TY  - GEN
AV  - public
CY  - Heidelberg
TI  - Evaluation of antigen-displaying adeno-associated virus-like particles (AAVLPs) as future candidates for personalized cancer vaccination
Y1  - 2021///
ID  - heidok30119
A1  - Neukirch, Lasse
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/30119/
N2  - Despite extensive research and significant advances in the past decades, cancer is still the second leading cause of deaths worldwide. Within cancer research, a promising and growing field is the immuno-oncology, which takes advantage of a patient?s immune system to elicit a protective response against malignant cells. Personalized vaccination against neoantigens is an encouraging approach to target different types of cancer. Neoantigens result from point mutations in the cancer cell genome and transform originally non-immunogenic sequences into immunogenic epitopes that overcome central immune tolerance. Despite different vaccine designs, which are primarily based on dendritic cells, DNA, RNA or synthetic peptides, additional strategies are required to reach sufficient immune responses.

In this study, a novel approach was tested by displaying (neo-)antigens on adeno-associated virus-like particles (AAVLPs) to effectively prime CD8+ T cell responses. AAV was chosen as an antigen-presentation-scaffold owing to its excellent safety profile in humans and tolerance towards genetic engineering of the capsid, allowing presentation of 60 antigen copies per particle. The general vaccination strategy was tested in mice with AAVLPs displaying the ovalbumin-derived model antigen SIINFEKL. Initial experiments showed induction of long-lasting CD8+ T cell responses, sufficient to protect mice completely from B16F10-OVA tumor growth. Based on the SIINFEKL vaccine, the strategy was optimized by defining the most suitable injection routes, adjuvants and capsid insertion sites. Highest CD8+ T cell responses were achieved when the vaccine was I) injected s.c. into the hock, II) adjuvanted with Montanide ISA 51, III) injected at a high local concentration and IV) was composed of vector DNA-containing particles that V) display the antigen in the VR-IV loop of the capsid proteins.

While tested prime-boost strategies and coupling of anti-CD40 to the capsid had no benefit for the vaccination, co-display of the immune stimulatory peptide J-ICBL improved T cell responses significantly. Interestingly, the presence of B cells was disadvantageous for the induction of antigen-specific CD8+ T cells and tumor protection, while the presence of CD4+ T cells was essential. Accordingly, T helper epitopes were identified within the AAVLP capsid sequence. In addition to SIINFEKL-presenting AAVLPs, particles were designed to present a set of different B16F10-derived neoantigens. While a head-to-head comparison showed no effect of a peptide vaccine against B16F10 tumor growth, injection of neoantigen-displaying AAVLPs significantly reduced the tumor growth rate. Although the general strategy requires further refinement and mechanistic analyses, neoantigen-AAVLPs represent an alternative for current therapy approaches and could be a promising candidate for future clinical applications.
ER  -