Immune Synapse Engagement as a Novel Approach for Cancer Immunotherapy

Monoclonal antibodies (mAbs) targeting immune checkpoints have revolutionized cancer treatment but exhibit several challenges, most notably, limited intratumor efficacy and relatively low patient response rates. Endowing these mAbs with immune-cell-recruitment capabilities may offer the solution to these drawbacks. This assumption is based on our recent findings that the effectivity of a given checkpoint mAb relies not only on its binding to its target T-cells receptor but also on the direct interaction of the targeted T-cell with dendritic cells (DCs). Our results suggest that the low-frequency or dysfunctionality of such stimulating immune synapses following checkpoint mAb treatments hinder their anti-tumor efficacy. Therefore, the outcome of not taking this T-cell-DC licensing loop mechanism into account in mAb design is suboptimal checkpoint mAbs. To overcome these limitations, we propose here to develop a series of bi- and muti-specific immune synapse engager antibodies as a new approach to enforce immune interactions for cancer immunotherapy. We will apply in-vivo genetic tools and high-dimensional analysis of the immune response on the spatial, cellular, proteomic and transcriptomic levels to provide critical insights into immune synapses that mediate effective T-cell anti-tumor activity. We will then harness this knowledge to apply antibody-engineering approaches and treatment regimens to maximize anti-tumor activity. We will explore and target T-cell-DC synapses that enable antagonistic (Aim 1) and agonistic (Aim 2) checkpoint mAbs and additional types of immune cell interactions underlying favourable immune surveillance of tumors (Aim 3). This study will introduce a novel approach for cancer immunotherapy using drugs that engage physical crosstalk between key immune cells. Ideally, this study will yield reagents with potent anti-tumor efficacy and well-characterized in-vivo activities that can be readily translated for evaluation in human patients.