  As an adoptive cellular therapy, Chimeric Antigen Receptor T-cell (CAR
T-cell) therapy has shown remarkable success in hematological malignancies, but
only limited efficacy against solid tumors. Compared with blood cancers, solid
tumors present a unique set of challenges that ultimately neutralize the
function of CAR T-cells. One such barrier is antigen heterogeneity -
variability in the expression of the antigen on tumor cells. Success of CAR
T-cell therapy in solid tumors is unlikely unless almost all the tumor cells
express the specific antigen that CAR T-cells target. A critical question for
solving the heterogeneity problem is whether CAR T therapy induces bystander
effects, such as antigen spreading. Antigen spreading occurs when CAR T-cells
activate other endogenous antitumor CD8 T cells against antigens that were not
originally targeted. In this work, we develop a mathematical model of CAR
T-cell therapy for solid tumors that takes into consideration both antigen
heterogeneity and bystander effects. Our model is based on in vivo treatment
data that includes a mixture of target antigen-positive and target
antigen-negative tumor cells. We use our model to simulate large cohorts of
virtual patients to gain a better understanding of the relationship between
bystander killing. We also investigate several strategies for enhancing the
bystander effect and thus increasing the overall efficacy of CAR T-cell therapy
for solid tumor.
