New therapies that promote anti-tumor immunity have revolutionized the way patients are treated. This talk will give a description of the discovery and characterization of a monoclonal antibody targeting CD96. It will go into more detail on the opportunities, and how anti-CD96 differs from other agents as an innovative biologics to activate immune system to fight cancer.

NKTR-255 is an engineered version of native IL-15, designed to have an improved pharmacokinetic profile, preserved binding to all endogenous IL-15 receptors, and to safely increase the proliferation, activity and survival of NK cells and memory CD8+ T cells. We will present preclinical and early clinical data of NKTR-255 in settings of advanced cancer.

Cell microarray screening of plasma membrane and tethered secreted proteins that are expressed in human cells enables rapid discovery of primary receptors as well as potential off-targets for a variety of biologics including: peptides, antibodies, proteins, CAR T and other cell therapies. 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.

Oncogenic-induced, membrane-bound NKG2D ligands stimulate NK and Cd8 T cell anti-tumor immunity. Conversely, tumor-edited soluble NKG2D ligands in the tumor microenvironment suppress anti-tumor immunity via multiple mechanisms. Here we present evidence that tumors shed soluble NKG2D ligand, the soluble MHC I chain-related molecule (sMIC), facilitates immune suppression of MDSCs. We also present evidence that targeting soluble MIC reprograms MDSC and primes the tumor immune microenvironment.

Immune checkpoint inhibitors (ICI) such as anti-PD1/PDL1 have revolutionized cancer treatments. However, only 10-30% of patients benefit from the treatment because of the complexity of tumor microenvironment (TME), which is usually “cold," and only “hot” tumors could be successfully treated by ICI. Many efforts including targeting innate immunity to turn the TME from “cold” to “hot” have been pursued and will be discussed.

Human pluripotent stem cells provide a key resource for cellular immunotherapies. Studies from our group have demonstrated that natural killer (NK) cells can be efficiently derived from both human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), which can be engineered to better target refractory malignancies. hESCs and iPSCs serve as a platform to express chimeric antigen receptors and other modifications to enhance anti-tumor activity. Importantly, hESC/iPSC-derived NK cells can be expanded to clinical scale in current GMP-compatible conditions. Since NK cells function as allogeneic cells, this strategy enables use of hESC/iPSC-derived NK cells as an “off-the-shelf” targeted cellular immunotherapy against refractory malignancies.

NK cells can achieve complete remission in patients with refractory AML. Limitations of current NK cell strategies include single donor products, allogeneic persistence, and tumor specificity. To enhance specificity, trispecific killer engagers can be used alone or with adoptive transfer. NK cell multi-dosing will be achieved with off-the-shelf, genetically modified, induced pluripotent stem cells overexpressing CD16 or CAR with an endogenous IL-15 signal to enhance persistence.

Within cell therapy development the use of in vivo animal models can present significant hurdles in translatability to humans. As a result, the establishment of complementary high-quality in vitro efficacy and safety studies to foster the development of such therapies has become critical before filing for Investigational New Drug (IND) status. Charles River has developed an in vitro efficacy package aimed at determining cell therapy activity, specificity and potency. In addition, we are able to generate an in vitro safety profile using primary and iPSC-derived cells.

Cell and gene therapy research requires the highest quality reagents as possible to achieve optimal experimental results. Abcam offers a broad portfolio of recombinant proteins and assays to enable & support research in the cell and gene therapy spaces. During this talk, we will share one of our latest new product offerings, our industry-leading premium proteins, which have the highest quality standards available, and present a few key proteins for cell and gene therapy research.

Chemically programmed T cell engaging bispecific antibodies combine (i) a small molecule that targets a cancer cell surface receptor and (ii) an antibody that recruits and activates T cells. Conceptually similar, chimeric antigen receptor T cells can also be put under the control of a small molecule by using a chemically programmed antibody as a switch. As such, chemically programmed antibodies can endow small molecules with the power of cancer immunotherapy.

To mimic T cell receptors recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules, the ORBIT platform at MD Anderson develops technology in discovery of antibody specific to tumor MHC complex,  and antibody leads are further engineered into suitable modalities like bispecific Ab and CAR T for selected targets. We will discuss multiple examples of TCR like antibody programs.

Immunotherapy approaches that target peptide-human leukocyte antigen (pHLA) complexes have the potential to access virtually all foreign/cellular proteins. Consequently, several protein engineering solutions have been applied to the natural ligand for pHLA, the T cell receptor (TCR), to enhance both its stability and affinity as a soluble drug. Here, the molecular consequences of these modifications on TCR target-selectivity are considered, with obvious implications for target-fidelity in the clinic.

Understanding the underlying mechanisms of T cell differentiation and function is critical for developing effective therapeutics. However, T cells are extremely heterogeneous and have variable responses to stimulation. This makes predicting specific T cell responses extremely difficult. To identify effective T cells within a heterogeneous sample, scientists must be able to characterize T cells at the single-cell level. However, most existing single-cell methods are destructive and prevent the correlation of cytokine secretion with other functional parameters like cytotoxicity or gene expression. Here we share use cases that demonstrate how the Opto™ Cell Therapy Development workflow makes it possible to fully characterize individual T cells, correlate key characteristics, and directly link phenotype to gene expression at a single-cell level — all on the same T cells — enabling the development of more efficacious therapies.