In this presentation, we will describe the design and mechansims of action of CodaLytic, a codon-modified influenza-based virotherapeutic. With a focus on immunotherapy-resistant preclinical models of breast cancer including orthotopic murine models and primary human tumoroids, we will highlight the combination benefit of CodaLytic with immune checkpoint inhibition. Together, this data provides reasons to believe for clinical translation of CodaLytic as a component of breast cancer immunotherapeutic regimens.

Eureka is developing ARTEMIS T cell therapy, a next-generation T cell immunotherapy for the treatment of solid tumors. Leveraging Eureka’s proprietary ARTEMIS cell receptor platform and E-ALPHA antibody discovery platform, our ARTEMIS T cells have demonstrated better safety profile, improved T cell infiltration, and persistence in proof-of-concept and preclinical studies. The company currently has two ongoing clinical programs: ECT204, targeting Glypican-3 (GPC3), and ET140203, targeting Alpha-Fetoprotein (AFP) for the treatment of liver cancers.

The tumor microenvironment (TME) is enriched in immunosuppressive cells, such as myeloid-derived suppressor cells and T regulatory cells, which mediate resistance to currently available immunotherapies. Novel approaches to deplete or reprogram these cells, with the goal to restore anti-tumor immune responses, will be discussed. Particular focus will be given to in vivo and ex vivo models to allow preclinical validation and ensure clinical translatability.

• Commonalities and differences between cancer vaccine modalities, ranging from personalized neoantigen vaccines using mRNA to cell-based vaccines to in situ vaccination using pathogens
• Scientific and clinical development lessons from prior waves of cancer vaccine clinical trials that enable the resurgence of the approach
• Future directions for modulation of antigen specificity and quality of T cell responses to cancer-specific antigens
  

• Discuss pros and cons of available models, including syngeneic and humanized
• Translation of results from mouse models to the clinic
• Discuss the future of modeling immunotherapy in mice

Gamma delta T cells are distinctively different from aßT cells in their TCR gene usage, which allows them to be used in an allogeneic treatment setting. We developed melanoma patient-derived organoids to test gamma delta T cell function. Inter-individual heterogeneity in gamma delta T cells may contribute to the observed varied clinical response in the patients. Gamma delta T cell levels in PBMC predict their expansion capacity. Our Vd2 Index Score may be used for donor selection. Costimulation of TCR gamma delta and TLR7/8 is an effective approach for gamma delta T cell expansion through enhancing the PI3K-Akt-mTOR signaling pathway and regulating inhibitory APC function. 

Talk will discuss a novel approach to developing a highly functional allogeneic cell chassis which accommodates dual targeting CAR T cells with optimal co-stimulation and metabolic fitness to enhance anti-tumor activity and equally prevents antigen escape in solid tumors.

T cell engagers (TCEs) represent a promising off-the-shelf treatment option for multiple tumor types; however, a large gap exists in our understanding of factors governing response or resistance to TCEs. Using preclinical immunocompetent mouse tumor models, we have elucidated immunotherapy combinations that can synergize with TCEs to enhance response in poorly T cell-infiltrated, checkpoint-refractory tumor types.

This presentation will provide an overview of the advantages and limitations of currently available humanized mouse models. We will describe current advancements in humanized models that enhance the development of innate immunity. We will discuss factors to be considered for the design of experiments with humanized mice to study tumor-immune cell interactions and to test therapeutics.

The pathogenic mechanisms of immune-related Adverse Events (irAEs) occurring in checkpoint inhibitor (CPI)-treated cancer patients are poorly understood. Clinical evidence suggests the hypothesis that many irAEs, including cutaneous irAEs, are caused by CPI-dependent activation of self-reactive T cells specific for tissue antigens. We developed a new engineered mouse model to test this hypothesis and understand how CPIs cause cutaneous immunopathology with features of lichenoid irAEs.

In order to overcome the intrinsic limitations of  2D in vitro and in vivo preclinical experimental models, currently available for Cancer Immunotherapy (CIT) drug development, we establish two distinct, fully human, imaging approaches for the dynamic visualization and characterization of interactions between cancer cells, immune cells, and stromal cells, and for the mid-throughput 3D in vitro screening of immune cell trafficking and infiltration to tumors in response to CIT-drugs.

Immune checkpoint inhibitors are a promising approach but suffer from variable response rates across patients and types of cancer, and current preclinical models are often not predictive of human responses. We report a microfluidic model that recapitulates the dynamic tumor microenvironment for the evaluation of immune checkpoint inhibitor efficacy. A novel 3D-printed platform provides customizable and multiplexed device configurations that simplify operation and permit ease of integration into pharmaceutical workflows.

Testing next-generation immune therapies requires more sophisticated ex vivo models. We developed a 3-dimensional microphysiological TME model using microfluidic technology, comprising cell line tumor spheroids and vascular models embedded in ECM-like hydrogels, to perform preclinical studies on cell therapies.

CAR T cell is a new immunotherapy for B cell acute lymphoblastic leukemia (B-ALL), yet, patient responses to this new therapy are variable which largely limits its clinical benefit. We herein developed a microfluidics-based human Cancer-on-a-Chip technology for in vitro modeling and screening of CAR T cell therapy. Such a microengineered human leukemia bone marrow in vitro model allows for a real-time monitoring of CAR T cell functionality such as T cell infiltration, activation, cytokine production, and B-ALL killing in a biomimetic B-ALL microenvironment, which may contribute significantly to the development of novel personalized CAR T cell therapies.