Patients with late-stage non-small cell lung cancer (NSCLC) and high levels of PD-L1 expression are eligible for treatment with immunotherapy; however, there is debate about which of these patients require chemotherapy in addition. Using a cohort of 334 immunotherapy treated, stage IV NSCLC patients, we have defined a novel blood-based biomarker indicative of response to immunotherapy and of predictive value as a complementary diagnostic for late-stage lung cancer treatment decisions.

There are many recent publications highlighting TGFb pathway activity in the context of chemo and immune therapy resistance. TGFb is a pleiotropic signaling molecule that impacts many cells within the tumor microenvironment. Several groups are moving forward with TGFb antagonists in clinical trials, but substantial clinical impact has remained elusive. I will discuss Novartis’ work on this target in preclinical models and in clinical trials: 1) What is the MoA of TGFb blockade? 2) How to assess activity of TGFb blockade in clinical trials? 3) What are potential combination partners for TGFb blockade? 4) How well do mouse models recapitulate potential clinical activity?

IGM-2323 is an engineered, high-affinity, high-avidity, bispecific, anti-CD20 IgM antibody TCE that is currently being studied as a monotherapy in a Phase II clinical trial for relapsed/refractory non-Hodgkin's lymphoma. IGM-2323 offers a novel treatment strategy for NHL: the recruitment of T cells to kill CD20-expressing tumor cells through T cell-dependent cellular cytotoxicity and complement-dependent cytotoxicity. We characterized the concentration versus response relationship of IGM-2323 and compared with bispecific IgG TCEs and built a mechanistic binding model based on preclinical data to aid in the prediction of an optimal dose of IGM-2323 in the clinic.

Immune checkpoint inhibitors show promise for increasing survival for many cancers, but response varies widely between patients and tumor types, highlighting an urgent need for more predictive preclinical models.  We present a high throughput perfused tumor microenvironment system capable of testing immunotherapy efficacy with biopsied human tumor fragments or spheroids. Integration of perfusion and circulating immune cells provide a platform suitable for applications across cancer drug discovery and precision medicine.

Our studies in NSCLC have included investigation of human cancer for unique factors that promote or inhibit TLS formation paired with a physiologically relevant, carcinogen (NNK) induced murine model of lung cancer that forms TLS. Specifically, we utilized multispectral imaging (Vectra Polaris) paired with spatial transcriptomics (Nanostring Digital Spatial Profiler) to interrogate TLS in NSCLC patients. We measured if key factors for TLS induction (CXCL13, IL21, CD40, and LTBR) were increased in tumor tissue compared to normal (nonsmoker and smoker) and COPD lungs.

Kickstarting therapeutic development by connecting innovation and outsourcing expertise reverberates far beyond lead selection, affecting the entire development pipeline, up to and including regulatory approval. We will look at the role cell microarray screening can play in an integrated antibody candidate selection process. Cell microarray screening of monomeric and heterodimeric plasma membrane proteins together with tethered secreted proteins expressed in human cells enables rapid discovery of primary receptors as well as potential off-targets for a variety of biotherapeutics including antibodies and related molecules. Case studies will demonstrate the power of the technology for identifying novel, druggable targets as well as for IND-enabling specificity screening and safety assessment.

Chimeric antigen receptor (CAR) T cell-based immunotherapy for cancer and immunological diseases has made great strides, but it still faces multiple hurdles. Finding the right molecular targets to engineer T cells toward a desired function has broad implications for the armamentarium of T cell-centered therapies. Here, we developed a dead-guide RNA (dgRNA)-based CRISPR activation screen in primary CD8+ T cells and identified gain-of-function (GOF) targets for CAR T engineering. Targeted knock-in or overexpression of a lead target, PRODH2, enhanced CAR T-based killing and in vivo efficacy in multiple cancer models. Transcriptomics and metabolomics in CAR T cells revealed that augmenting PRODH2 expression reshaped broad and distinct gene expression and metabolic programs. Mitochondrial, metabolic, and immunological analyses showed that PRODH2 engineering enhances the metabolic and immune functions of CAR T cells against cancer. Together, these findings provide a system for identification of GOF immune boosters and demonstrate PRODH2 as a target to enhance CAR T efficacy.

New immunotherapeutics brought remarkable benefits for cancer patients over the last decade. Due to the poor translation of in vitro results to human therapy, in vivo human knock-in mouse models have shown significant utility for future developments in the field of immunotherapy. In vivo human knock-in mouse models allow studying tumor efficacy, analyzing immunological responses, testing drug combinations, and assessing PK/PD of novel therapeutics.

Computational tools are increasingly used to aid in the design of biotherapeutics. This presentation will discuss three case studies where Model-informed Drug Discovery and Development was used to: 

• Predict systemic cytokine exposure in human after IV administration of an oncolytic myxoma virus

• Model GITR-mediated T-cell dynamics in Mouse Tumor Micro Environment

• Provides Insight into Inter-mouse Variability of Anti-CTLA4 Response 

We used droplet emulsion microfluidics to generate thousands of micro-organospheres (MOS) from low-volume patient tissues. A clinical study demonstrated MOS reliably predicted tumor drug response within 14 days. MOS capture original tumor stromal and immune content, providing a clinical assay for testing immuno-oncology (IO) therapies such as checkpoint blockade, bispecific antibodies, and T cell therapies on patient tumors.

Anti-tumor immunity depends upon functional, activated CD8 T cells, however, the mechanisms that license their accumulation in tumors remain incompletely understood. We explore the role of antigen encounters in tumor microenvironments on CD8 T cell function and migratory potential. We demonstrate that high-affinity antigens are necessary for retention, while suboptimal or no antigen encounter renders CD8 T cells susceptible to lymphatic-derived gradients that direct their exit from tumors and limit immunotherapy.

Immunotherapy development is hampered by the lack of clinically relevant preclinical models, resulting in an enormous number of clinical trials, high attrition rates and developmental costs. HUB Organoids are patient-derived in vitro models that recapitulate patient diversity and preserve tumor-specific antigens. Co-cultured with immune cells offers a scalable and predictive platform for immunotherapy development. Adopting HUB Organoids in immunotherapy development shortens the timelines to drug approval, allows to identify responders, and results in clinical candidates with a higher chance of success on patients.

- Represent the tumor vascular heterogeneity and cross-talk to investigate the effect of cell-based cancer immunotherapies in thoracic malignancies

- Co-opt innate immunity and vascular barrier to target solid tumors

- Exploring next-generation microphysiological systems to recapitulate more relevant human models in vitro

Founded in 2000, Shanghai Model Organisms Center Inc. (SMOC) is a leading company in Asia to offer high-quality animal models and related services to global customers with its highly efficient and reliable technology platforms. Committed to gene editing and disease fighting, SMOC has dedicated to developing a comprehensive product portfolio like GEM models and off-the-shelf products. 

Using the architecture for the Hubble telescope, we have recently developed a platform which allows for multiplex immunofluorescence (mIF) histopathologic maps at single cell resolution across whole slides named ‘AstroPath.' This technology is applied to the whole slide mIF mapping of samples from pre- and on-treatment samples from patients treated with immune checkpoint inhibitors (ICIs), enabling the development of biomarkers of response and resistance to ICIs.

Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to immune checkpoint inhibitor (ICI) utility in anti-cancer therapy. The pathogenesis of ICI-myocarditis is poorly understood. In this presentation, I will discuss murine models and human correlatives that describe the putative causal relationship between CD8 T cells autoreactive against alpha myosin and ICI-induced myocarditis.

CAR T cell therapy represents a potential cure for B cell malignancies. However, the majority of CAR T cell-treated patients are destined to relapse. Several pitfalls have been associated with CAR T cell treatment failure, including pre-infusion barriers, tumor intrinsic factors, the immunosuppressive tumor microenvironment, and the characteristics of the product. In this talk, he will discuss the most recent advancement in the field and new strategies to overcome them.