Transcera builds upon fundamental discoveries in sphingolipid biology to enable a new modality for extracellular protein degradation. By harnessing native ceramide trafficking pathways, Transcera develops novel degraders that work across multiple tissue types, have extended half-life for durable target depletion, and are simple to manufacture. With a rapidly advancing pipeline focused on immune disorders, we aim to transform the treatment landscape for chronic diseases driven by extracellular proteins.

Refractory malignant tumors create an immunosuppressive tumor microenvironment (TME), which renders them resistant to standard-of-care immune checkpoint inhibitors. We developed RNAi agents to silence PD-L1 in tumor-associated immune cells, which mediate immune suppression in the TME. Silencing PD-L1 in antigen presenting cells remodeled the TME, increased cytotoxic T cell infiltration, and mediated single agent activity in immunotherapy-resistant pre-clinical tumors. Human active PDL1 RNAi is currently in Phase 1 clinical trials for immunotherapy-refractory cancers (NCT06504368).

We are developing a cell engineering platform directed at pathogenic fibroblasts to locally modulate immune responses and disrupt fibrotic signaling in chronic diseases. Engineered fibroblasts are programmed to deliver immunomodulatory decoy receptors to reprogram diseased tissue environments as a means to  treat conditions like endometriosis and pulmonary fibrosis. We are pioneering a new class of cell therapies that reshape the fibrotic niche, including its immune landscape, toward a healthy state. We plan to develop an in vivo delivery method to expand clinical impact.

Immune modulation therapies offer promising treatment options for various diseases but have significant safety risks that must be carefully managed. Increased susceptibility to infections, development of secondary autoimmune diseases, malignancy risk, and organ toxicity are among the primary concerns. Healthcare providers must remain vigilant in monitoring patients, providing prophylactic measures, and adjusting treatments to mitigate these risks. The presentation will address the safety risks associated with immune modulation therapies and innovative strategies to optimize their benefits while minimizing potential harm to patients.

Spatial profiling technologies, coupled with scRNAseq, enable a multi-factorial, multi-modal characterization of the tissue microenvironment. Objective scoring methods inspired by recent advances in statistics and ML can aid the interpretation of these datasets, as well as their integration with companion data like bulk and single-cell genomics. I will discuss analysis paradigms from ML that can be used to integrate and prioritize gene regulatory programs (and therapeutic candidates) underlying oncogenesis.

The STING (Stimulator of Interferon Genes) pathway functions as a tumor suppressor by translating DNA damage signals into innate immune activation and ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) is the predominant ectoenzyme that hydrolyzes extracellular cGAMP, a potent STING agonist, thereby dampening STING-dependent innate immune responses. ENPP1 also contributes to production of adenosine, a key immunosuppressive metabolite within the tumor microenvironment (TME) that promotes tumor progression. We hypothesized that small-molecule ENPP1 inhibition would simultaneously preserve cGAMP–STING signaling and limit adenosine generation, restoring innate immunity and countering tumor growth and metastasis.

Abstract: CD59 is a key immune regulator exploited by both pathogens and cancer cells to evade immune clearance. We developed the first macrocyclic peptide inhibitors of CD59, enabling potent, selective modulation of its activity in cells. These compounds enhance antibody-dependent cytotoxicity and block bacterial toxin-mediated lysis, offering a novel therapeutic approach to overcome resistance in cancer and infection. This work opens new avenues for targeting immune evasion with drug-like, non-antibody modalities.

The therapeutic potential of cytokines is often hindered by significant challenges, namely their extremely short half-lives and systemic toxicity. This volatility necessitates a multi-pronged approach to harness their full power with sophisticated protein engineering to improve stability and target specificity, the use of novel modalities to create controlled delivery systems, innovative routes of administration to minimize systemic exposure while maximizing local effect. Furthermore, strategic combinations with other therapeutic agents will be crucial to mitigate toxicity and achieve synergistic anti-tumor effects, ultimately moving these potent molecules from a promising concept to a safe and effective treatment reality.