Cancer immunotherapy with immune checkpoint blockade has transformed the treatment of patients with advanced melanoma, but strategies to overcome resistance are limited. Using molecular and pharmacologic tools, we have confirmed TANK-binding kinase 1 (TBK1) as a novel target to overcome resistance to PD-1 blockade, further supporting the preclinical and clinical development of this novel combination strategy.

By performing an unbiased interrogation of tumor mesenchymal cells, our study shows that TGFβ-neutralization leads to a profound remodeling of CAF dynamics, greatly reducing the frequency and activity of myofibroblasts, while promoting the formation of a novel fibroblast population characterized by strong response to interferon and heightened immunomodulatory properties. These changes are sufficient to drive productive anti-tumor immunity, laying the foundation for future investigations aimed at defining strategies to reprogram CAF composition for cancer therapy.

The JAX® NSG™ immunocompromised is the perfect host for CD34+ humanization and tumor engraftment, permitting assessment of antibody-based therapy efficacy. The JAX® NSG™ immunocompromised is the perfect host for CD34+ humanization and tumor engraftment, permitting assessment of antibody-based therapy efficacy. 

PF-07062119 is a novel T cell-redirecting bispecific against tumors expressing Guanylate Cyclase 2C (GUCY2C), a target expressed in more than 90% of CRC, and in other gastrointestinal cancers. We demonstrate tumor-selective and potent in vitro and in vivo efficacy with PF-07062119 in human xenograft models with T cell adoptive transfer, as well as in an immunocompetent syngeneic model. PF-07062119 shows combination benefits with checkpoint inhibitors and with chemo- and anti-VEGF therapy.

Tregs are CD4+ T lymphocytes that are central to peripheral immune tolerance, actively inhibiting inflammation upon antigenic stimulation. Tregs thus play a conflicting dual role: as endogenous suppressors of inflammation in autoimmune diseases, while also inhibiting effector CTL from killing tumor cells. In this presentation, we will localize Tregs and CTL by multiplex immunofluorescence and demonstrate spatial mapping of these cells in inflammatory microenvironments by digital pathology using artificial intelligence.

Chronic inflammation via the inflammasome pathway plays a key role in carcinogenesis by accelerating tumor invasiveness, growth, and metastatic spread by promoting an immunosuppressive tumor microenvironment. Our work highlights the pathophysiological role of inflammasome mediator, IL-1b, in tumor immunomodulation and that IL-1b blockade might have important consequences on T cell function and checkpoint blockade in cancer.

The ability for cancer cells to phenotypically switch and survive under drug pressure, referred to as drug-induced resistance or tolerance, is an emerging, yet poorly understood, mechanism of anticancer therapy failure. We discovered a novel metabolic pathway induced by a standard chemotherapy combination, which leads to multi-drug resistance and eventually relapse in patients. To target this mechanism, we engineered small-molecule inhibitors of upstream glucose metabolism with anthracyclines using a ‘smart’ release mechanism that deploys the drugs in highly metabolic cells. This therapeutic improves responses in vitro and in vivo while protecting against systemic toxicity. The result of this novel therapeutic approach means more drug can be distributed into the body while reducing side effects of treatment.

CD137 is a validated target for cancer immunotherapy, but antibody approaches targeting CD137 thus far had limited success, likely due to systemic immune activation. I'll discuss how Bispecific tumor targeted modality has been emerging as an effective approach to exploit the beneficial effects of CD137 agonism in cancer immunotherapy.

The efficacy of the host immune response against cancer largely depends on the behavior of the tumor microenvironment (TME). Many TME components were shown to impact different aspects of cancer immunity, ranging from T cell priming, effector function, and exhaustion to memory. However, the highly heterogeneous TME is often a big hurdle for the clinical translation of TME targets. We are interested in the interplay between components of the TME and the key node that can truly perturb the TME balance.

The success rate of experimental therapy is difficult to predict, as its efficacy often depends upon the characteristics of the preclinical animal models. The presentation will cover different non-invasive imaging techniques to characterize animal models and the information used to guide combination therapies in animal models.

There is a great need for robust in vivo preclinical models for evaluation of drugs interfering with metastasis. We have developed several transplantable, syngeneic metastasis models and used these to assess: 1) interventions to prevent colonization and growth in distant organs; and 2) treatment-induced abscopal effects on distant metastases. In preliminary studies, an immune-targeting, intratumorally injected drug candidate reduced metastatic burden and improved survival in one such model.

There has been much progress towards the experimental development of robust, scalable, and reproducible 3D cellular models, including spheroids, organoids, biofabricated tissues and microphysiological on chip systems, as assay platforms for preclinical drug testing.  However, there is a need for systematic physiological and pharmacological validation and benchmarking of the different 3D cellular models to establish their true clinical predictability and use for decision making in the drug discovery and development pipeline.