Improving Immunotherapy Efficacy and Safety
- 5:00 pm Main Conference Registration1:00 pm
Recommended Pre-Conference Short Course2:00 pm
SC1: Antibody Drug Discovery: From Target to Lead
*Separate registration required. See short courses page for details.
Registration and Morning Coffee7:00 am
NEW FRONTIERS IN IMMUNOTHERAPY
Engineering Human Neuraminidase as a Novel Cancer Immunotherapy to Enhance T Cell Immunity by Degrading Immunosuppressive Sialoglycans
Sialoglycans have emerged as an important immune checkpoint orthogonal to the PD-1/PD-L1 axis. We engineered a novel first-in-class drug candidate (Bi-Sialidase), consisting of an engineered human sialidase (Neu2) Fc fusion, to degrade immunosuppressive sialoglycans. Bi-Sialidase potentiates T cell immune response and demonstrates single-agent antitumor activity and a wide safety margin in preclinical animal models, offering a novel immunomodulatory approach to treat cancer.
Boosting the Efficacy of Bispecific T Cell Engagers via Removal of Cell-Surface Sialoglycans
Bispecific T cell engager (BiTE)-based cancer therapies that activate T cells of a patient’s own immune system have had success in treating blood cancers, but with limited efficacy in targeting solid tumors. Here, I will discuss the development of BiTE-sialidase fusion proteins that enhance tumor cell susceptibility to BiTE-mediated cytolysis by T cells via targeted desialylation at the T cell-tumor cell interface.
High throughput, functional single-cell assays can dramatically accelerate cell and immune therapy research and cell line development. Here, we demonstrate how functional, single-cell, droplet-based assays reveal subpopulations of immune cells with high cytokine secretion and quantifies the fraction of killer cells with the capacity to kill a co-encapsulated target cancer cell. High secreters or killers can be analyzed and isolated from millions of inactive cells in a one-day workflow.
We here introduce Enrich TROVO, a versatile and compact cell culture/capture system compatible with traditional cell culture protocols and equipment while facilitating long-term single cell behavior analysis and isolation. We demonstrated the TROVO application for mapping and isolating high-performing CAR-T cells. The system is designed for culture plates. Both positive and negative capture are allowed, ensuring the high cell viability for fragile cells in adherence or suspension.
Networking Coffee Break10:00 am
Immunomodulation by Genomic “Dark Matter” and Extracellular Vesicles in Cancer
Non-coding regions or the ‘dark matter’ of the genome (representing over 70% of the genome) have been largely ignored in cancer immunotherapy. This presentation will describe how otherwise silent, non-coding regions of the human genome containing retroelements (REs) and human endogenous retroviruses (HERVs) are activated in human cancer and their implications on immunoregulation. REs and HERVs can induce anti-tumor immune responses, but we have also found that they can induce chronic inflammation and a profound immunosuppression in cancer patients through a unique mechanism.
Charles River's unique Cell Microarray technology identifies human receptor binding with a high degree of specificity and sensitivity, providing valuable data to de-risk biotherapeutic candidates from early in the lead selection process, up to generating IND-enabling data for regulatory submissions. Industry case examples demonstrate identification of on- and off-target binding events against >6,500 human proteins expressed in human cells. Cell Microarray datasets have been included in successful IND submissions to regulatory agencies, such as the FDA EMA, NMP and PMDA.
Developing Antibody Drug Conjugates (ADCs) is time-consuming and costly. To help clients streamline the pre-clinical development process of ADC drugs in a cost-efficient way, GenScript Probio has established an integrated ADC discovery platform that offers a comprehensive suite of services, including antibody lead generation using various platforms (hybridoma, phage display, single B cell), cell-based screening assays for linkers/payloads, and in vivo lead characterizations in rodent models (efficacy/PK/PD/Toxicity).
Interactive Discussions are informal, moderated discussions, allowing participants to exchange ideas and experiences and develop future collaborations around a focused topic. Each discussion will be led by a facilitator who keeps the discussion on track and the group engaged. To get the most out of this format, please come prepared to share examples from your work, be a part of a collective, problem-solving session, and participate in active idea sharing. Please visit the Interactive Discussions page on the conference website for a complete listing of topics and descriptions.
TABLE 3: Immunomodulation by Genomic “Dark Matter” and Extracellular Vesicles in Cancer - IN-PERSON ONLY
Session Break1:30 pm
ENHANCING IMMUNOTHERAPY AND LONG-TERM FUNCTION
Engineering Next-Generation Proteins to Enhance Adoptive Cell Therapy
Adoptive cell therapy (ACT) with genetically modified T cells is a promising approach, however, the tumor microenvironment can establish several obstacles. We develop engineered fusion proteins (FPs) that combine a receptor ectodomain with a different costimulatory endodomain. Intentionally engineered FPs can “armor” T cells by multiple mechanisms and new generations also promote endogenous antitumor immunity, resulting in significantly improved therapeutic efficacy against hematological and solid tumors.
RASA2 Ablation in T Cells Boosts Antigen Sensitivity and Long-Term Function
We performed multiple genome-wide CRISPR screens under different immunosuppressive conditions to identify genes that can be targeted to prevent T cell dysfunction. These screens converged on RASA2, a RasGAP that we identify as a signaling checkpoint in human T cells. RASA2 ablation in T cells enhanced signaling and cytolytic activity in response to target antigen, as well as persistent effector function in the setting of repeated tumor antigen stimulations. Ablation of RASA2 in multiple preclinical models of T cell receptor and CAR T cell therapies prolonged survival in mice xenografted with either liquid or solid tumors.
This talk will introduce a high-throughput screening technology platform capable of observing single T cells in co-culture with antigen-presenting cells (APC’s). During the time-course observation, >1,000 single T cells are monitored for their ability to kill APC’s in co-culture, surface marker expression, and cytokine secretion. Recovering functional T cells from patient samples using this 2-day workflow can accelerate therapeutic TCR discovery, T cell vaccine development, and patient immune monitoring.
Networking Refreshment Break3:20 pm
Transition to Plenary Keynote Session3:50 pm
PLENARY KEYNOTE SESSION
Advances in CAR T Therapy
Carl H. June, MD, Richard W. Vague Professor in Immunotherapy; Professor of Medicine; Director, Center for Cellular Immunotherapies; Director, Parker Institute for Cancer Immunotherapy, University of Pennsylvania Perelman School of Medicine
Advances in the understanding of basic immunology have ushered in two major approaches for cancer therapy over the past 10 years. The first is checkpoint therapy to augment the function of the natural immune system. The second uses the emerging discipline of synthetic biology and the tools of molecular biology and genome engineering to create new forms of engineered cells with enhanced functionalities. The emergence of synthetic biology approaches for cellular engineering provides a broadly expanded set of tools for programming immune cells for enhanced function. Barriers to therapy of solid tumors will be discussed.
The Next Frontier in Machine Learning and Biologics: "Lab in a Loop" Large Molecule Drug Discovery, From Optimization to de novo Discovery
A key opportunity in applying machine learning to augment biologic drug discovery and development is through constant iteration - a process we call "lab in a loop." By developing integrated methods for optimizing affinity and multiple developability parameters, as well as a close integration of antibody engineering, machine learning, and structural biology, we have the potential to more rapidly identify and test novel candidate molecules. Sophisticated machine learning frameworks allow us to integrate later stages of optimization into the earliest stages of discovery, while high-throughput experimental systems allow rapid improvement of all methods and molecules. This process starts with the integration of people and scientific culture and ends with tightly integrated computational and experimental systems.
Welcome Reception in the Exhibit Hall with Poster Viewing5:40 pm
PEGS BOSTON COMMON: YOUNG SCIENTIST MEET UP
Young Scientist Meet Up - IN-PERSON ONLY
The young scientist meet up is an opportunity for scientists entering the field to develop connections across institutions, and for established leaders to come build relationships with the next generation of scientists. The meet-up will pave the way for mentorships, professional opportunities, and scientific discovery.
- Get to know fellow peers and colleagues
- Make connections and network with other institutions
- Inspire others and be inspired!
Close of Day7:00 pm
Registration and Morning Coffee8:00 am
IMPROVING RESPONSE AND CURE RATES
Uncovering the Mode of Action of Engineered T Cells in Patient Cancer Organoids
Here we describe a system, called BEHAV3D, developed to study the dynamic interactions of immune cells and patient cancer organoids by means of imaging and transcriptomics. We apply BEHAV3D to live-track >150,000 engineered T cells cultured with patient-derived, solid-tumor organoids, identifying a ‘super engager’ behavioral cluster comprising T cells with potent serial killing capacity.
New Modes of T Cell Recognition and Novel Broadly-Expressed T Cell Epitopes by Dissection of Cancer Immunotherapy Success
We have employed three different successful pipelines for discovering what so-called “orphan T cells” recognize and applied these to dissect what dominant persistent anti-cancer T cells recognize during successful immunotherapy for solid cancer. This work has uncovered a new, unanticipated, mode of T cell recognition. I will discuss these results and how they point to potentially exploitable correlates of success.
A Genome-Scale Screen for Synthetic Drivers of T Cell Proliferation
The engineering of autologous patient T cells for adoptive cell therapies has revolutionized the treatment of several types of cancer1. However, further improvements are needed to increase response and cure rates. CRISPR-based loss-of-function screens have been limited to negative regulators of T cell functions2,3,4 and raise safety concerns owing to the permanent modification of the genome. Here we identify positive regulators of T cell functions through overexpression of around 12,000 barcoded human open reading frames (ORFs).
Sponsored Presentation (Opportunity Available)10:00 am
Coffee Break in the Exhibit Hall with Poster Viewing10:30 am
Scalable Discovery Systems for Human Cell Therapies
Effective cellular therapies for solid tumors remain elusive. We present a highly scalable platform to rapidly associate large pools of T cell genetic modifications with high-dimensional single-cell phenotypes across diverse disease contexts. The resulting genotype x phenotype maps have nominated unique novel cell therapy targets with improved in vitro and in vivo performance for further clinical development.
Engineering T Cell Antigen Density Sensors for Cancer Immunotherapy
Current CAR T cells fail to discriminate between cells expressing high and low levels of antigens which limits its use against solid tumors. We are engineering T cell circuits that can sense antigen density with an ultrasensitive tunable response. We have designed a two-step recognition-activation circuit where an initial recognition event, via a Synthetic Notch receptor, alters the potency of a subsequent response, CAR expression, and activation.
Engineering Bacteria Cancer Therapy
Synthetic biology is driving a new era of medicine through the genetic programming of living cells. This transformative approach allows for the creation of engineered systems that intelligently sense and respond to diverse environments, ultimately adding specificity and efficacy that extends beyond the capabilities of molecular-based therapeutics. One focus has been on engineering bacteria for cancer therapy, where several studies have demonstrated selective bacterial colonization of solid tumors, primarily due to reduced immune surveillance in tumor cores. In this talk, I will discuss efforts in programming bacterial safety systems and delivery of therapeutic payloads ranging from cytotoxic to immunomodulatory agents.
Assessment of off-target antibody reactivity is a regulatory requirement for clinical development; however, conventional screening methods are often ineffective in screening newer therapeutic modalities including cell therapies. We will present the Membrane Proteome Array (MPA), a 6,000-protein cell-array for specificity screening, case studies describing its successful use for regulatory filings, and the status of the MPA being developed as a qualified Drug Development Tool under consideration by the FDA
Immune cell engagers, redirecting immune effector cells to kill cancer cells, are emerging as a promising therapeutic modality for cancer treatment. Building upon our understanding of the biology, clinical promises and challenges of TCEs in both hematologic and solid tumors, our unique proprietary CD3 mAb, and leading bispecific and multispecific antibody platforms, we are developing next generation ICE technologies to enable our clients to discover potentially best or first-in-class drugs.
Close of Improving Immunotherapy Efficacy and Safety Conference1:40 pm
Recommended Dinner Short Course6:30 pm
SC8: CAR T Cells: Improving Safety While Retaining Therapeutic Activity
*Separate registration required. See short courses page for details.