs may be more effective in inducing an anti-tumor response ( 136 ). Furthermore, Crowley et al ( 137 ) developed nanobody-conjugated peptide vaccines targeting MHC-II for APC delivery, demonstrating enhanced vaccine-mediated CD8 + T cell activation in vivo .…”