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Defining key parameters of therapeutic activity using mouse cancer neoepitopes
Summit Singhaviranon1, Joseph P Dempsey1, Hakimeh Ebrahimi-Nik1
1Department of Immunology and Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT, United States.
Abstract:
Cancer neoepitopes have emerged as strong candidates as cancer vaccines. Mouse models of cancer neoepitopes often test their activity in models of prophylaxis, while the human setting is always in therapy of preexisting disease. We have previously identified 7 MHC I-presented cancer neoepitopes of the BALB/c sarcoma Meth A by mass spectrometry; 3 of the 7 neoepitopes showed anti-tumor activity in assays of prophylaxis. Here, we test these neoepitopes for activity in treatment of preexisting 3-, 10- and 17-d old cancers, and observe that: (i) activity in prophylaxis is not predictive of efficacy in treatment of preexisting cancers. (ii) The higher activity of a neoepitope in therapy, albeit not in prophylaxis, correlates well with the high precursor frequency of CD8 T cells. (iii) Co-immunization with CD4 and CD8 neoepitopes is essential for optimal therapeutic efficacy. CD4 help can be obtained from an MHC II-restricted neoepitope of the tumor, or from an irrelevant MHC II-epitope. (iv) The CTL and helper epitopes, linked or un-linked to each other, are equally effective. These insights stress and stretch some of our current suppositions and shall inform designs for use of neoepitopes in cancer treatment.
Insights
Cancer neoepitope vaccines show therapeutic potential, but prophylactic efficacy doesn't predict treatment success. Optimal cancer therapy requires CD8 T cell response and CD4 T cell help, informing future vaccine design.
Area of Science:
- Immunology
- Oncology
- Vaccinology
Background:
- Cancer neoepitopes are promising vaccine candidates.
- Mouse models often use prophylaxis, unlike human therapeutic settings.
- Previous work identified 7 MHC I-presented neoepitopes in BALB/c sarcoma Meth A.
Purpose of the Study:
- To evaluate neoepitopes for treating established cancers, not just prophylaxis.
- To determine predictors of therapeutic efficacy for cancer neoepitopes.
- To optimize cancer vaccine design by understanding CD8 T cell and CD4 T cell help requirements.
Main Methods:
- Testing 3 previously identified MHC I-presented neoepitopes in established Meth A sarcoma models (3, 10, 17 days old).
- Assessing anti-tumor activity in therapeutic settings.
- Evaluating the role of CD8 T cell precursor frequency and CD4 T cell help (MHC II-restricted neoepitopes).
Main Results:
- Prophylactic anti-tumor activity did not predict therapeutic efficacy.
- Higher therapeutic activity correlated with high CD8 T cell precursor frequency.
- Co-immunization with CD4 and CD8 neoepitopes was crucial for optimal therapeutic effect.
- Both linked and unlinked CTL and helper epitopes were effective.
Conclusions:
- Neoepitope vaccine efficacy in established cancer treatment differs from prophylactic models.
- CD8 T cell precursor frequency is a key factor for therapeutic neoepitope vaccines.
- CD4 T cell help is essential for optimal cancer neoepitope vaccine therapy, achievable via tumor-derived or irrelevant MHC II epitopes.
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