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. Author manuscript; available in PMC: 2022 Mar 7.
Published in final edited form as: Cell. 2020 Apr 2;181(1):46–62. doi: 10.1016/j.cell.2020.03.001

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