Hurdles for activation of tumor-specific immunity in vivo and approaches to address thema
| Hurdle . | Approaches . | Recent results . |
|---|---|---|
| Quality of therapy-induced T cells | -Optimize priming signals by including costimulation and cytokines | Optimal pathway to trigger and molecule use TBD |
| -Evaluate NeoAg targets and “dark” antigens | Single cell analysis and TCR-based tracking is allowing identification of antigen-specific T cells; broader antigen classes being tested | |
| T cell polyfunctionality and exhaustion | -Evaluate truncal NeoAgs and more recently expressed “branch” antigen targets | Single cell analysis and TCR-based tracking is allowing identification and functional profiling of antigen-specific T cells |
| -Optimize priming and/or boosting signals by including costimulation and cytokines | Optimal pathway and molecule use TBD, IL-12 continues to be evaluated | |
| Vaccine trafficking to tumor and tumor tissue penetration | -Inject the tumor or tumor bed with an activating signal (chemokine, oncolytic virus, and/or stimulatory tumor killing agent) to optimize tumor targeting | Oncolytic viruses continue to be developed, cocktails of costimulation with checkpoint blockade have shown distant tumor regressions |
| Heterogeneity of antigen expression | -Include multiple antigens in the T cell activating drugs | Multiple antigens increasingly included in vaccines and NeoAg therapeutics (up to >200) |
| -Promote epitope spreading | More commonly evaluated in trials | |
| Antigen loss or MHC loss | -Include multiple antigens presented by multiple human lymphocyte antigen molecules | Multiple antigens increasingly included in vaccines |
| -Promote epitope spreading | More commonly evaluated in trials | |
| -Provide intratumoral IFN-γ signal to up-regulate MHC class I | Optimal pathway and molecule use TBD |
| Hurdle . | Approaches . | Recent results . |
|---|---|---|
| Quality of therapy-induced T cells | -Optimize priming signals by including costimulation and cytokines | Optimal pathway to trigger and molecule use TBD |
| -Evaluate NeoAg targets and “dark” antigens | Single cell analysis and TCR-based tracking is allowing identification of antigen-specific T cells; broader antigen classes being tested | |
| T cell polyfunctionality and exhaustion | -Evaluate truncal NeoAgs and more recently expressed “branch” antigen targets | Single cell analysis and TCR-based tracking is allowing identification and functional profiling of antigen-specific T cells |
| -Optimize priming and/or boosting signals by including costimulation and cytokines | Optimal pathway and molecule use TBD, IL-12 continues to be evaluated | |
| Vaccine trafficking to tumor and tumor tissue penetration | -Inject the tumor or tumor bed with an activating signal (chemokine, oncolytic virus, and/or stimulatory tumor killing agent) to optimize tumor targeting | Oncolytic viruses continue to be developed, cocktails of costimulation with checkpoint blockade have shown distant tumor regressions |
| Heterogeneity of antigen expression | -Include multiple antigens in the T cell activating drugs | Multiple antigens increasingly included in vaccines and NeoAg therapeutics (up to >200) |
| -Promote epitope spreading | More commonly evaluated in trials | |
| Antigen loss or MHC loss | -Include multiple antigens presented by multiple human lymphocyte antigen molecules | Multiple antigens increasingly included in vaccines |
| -Promote epitope spreading | More commonly evaluated in trials | |
| -Provide intratumoral IFN-γ signal to up-regulate MHC class I | Optimal pathway and molecule use TBD |
TBD, to be determined.
Updated from Adamik and Butterfield (2022).