FAST vaccines based on frameshift neoantigens may have advantages over personal vaccines

It is widely hoped that personal cancer vaccines will extend the number of patients benefiting from checkpoint and other immunotherapeutics. However, it is clear creating such vaccines will be challenging. It requires obtaining and sequencing tumor DNA/RNA, predicting potentially immunogenic neoepitopes and manufacturing a one-use vaccine. This process takes time and considerable cost. Importantly, most mutations will not produce an immunogenic peptide and many patient’s tumors do not contain enough DNA mutations to make a vaccine. We have discovered that frameshift peptides (FSP) produced in tumors though errors in RNA production are a rich source of neoantigens. There are ~220K bioinformatically predictable possible FSP allowing us to make arrays representing them as 15aa peptides. These arrays can then be used to screen cancer patient blood antibodies for reactivity to the arrays. In screening many cancer patients blood on these array, we found both personal and cancer-type specific peptides. This suggests a new type of vaccine consisting of pre-made FSP components for a specific type of cancer. We term these FAST vaccines. Here we use the mouse 4T1 breast cancer model to test the relative effectiveness of a FAST and a PERSONAL vaccine. To create the vaccines, we initially challenged mice subcutaneously with 4T1 tumor cells and, seven days later, sera were collected. Pre-challenge and 7-days sera were assayed on peptide microarrays containing 200 FS neoantigens. For the PERSONAL vax, the top 10 candidates (higher median intensity fluorescence) were select and personal vaccines constructed and administrated to respective mice (n=10). For the FAST vax, we selected the top 10 candidates with higher prevalence among all the mice challenged (n=24), a common Breast cancer FAST vax was constructed (mBC FAST-vax). Mice were challenged with 4T1 cells subcutaneously. Vaccines were then, administrated twice with one-week interval, combined or not with checkpoint inhibitor (CPI) (anti- PD-L1/ CTLA-4). Our results demonstrated that both vaccine approaches, FAST and PERSONAL vax, alone reduced tumor growth as well as increased animal survival. Nonetheless, the FAST vax protected 70 % of mice (7/10 - tumor free) even after re-challenge, 29 days after vaccine regimen. For the Personal vax group, co-administration with CPI resulted in enhancement of tumor control with 57 % of the mice strongly controlling the tumor. The FAST vax performance was not improved by CPI. Both vaccine approaches elicited a robust and homogenous B- and T- cell immune response against both vaccine peptides and tumor cells. Additionally, use of Non-reactive FSPs and a Non-Breast cancer FAST vax were not able to control tumor development. We conclude that the FAST technology may open new opportunities to develop a low cost, feasible and efficacious vaccines against cancer. Citation Format: Milene Tavares Batista, Sierra Nicole Murphy, Ji9an Zhang, Luhui Shen, Phillip Stafford, Stephen A. Johnston. FAST vaccines based on frameshift neoantigens may have advantages over personal vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1463.