Comparison of personal and shared frameshift neoantigen vaccines in a mouse mammary cancer model
Milene Peterson1, Sierra Nicole Murphy2, John Lainson2
1Center for Innovations in Medicine, The Biodesign Institute, Arizona State University, Tempe, AZ, 85287, USA. mtavare1@asu.edu.
Background:
It is widely hoped that personal cancer vaccines will extend the number of patients benefiting from checkpoint and other immunotherapies. 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) created from errors in the production of RNA rather than from DNA mutations are potentially a rich source of neoantigens for cancer vaccines. These errors are predictable, enabling the production of a FSP microarray. Previously we found that these microarrays can identify both personal and shared neoantigens. Here, we compared the performance of personal cancer vaccines (PCVs) with that of a shared antigen vaccine, termed Frameshift Antigen Shared Therapeutic (FAST) vaccine, using the 4 T1 breast cancer model. Sera from 4 T1-tumor bearing mice were assayed on the peptide microarray containing 200 Fs neoantigens, for the PCV, the top 10 candidates were select and personal vaccines constructed and administrated to the respective mice. For the FAST, we selected the top 10 candidates with higher prevalence among all the mice challenged. Seven to 12 days challenged mice were immunized, combined or not with immune checkpoint inhibitor (ICI) (αPD-L1 and αCTLA-4). Primary and secondary tumor clearance and growth were evaluated as well as cellular and humoral immune response against the vaccine targets by IFN-γ ELISPOT and ELISA. Lastly, we analyzed the immune response of the FAST-vaccinated mice by flow cytometry in comparison to the control group.
Results:
We found that PCVs and FAST vaccines both reduced primary tumor incidence and growth as well as lung metastases when delivered as monotherapies or in combination with ICI. Additionally, the FAST vaccine induces a robust and effective T-cell response.
Conclusions:
These results suggest that FSPs produced from RNA-based errors are potent neoantigens that could enable production of off-the-shelf shared antigen vaccines for solid tumors with efficacy comparable to that of PCVs.
Insights
Personal cancer vaccines (PCVs) and Frameshift Antigen Shared Therapeutic (FAST) vaccines effectively reduced tumor growth and metastases. The FAST vaccine, utilizing frameshift peptides (FSPs) from RNA errors, demonstrated comparable efficacy to PCVs and induced a robust T-cell response.
Area of Science:
- Oncology
- Immunology
- Vaccine Development
Background:
- Personal cancer vaccines (PCVs) face challenges including cost, time, and reliance on sufficient tumor DNA mutations.
- Frameshift peptides (FSPs), arising from RNA production errors, represent a potential source of neoantigens for cancer vaccines.
- FSP microarrays can identify both personal and shared neoantigens, offering an alternative to DNA mutation-based approaches.
Purpose of the Study:
- To compare the efficacy of personal cancer vaccines (PCVs) with a shared antigen vaccine (FAST vaccine) in a preclinical breast cancer model.
- To evaluate the potential of frameshift peptides (FSPs) as a source for developing off-the-shelf cancer vaccines.
- To assess the impact of FSP-based vaccines, alone and in combination with immune checkpoint inhibitors (ICIs), on tumor growth and immune response.
Main Methods:
- The 4T1 breast cancer model was used to compare PCVs and Frameshift Antigen Shared Therapeutic (FAST) vaccines.
- Mice were immunized with either PCVs or FAST vaccines (top 10 prevalent FSPs), alone or with ICIs (αPD-L1 and αCTLA-4).
- Tumor growth, metastasis, and immune responses (IFN-γ ELISPOT, ELISA, flow cytometry) were evaluated.
Main Results:
- Both PCVs and FAST vaccines significantly reduced primary tumor incidence, growth, and lung metastases.
- The FAST vaccine demonstrated efficacy comparable to PCVs when used as monotherapy or in combination with ICIs.
- The FAST vaccine induced a robust and effective T-cell response.
Conclusions:
- Frameshift peptides (FSPs) derived from RNA errors are potent neoantigens for cancer vaccines.
- Off-the-shelf shared antigen vaccines, like the FAST vaccine, show comparable efficacy to personalized vaccines for solid tumors.
- FSP-based vaccines offer a promising strategy for cancer immunotherapy, potentially overcoming limitations of current personalized approaches.
