417 Design of programmable immune reactive cells (PIRCs) with precision type I interferon and cytotoxicity response in solid tumors

<h3>Background</h3> Modulating the host immune response is pivotal for achieving successful anti-tumor effects within the tumor microenvironment (TME). Key features, such as immune cell recruitment and activation, cytotoxicity, antigen presentation, and release of type I interferons (IFNs) are all seen as important attributes for mounting a strong and local anti-tumoral response in the TME. Despite recent therapeutic advances, the challenge remains - How can we create cancer immunotherapies that fulfill the requirements of systemic administration while ensuring a precise local response in the TME with minimal systemic immune effects? Plasmacytoid dendritic cells (pDCs) are a rare lymphoid immune cell that rapidly migrate to sites of inflammation, orchestrating a host immune response against foreign threats. PDCs are renowned for their antiviral functions of eliciting IFNs and inflammatory cytokines. In cancer settings, tumor associated pDCs have been correlated with better outcome, though in some settings they are also found to be immunosuppressed and lack the capacity to mount an IFN response. In theory, pDCs offer potential in the immunotherapeutic field but face major hurdles by being scarce, fragile, and technically impossible to engineer. <h3>Methods</h3> Here, we describe Programmable Immune Reactive Cells (PIRCs) – a first-in-class adoptive cell therapy leveraging pDC-like properties with immune-programmable specificity. Generated from hematopoietic stem and progenitor cells (HSPCs) and combined with the SyNthetic Intramembrane Proteolysis Receptor (SNIPR) system, PIRCs are genetically engineered to prompt an antigen-dependent induction of an immune response, through the stimulation of a STING gain-of-function gene (STING_V155M). <h3>Results</h3> Preclinically, billions of PIRCs are produced from as little as 100.000 HSPCs under serum-free GMP-compliant conditions. These cells exhibit precision activation towards tumor antigens of choice, triggering a rapid and broad immune response, including type I IFN (mainly IFNα) and chemokines, including numerous CXCR3 ligands. Importantly, PIRCs demonstrate direct killing of cancer cells in both 2D and 3D organoid tumor models, recruitment of immune cells, and elevated NK cell cytotoxic functions. In NSG mice engrafted with solid human tumors, intravenously infused PIRCs infiltrate tumors within 1–2 hours and remain present for days and can induce a local inflammatory signature. <h3>Conclusions</h3> Collectively, PIRC therapy will change the paradigm of current solid tumor therapy by overcoming the immunosuppressive TME. Combining direct killing and immune modulating effects, PIRCs represent a unique precision-programmed effector cell therapy engaging both innate and adaptive immunity. We are currently moving toward a Phase I study to evaluate the safety and efficacy of autologous PIRCs.