Cytokines emerged as promising molecules for therapeutic intervention in order to modulate the immune response. However, their often pleiotropic nature combined with their high potency when administered systemically restricts their therapeutic applicability. We have generated cytokine mimetics with tailor-made mode-of-actions based on multifunctional antibody derivatives.

IL-21 is a clinically validated cytokine that showed monotherapy activity in melanoma and renal cell carcinoma. Further clinical development of IL-21 was discontinued, likely due to limitations such as short half-life and poor bioavailability. The pleiotropic effects of IL-21 may have also limited its effectiveness. To maximize the therapeutic potential of IL-21, we have developed AB821, a cis-targeted IL-21 that selectively activates CD8+ T cells and exhibits improved bioavailability. Preclinically, AB821 demonstrates superior anti-tumor activity over WT IL-21. AB821 promotes cytotoxicity and memory CD8+ T cells in the context of antigen activation and synergizes with PD1 blockade in PD1-resistant tumors.

XMT-2056 is a systemically-administered novel Immunosynthen STING agonist ADC that targets a novel HER2 epitope and activates STING pathway in both tumor cells and tumor-resident immune cells, stimulating anti-tumor immune responses in preclinical studies. XMT-2056 exhibited potent anti-tumor activity in multiple tumor models as single-agent and in combination with anti-PD1 and other HER2-targeted therapies. This presentation will focus on the MOA of the anti-tumor activity elicited by XMT-2056.

Targeted protein degradation and molecular glues show great potential for treating diseases with “undruggable” pathogenic protein targets. Here we use data from the CAS Content Collection and provide a landscape view of this research field: Advantages of molecular glues and their advances in drug discovery practices; a thorough review of drug candidates in targeted protein degradation through E3 ligase recruitment; progression of molecular glues in drug discovery pipelines and their targeted diseases. We hope our work provides a comprehensive reference to support the future development of molecular glues in medicine.

• What recent developments in targeting TME have influenced the field the most?
• What could tumor associated macrophage targeting therapies achieve in the next 5-7 years?
• What are some of the challenges and unmet needs in biomarker development for myeloid therapies?​

•  AI has established its role in diagnostics, and therapy response, what are the opportunities in drug delivery developments?
• Reliability of AI in predicting? How can we prevent a Junk in- junk out the outcome
• Are our current understanding of machine learning advanced enough? How much we are in charge?
• What the ethics in using technology? Are we in control?​

To develop a novel anti-tumor adjuvant, a STING-activating CDN-prodrug conjugated to a PEGylated lipid was incorporated into lipid nanodiscs (LNDs). When administered intravenously, LND-CDNs outperformed the parent drug and liposomes-- and induced rejection of established tumors with the formation of immune memory against rechallenge. A range of experimental data demonstrating the unique ability of LND-CDNs to penetrate throughout the tumor bed and promote productive DC activation will be highlighted.

This talk will center around an understudy checkpoint blockade CD200R and a newly discovered and developed activation receptor called the CD200AR-L which OX2 currently is using to treat recurrent glioblastoma patients along with a planned trial for pediatric DIPG.

Numerous IO modalities are developed but their benefit only reaches to >20% of eligible patients. A major source of the lack of efficacy is the tumor microenvironment (TME), which enables resistance to natural antitumor activities and therapies. Normalizing TME by reprogramming pro-tumor immune cells (Regulatory T cells) and enhancing the delivery of reactivated anti-tumor cells are among the modalities that can alleviate resistance and synergize with the standard of care.

Tumors are heavily infiltrated with tumor-associated macrophages, facilitating tumor progression and directly and indirectly mounting an immune suppressive effect. I will present a nanotechnology-based approach called supramolecular nanotherapeutics, which can focally modulate the tumor immune contexture towards the immune responsive mode with minimal systemic side effects. Supramolecular nanotherapeutics exert a sustained tumor regression in syngeneic murine breast cancer and melanoma models by efficiently converting immunosuppressive tumor macrophages to effector macrophages.

A common basis for cancer immunotherapy treatment failure appears to be the suppressive tumor microenvironment (TME). We are investigating the B cell repertoire of immunotherapy responders to identify antibodies that can relieve immunosuppression in the TME. I will present data on OR2805, a clinical stage anti-CD163 antibody, derived from an Elite Responder to checkpoint inhibitor therapy, that relieves immunosuppression caused by macrophages. I will also present discovery and preclinical characterization of OR502, an anti-LILRB2/ILT4 antibody that rescues T cells from macrophage-mediated suppression and induces anti-tumor responses.

Lack of selectivity has posed a significant challenge to expanding the range of immunotherapy options for patients. Sensei Biotherapeutics is developing conditionally active antibodies that function selectively in the low-pH of the tumor microenvironment to promote anti-tumor activity without on-target off-tumor effects. SNS-101, Sensei’s VISTA-blocking antibody, has demonstrated its potential to deliver powerful anti-tumor activity without the negative effects that have thwarted past efforts against this target.

Developing effective antibody drug conjugates (ADCs) for solid tumors remains challenging, particularly for potent payloads like pyrrolobenzodiazepines (PBD), due to toxicity prior to reaching the efficacious dose (i.e. narrow therapeutic index). In this presentation, we highlight bioconjugation for precise (site-specific), flexible (site-selective), and scalable production of PBD-based ADCs using unnatural amino acid incorporation into the antibody backbone. The best performing BrickADCs were selected for optimal biophysical properties and successfully shielded the toxicity of highly potent, hydrophobic payloads while maintaining their superior activity. Finally, up to 3-fold enhanced efficacy was attributed to an optimal conjugation site.

TANK-binding kinase 1 (TBK1) is a versatile innate immune protein kinase nominated as a candidate immune evasion gene in a number of pooled genetic screens. Using genetic and pharmacologic tools across multiple experimental model systems, we have confirmed a role for TANK-binding kinase 1 (TBK1) as an immune evasion gene. Taken together, our results demonstrate that targeting TBK1 is a novel and effective strategy to overcome resistance to cancer immunotherapy.