Targeting Driver Oncogenes and Other Public Neoantigens Using T Cell Receptor-Based Cellular Therapy
Related Experiment Video
Updated: Jul 17, 2025
Non-Viral Engineering of Primary Human T Cells via Homology-Mediated End-Joining Targeted Integration of Large DNA Templates
Published on: May 9, 2025
Tijana Martinov1, Philip D Greenberg1,2
1Program in Immunology and Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
Abstract:
T cell reactivity to tumor-specific neoantigens can drive endogenous and therapeutically induced antitumor immunity. However, most tumor-specific neoantigens are unique to each patient (private) and targeting them requires personalized therapy. A smaller subset of neoantigens includes epitopes that span recurrent mutation hotspots, translocations, or gene fusions in oncogenic drivers and tumor suppressors, as well as epitopes that arise from viral oncogenic proteins. Such antigens are likely to be shared across patients (public), uniformly expressed within a tumor, and required for cancer cell survival and fitness. Although a limited number of these public neoantigens are naturally immunogenic, recent studies affirm their clinical utility. In this review, we highlight efforts to target mutant KRAS, mutant p53, and epitopes derived from oncogenic viruses using T cells engineered with off-the-shelf T cell receptors. We also discuss the challenges and strategies to achieving more effective T cell therapies, particularly in the context of solid tumors.
Insights
Targeting shared public neoantigens, like those from mutant KRAS, p53, or viruses, offers a promising avenue for effective cancer immunotherapy. Engineered T cells show potential for treating solid tumors with these common targets.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- T cell reactivity against tumor neoantigens is crucial for antitumor immunity.
- Most neoantigens are patient-specific (private), necessitating personalized therapies.
- Public neoantigens, arising from common mutations or viral proteins, are shared across patients.
Purpose of the Study:
- To review strategies for targeting public neoantigens using engineered T cells.
- To highlight the clinical utility of targeting mutant KRAS, mutant p53, and viral oncogenic proteins.
- To discuss challenges and solutions for enhancing T cell therapies in solid tumors.
Main Methods:
- Review of recent studies on targeting public neoantigens.
- Focus on T cells engineered with off-the-shelf T cell receptors (TCRs).
- Analysis of strategies for targeting specific oncogenic mutations and viral antigens.
Main Results:
- Public neoantigens are uniformly expressed and essential for cancer cell survival.
- Engineered T cells show promise for targeting shared tumor antigens.
- Off-the-shelf TCR therapies offer a potential alternative to personalized treatments.
Conclusions:
- Targeting public neoantigens represents a viable strategy for broad cancer immunotherapy.
- Engineered T cell therapies, particularly using off-the-shelf TCRs, hold significant clinical potential.
- Overcoming challenges in solid tumor treatment is key to advancing T cell therapies.
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