Stimuli-responsive Nanomaterials for Imaging Immunotherapy Response

Immunotherapy such as immune checkpoint inhibitor antibodies have revolutionized the treatments for hard-to-treat cancers, with durable responses observed in clinics. However, the overall response is observed only in a small subset of patients. Also, immunotherapy induces delayed on-set of responses and novel patterns of the anti-tumor response which makes it challenging to identify patient responders and non-responders early on, often leading to undertreatment or overtreatment. To address these challenges, we engineered a ‘stimuli-responsive nanomaterial’ (SRN) that can not only deliver an immune checkpoint inhibitor to the tumor but also report back on its efficacy in real time. We rationalized that this could be achieved by a novel two-staged stimuli-responsive polymeric nanomaterial with well-defined ratio of an immunotherapy drug and a drug-function activatable imaging agent. To accomplish this, we engineered a stimuli-responsive nanomaterial which comprises of three building blocks: an immunotherapy drug (anti-PDL1 antibody), an enzyme activatable imaging agent and a polymeric backbone that holds both elements together. In preliminary studies, we observed that anti-PD-L1 antibody conjugated SRNs inhibited PD1-PDL1 interactions efficiently and induced T-cell mediated cancer cell apoptosis that can be imaged using activatable imaging probe. SRNs not only enabled real-time immunotherapy response imaging in tumor bearing mice but also distinguished between highly responsive and partially responsive tumors. Furthermore, increasing doses resulted in better response and enhanced sensitivity in partially responsive tumors. This study shows that the treatment with SRNs induced a potent anti-tumor immune response that can be directly imaged and is more effective in imaging response than current agents.