Table 1.

Challenges and Opportunities for Immune Cell Therapies of Cancer

Targeting Receptor	Opportunities	Challenges
TCR targeting overexpressed cancer associated self-antigens	• Can target a wide range of intracellular or cell surface molecules overexpressed in cancer • Antigens are prevalent in a wide range of cancer histologies • Early evidence for a therapeutic window enabling safe targeting (e.g. NY-ESO-1/LAGE TCR, WT1 TCR)	•MHC restriction limits clinical applicability of any specific TCR • Requirement for affinity maturation is labor intensive and increases risk of off-target toxicity • Risk of toxicity due to low level antigen expression on normal tissues • Most antigens in this class do not contribute to oncogenic fitness, increasing the risk of selection of antigen neg variants
TCR targeting individualized neoantigens	•TCRs do not require affinity maturation • Likely to be safe since the antigen is not expressed in normal tissue	• Labor and cost intensive process to generate unique products for individual patients limits availability • Most neoantigens are passenger mutations, increasing the risk of selection of antigen neg variants
TCR targeting public neoantigens in “hot spot” regions of oncogenes	• TCRs do not require affinity maturation • Mutations likely contribute to oncogenic fitness diminishing the risk of antigen neg variants • Modern oncology sequencing platforms can identify subsets of patients with targetable mutations	• MHC restriction limits clinical applicability of any specific TCR • Limited immunogenicity of most tumor-specific mutations renders it likely that TCRs availability will be restricted to unique MHC alleles
CAR targeting overexpressed cell surface molecules	• Lack of MHC restriction enables applicability to all patients regardless of MHC allele expression • MHC downregulation does not confer resistance • Requirement for high antigen density for optimal CAR activation provides the potential for a therapeutic window even when targeting molecules expressed on normal tissues • scFvs and other binders can be generated to specifically recognize a vast array of molecules, including post-translational modifications	• Risk of toxicity due to low level expression on normal tissues • Heterogeneous antigen expression increases the risk of antigen neg escape • Requirement for high antigen density for optimal CAR activation increases the risk of antigen neg and antigen lo escape