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Research article
Milene Peterson
Arizona State University Biodesign Institute
Corresponding Author
ORCiD: https://orcid.org/0000-0002-2102-244X
License:
This work is licensed under a CC BY 4.0 License. Read Full License
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 4T1 breast cancer model. Sera from 4T1-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.
Keywords
Personalized cancer vaccine, shared-neoantigen vaccine, frameshift peptides, breast cancer, mouse model, immunotherapy
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CURRENT STATUS: Under Review
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Posted 31 Mar, 2020
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Review #2 received
Received 02 Apr, 2020
Editor assigned
On 26 Mar, 2020
Reviewers invited
Invitations sent on 26 Mar, 2020
Reviewer #1 agreed
On 26 Mar, 2020
Reviewer #2 agreed
On 26 Mar, 2020
Review #1 received
Received 26 Mar, 2020
Submission checks complete
On 25 Mar, 2020
Editor invited
On 25 Mar, 2020
No comments provided
Review #1 received
Received 28 Feb, 2020
Editorial decision: Major revision
On 28 Feb, 2020
Review #2 received
Received 20 Feb, 2020
Reviewer #2 agreed
On 07 Feb, 2020
Editor assigned
On 06 Feb, 2020
Reviewers invited
Invitations sent on 06 Feb, 2020
Reviewer #1 agreed
On 06 Feb, 2020
Submission checks complete
On 05 Feb, 2020
Editor invited
On 05 Feb, 2020
First submitted
On 29 Jan, 2020
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This preprint is under consideration at BMC Immunology. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Milene Peterson
Arizona State University Biodesign Institute
Corresponding Author
ORCiD: https://orcid.org/0000-0002-2102-244X
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 2
Posted 31 Mar, 2020
No community comments so far
Review #2 received
Received 02 Apr, 2020
Editor assigned
On 26 Mar, 2020
Reviewers invited
Invitations sent on 26 Mar, 2020
Reviewer #1 agreed
On 26 Mar, 2020
Reviewer #2 agreed
On 26 Mar, 2020
Review #1 received
Received 26 Mar, 2020
Submission checks complete
On 25 Mar, 2020
Editor invited
On 25 Mar, 2020
No comments provided
Review #1 received
Received 28 Feb, 2020
Editorial decision: Major revision
On 28 Feb, 2020
Review #2 received
Received 20 Feb, 2020
Reviewer #2 agreed
On 07 Feb, 2020
Editor assigned
On 06 Feb, 2020
Reviewers invited
Invitations sent on 06 Feb, 2020
Reviewer #1 agreed
On 06 Feb, 2020
Submission checks complete
On 05 Feb, 2020
Editor invited
On 05 Feb, 2020
First submitted
On 29 Jan, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
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 4T1 breast cancer model. Sera from 4T1-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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
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