Simulating the Selection of Resistant Cells with Bystander Killing and Antibody Coadministration in Heterogeneous HER2 Positive Tumors.

Intratumoral heterogeneity is a leading cause of treatment failure resulting in tumor recurrence. For the antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1), two major types of resistance include changes in HER2 expression and reduced payload sensitivity, often exacerbated by heterogenous HER2 expression and ADC distribution during treatment. ADCs with bystander payloads such as trastuzumab-monomethyl auristatin E (T-MMAE) can reach and kill adjacent cells with lower receptor expression that cannot be targeted directly with the ADC. Additionally, coadministration of T-DM1 with its unconjugated antibody, trastuzumab, can improve distribution and minimize heterogeneous delivery. However, the effectiveness of trastuzumab coadministration and ADC bystander killing in heterogenous tumors in reducing the selection of resistant cells is not well-understood. Here, we use an agent-based model to predict outcomes with these different regimens. The simulations demonstrate that both T-DM1 and T-MMAE benefit from trastuzumab coadministration for tumors with high average receptor expression (up to 70 and 40% decrease in average tumor volume, respectively), with greater benefit for non-bystander payloads. However, the benefit decreases as receptor expression is reduced, reversing at low concentrations (up to 360 and 430% increase in average tumor volume, respectively) for this mechanism that impacts both ADC distribution and efficacy. For tumors with intrinsic payload resistance, coadministration uniformly exhibits better efficacy than ADC monotherapy (50-70% and 19-36% decrease in average tumor volume for T-DM1 and T-MMAE, respectively). Finally, we demonstrate that several regimens select for resistant cells at clinical tolerable doses, highlighting the need to pursue other mechanisms of action for durable treatment responses. Significance Statement Experimental evidence demonstrates heterogeneity in the distribution of both ADCs and the target receptor in the tumor microenvironment, which can promote the selection of resistant cells and lead to recurrence. Here we quantify the impact of increasing the antibody dose and/or utilizing bystander payloads in heterogeneous tumors using an agent-based model and highlight the need for alternative cell killing mechanisms to avoid enriching resistant cell populations.