A major hurdle to CAR T cell efficacy in solid tumors is their suppression by both cancer cells and their environmental surroundings. In this talk, we will demonstrate how CAR T cell activity can be boosted by modulating both TME and tumor-derived or associated factors.

T cell therapies of solid tumors face challenges including limited homing, antigen escape, immunosuppression, and toxicity. Coengineering strategies can circumvent many of these obstacles. To that end, we developed a dual inverted lentiviral vector enabling constitutive expression of a TCR or CAR and activation-inducible gene-cargo. We have also built remote-control CARs and explored a variety of gene-cargo including IL-15, IL-2v, GLUT3, and a SiRPa decoy to safely augment tumor control.

CAR T therapies for solid cancers have proven susceptible to T cell exhaustion and antigen escape, leading to relative clinical failure. We have focused on commonly expressed antigen B7H3, and have developed CARs based on high-avidity binders capable of response to antigen-dim targets. To mitigate exhaustion caused by chronic signaling we have developed IMiD drug-sensitive degron sequences that control rapid and reversible receptor proteosomal degradation, which can reverse antigen-induced exhaustion.  

Multiple barriers unique to solid tumours contribute to the limited efficiency of CAR T cells. The immunosuppressive TME poses formidable barriers to CAR T cells. Tumour antigen heterogeneity presents another major challenge in CAR T cell therapy. Here, a study is discussed looking into the limitations in efficiency of CAR T cell therapy in an antigen-heterogeneous syngeneic tumor model, and whether this can be overcome by CAR T cell induction of bystander effects.

CAR T cells have proven their tremendous potential to cure hematologic malignancies. However, their highly individualized, expensive, and time-consuming manufacturing make broader applications difficult. Towards converting the strategy to an off-the-shelf approach, we generated receptor-targeted lentiviral and AAV vectors redirected to T cells for direct in vivo generation of CAR T cells.

A platform that can selectively transduce specific immune cells in vivo can enable a range of personalized cellular and biologics immunotherapy. Towards this goal, our group has employed various principles from molecular biology and pharmaceutics to engineer different viral vector systems that can selectively transduce B and T cells in vivo with exceptional fidelity and potency. We will present both published and unpublished data.

CAR T cells likely require enhancements to be clinically effective against solid tumors. We have identified multiple features for integration into T cells to increase tumor specificity and potency. However, combining multiple features may result in unpredictable interactions between components such as the receptor's single-chain variable fragments. Here we describe high-throughput screening to select optimized receptor combinations in highly engineered integrated circuit T cells for the treatment of kidney cancer.

Despite clinical success with cell therapies targeting hematological malignancies, achieving a safe and persistent efficacious dose in patients with solid tumors remains a challenge. Serotiny’s high-throughput platform is built to engineer next-generation multi-domain protein designs, including chimeric antigen receptors (CARs), that overcome these challenges. Serotiny has demonstrated the use of its high-throughput platform to build and deliver CARs that improve in vivo responses in preclinical studies.