AICs are a new generation of tumor antigen-targeting antibody-immune agonist (vs. cytotoxic drugs) conjugates that stimulate innate and adaptive immunity, providing dual therapeutic MOAs in eliminating cancers. While providing great promises, many early AICs were terminated in clinical development due to poorly manageable toxicities, immunogenicity, poor PK, and limited clinical efficacy. The presentation will comprehensively review ISACs' composition and function, lessons learned from failed AICs, and the challenges and opportunities in developing the next generation of clinically efficacious AICs.

The use of cytokine muteins to target and activate the immune system is a promising approach to treating cancer, but several challenges are affecting its applicability—as the discovery process can be time-consuming and restrictive due to the limitations of the natural cytokine. Bivalent agonist antibodies possess distinct developability features that present the opportunity to selectively address unmet needs that were not druggable with conventional muteins.

Small bicyclic peptides constrained by a central scaffold can have pharmacologic and pharmacodynamic properties that fit very well with the design goals and are therefore ideally positioned to deliver immune agonists in a way not practically feasible with traditional antibodies. We will demonstrate that Bicycle TICAs (tumor-targeted immune cell agonists) can potently activate anti-tumor immunity in cancer, in particular via the activating receptors CD137 and NKp46 in a tumor-targeted manner.

Adoptive cell transfer therapy is a new paradigm in cancer treatment. However, during the ex vivo expansion process, T cells undergo exhaustion—as a result they lose the ability to persist after adoptive transfer. In this talk, I will discuss small molecule modulators discovered in my lab which can facilitate T cell proliferation and generate T cells with stem cell-like properties. Upon transfer, they confer excellent tumor control.

Refractory malignant solid tumors create an immunosuppressive tumor microenvironment (TME), which renders them resistant to standard-of-care immune checkpoint inhibitors. We developed RNAi agents to silence STAT3 or PD-L1 targets in tumor-associated immune cells, which mediate immune suppression in the TME. Silencing these genes remodeled the TME and increased cytotoxic T-cell infiltration into the tumor. Human active STAT3 and PDL1 RNAi conjugates are currently in Phase 1 clinical trials for immunotherapy-refractory cancers.

Affini-T, a precision immunotherapy company, develops potentially curative therapies for solid tumors by targeting oncogenic driver mutations, beginning with KRAS. We are advancing two distinct therapeutic modalities, adoptive cellular therapies and bispecific T cell engagers, designed to harness T cell immunity with unprecedented precision and potency. Our TCR-T cell therapy-enabling platforms utilize state-of-the-art TCR discovery, synthetic biology, and gene editing to modify the tumor microenvironment and optimize T cell functions.

Spatial profiling technologies like hyper-plex immunostaining in tissue, spatial transcriptomics etc have the potential to enable a multi-factorial, multi-modal characterization of the tissue microenvironment. Scalable, quantitative methods to analyze and  interpret spatial patterns of protein staining and gene expression are required to understand cell-cell relationships in the context of local variations in tissue structure. Objective scoring methods inspired by recent advances in statistics and machine learning can serve to aid the interpretation of these datasets, as well as their integration with other, companion data like genomics. In this talk, we will discuss elements of spatial profiling from multiple studies as well as paradigms from statistics and machine learning in the context of these problems.

Belharra Therapeutics is the next wave in chemoproteomics focused on applying a novel chemistry enabled non-covalent probe library and quantitative mass spectrometry to identify chemical probes that selectively bind any pocket, on any protein, in live cells. The platform is identifying chemical probes that selectively engage diverse protein classes including transcription factors, adaptors, ion channels, and transporters. Most proteins identified as being selectively engaged by our probe library do not have a reported ligand in drug bank demonstrating the ability of the platform to identify novel pockets and potential chemical probe starting points for these targets.