What are the top three challenges in T cell therapy today?
The lack of success in treating solid tumors, significant toxicities related to hyperactivation of T cells, and the high costs and consequences of those toxicities. Although the recent clinical data generated by the initial class of T cell therapies showed exciting results in hematological cancers, it’s hard to realize their full potential due to these current limitations.
What difficulties do these challenges pose?
The currently preferred T cell therapy platform to target solid tumors is T-cell receptor engineered T cells, or TCR-T. However, TCR-T therapies face several challenges: T-cell receptors (TCRs) have suboptimal affinity for their target antigens; enhancing their affinity for therapeutic purposes can introduce off-target toxicity; and engineered TCRs can mispair with endogenous TCRs, leading to cross-reactivity with unknown consequences.
The uncontrolled activation of T cells can lead to a cytokine release syndrome, or CRS. Current CAR-T therapies include a boxed warning citing fatal or life-threatening risks of CRS and neurotoxicity. We believe these severe toxicity risks will limit adoption in community outpatient settings as well as in earlier lines of treatment.
The toxicities are very costly side effects to manage. The risk of these occurrences results in complicated standard treatment protocols that can add significant indirect costs. Experimental strategies, such as restrictive enrollment screening criteria, are used to reduce the potential for CAR-T related toxicities. Such screening would decrease the number of patients eligible for these therapies, and could also increase the overall burden and cost of treatment.
How could research solve these challenges?
To treat solid tumors, we are searching for molecules from inside cells to attack. Most cancer-specific antigens are within cancer cells and peptides derived from them are presented on the cell surface by the major histocompatibility complex, or MHC. T cells are the most efficient soldiers in the human immune system, and they are triggered by TCRs that bind to peptide/MHC targets. Eureka is developing TCR-mimic antibodies that recognize these peptide/MHC complexes on solid tumor cells. TCR-mimic antibodies inherently display better binding affinity and specificity than TCRs. Once we identify an antibody that selectively binds to the target, we arm it on a T cell that we can then develop into our drug candidate.
The hyperactivity of T cells is mostly the result of putting an antibody and costimulatory signal in one construct. This couples cytokine hyperstimulation with the drug’s efficacy. Instead, scientists are working on ways to decouple these functions. Separating them by using more natural pathways could take advantage of the natural checks and balances acquired over millions of years of evolution. This could tamper the hyperactivation, create lower levels of cytokines, and reduce the risk of CRS and neurotoxicity. So, these advances would address the other two challenges: toxicity and the resulting costs.
To learn more about what scientists are doing to improve CAR-T Cell therapies, visit our article.