The identification of new targets and preclinical evaluation of existing and new targets is critically important for the prioritization of which agents should move forward for testing in clinical trials. This process has not been optimal for the identification of effective immune-oncology therapies. New approaches to target identification and preclinical testing using animal models and new ex vivo immune-oncology models will be discussed.

Chimeric antigen receptor T (CAR T) cells, an emerging class of cellular therapeutics, have produced impressive clinical results in some hematologic cancers. Rigorous research is underway to develop next generation CAR T cells for treating hematologic and solid tumors. This presentation is a summary of how mouse tumor models have been used to develop next generation CAR T cells in recent years. Advantages and limitations of different types of models will be discussed.

The field of immuno-oncology (IO) is continuously evolving due to breakthroughs in the development of translational in vivo models. Humanized immune system (HIS) mice offer better evaluation of preclinical cancer therapeutics due to their abilities to enable more translational cancer research by supporting improved engraftment of patient derived tumor xenografts. This presentation will discuss the application of HIS models for IO and the investigation of myeloid, NK, and T cell-based therapies. 

Genetically engineered mouse models (GEMMs) hold great potential to recapitulate more accurately disease models but their cost and complexity have stymied their widespread adoption in discovery, early or late drug screening programs. Recent advancements in genome editing technology made possible by the discovery and development of the CRISPR/Cas9 system has opened the opportunity of generating disease-relevant animal models by direct mutation of somatic cell genomes in an organ or tissue compartment of interest.

We describe the use of anti-CD8 nanobodies conveniently labeled with fluorine-18 for the serial non-invasive imaging of CD8+ T cells in subjects undergoing cancer immunotherapy. This approach offers excellent same-day image quality and a radiation burden low enough to enable multiple imaging sessions in the same patient.  This fluorine-18 approach also overcomes some of the operational difficulties encountered in promptly analyzing radioactive tissue biomarker samples by FACS, for example.

This presentation will discuss how our preclinical data have been instrumental in testing a very potent off-the-shelf combination treatment for redirecting T cells against tumors.

VISTA is a co-inhibitory B7 family member that has been linked to immune suppression and resistance to cancer immunotherapy. Recently, we discovered that VISTA selectively engages its ligand in acidic microenvironments such as are often found in solid tumors. To exploit this unique mechanism of action, we engineered antibodies which themselves selectively bind VISTA at acidic pH. Here we present the pre-clinical models and tools used to assess pH-selective therapeutics.

Rapid advances in cancer immunotherapy have created a need for translational strategies to study interactions between human immune systems and tumors and to validate therapeutics. Immunocompromised mice engrafted with human immune systems and tumors have proven useful as a translation tools for the scientific investigation of therapies targeting immune responses to cancer. While studies with humanized mouse have limitations, recent advancements show promise for immuno-oncology studies.

Natural Killer (NK) cell immunotherapy has garnered a lot of interest in recent years. Our group has developed novel tri-specific killer engager molecules, TriKEs, that target NK cells to a variety of tumors while also providing a localized cytokine signal. To test these molecules in preclinical settings human NK cells and human tumor we have employed a variety of xenogeneic mouse models, which provide insight into how these therapeutics will work in patients before entering the clinic. In these models we track tumor progression using bioluminescent imaging as well and the fate of the NK cells mediating tumor control.

Predicting patient response to novel cancer immunotherapies remains a major challenge. We developed an ex vivo fresh culture of human tumors from surgical specimens. Differentially expressed genes under PD-1 blockade in the ex vivo cultures are compared to gene expression profiles of tumors where biopsies were taken before and after clinical treatment both before and after PD-1 therapy. Our ex vivo cultures can recapitulate the effect of PD-1 blockade on the immune system within the tumor microenvironment seen in real patients 3-4 weeks into therapy.