Since the 1990’s, we have conducted clinical trials of gene modified T cells. Gene editing has created T cells resistant to HIV infection. Chimeric antigen receptor (CAR) T cells targeting CD19 on B cells leukemias and lymphomas have induced durable complete responses in patients who are relapsed or refractory to all other available treatments. New designs for genetically modified T cells include switches and potency enhancements that will be required for targeting solid tumors. In one such approach, multiplex gene editing was accompanied by lentiviral transduction of a T Cell Receptor against the cancer antigen NY-ESO-1. The first use of CRISPR in the US in humans demonstrated that multiplex human genome engineering is safe and feasible. Translation of these technologies from research bench to clinical application requires knowledge of the critical quality attributes of the engineered cell product and acceptable limits. Determining dose, potency, and anticipating pharmacokinetics of a living, dividing drug presents unique challenges. The road forward for wide patient access to engineered cellular therapies depends not only on scientific progress in targeting, gene modification and cellular manipulation methods, but also on meeting automation, engineering, clinical site onboarding, and health policy challenges.

Dr. Bruce Levine, Barbara and Edward Netter Professor in Cancer Gene Therapy, is the Founding Director of the Clinical Cell and Vaccine Production Facility (CVPF) in the Department of Pathology and Laboratory Medicine and the Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania. He received a B.A. (Biology) from Penn and a Ph.D. in Immunology and Infectious Diseases from Johns Hopkins. First-in-human adoptive immunotherapy trials include the first use of a lentiviral vector, the first infusions of gene edited cells, and the first use of lentivirally-modified cells to treat cancer. The Facility has manufactured, tested and released of 3,200 cellular products administered to >1,400 patients in clinical trials since 1996. Dr. Levine is co-inventor of the first FDA approved gene therapy (Kymriah), chimeric antigen receptor T cells for leukemia and lymphoma, licensed to Novartis. Dr. Levine is co-inventor on 29 issued US patents and co-author of >200 manuscripts and book chapters with a Google Scholar citation h-index of 94. He is a Co-Founder of Tmunity Therapeutics, a spinout of the University of Pennsylvania. Dr. Levine is a recipient of the William Osler Patient Oriented Research Award, the Wallace H. Coulter Award for Healthcare Innovation, the National Marrow Donor Program/Be The Match ONE Forum 2020 Dennis Confer Innovate Award, serves as President of the International Society for Cell and Gene Therapy, and serves on the Board of Directors of the Alliance for Regenerative Medicine. He has written for Scientific American and Wired and has been interviewed by the NY Times, Wall Street Journal, Washington Post, NPR, Time Magazine, National Geographic, Bloomberg, Forbes, BBC, and other international media outlets.

The S100A1 protein is a multifunctional target regulating normal cardiac function and, therefore, was a promising target of interest for the treatment of heart failure. Published data has shown S100A1 to be depleted in failing cardiomyocytes from human heart failure biopsies and in heart failure rodent animal models. A gene therapy approach leading to increased expression levels of the protein directly in the heart could potentially lead to restoration of contractile function and improve overall cell survival. This talk highlights the issues and considerations as well as learnings of the progression of S100A1 gene therapy approach in Drug Discovery.

Petia Shipkova, Ph.D. is currently a Scientific Senior Director at Bristol-Myers Squibb (BMS), NJ. She leads an LCMS-focused analytical and bioanalytical groups providing support for all Drug Discovery programs at BMS. The research efforts include high order structure characterization and epitope mapping as well as in vivo quantitation of all modality drug candidates, target proteins and biomarkers, including metabolomics profiling assays.

Paul Levesque, Ph.D. is a Scientific Executive Director at Bristol-Myers Squibb. He leads a Cardiovascular Safety Pharmacology group that provides cardiovascular risk assessment and mitigation for all discovery and development programs at BMS. He also provides toxicology support for cardiovascular programs throughout all phases of drug discovery. Research interests in his group include utilizing new methodologies such as human induced-pluripotent stem cell derived cardiomyocyte preparations and a variety of functional assay platforms to select and progress cardiac drug discovery targets and to improve nonclinical to clinical translation of cardiovascular risk assessment.

Intellia Therapeutics uses CRISPR/Cas9 genome editing technology to develop ex vivo and in vivo therapies. This modular-based approach allows focused and streamlined drug development from bench to bedside. It is critical to understand ADME, activity, and safety properties of these investigational compounds, and most importantly, animal to human translation. Bioanalytical methods have been established to support drug development through different stages including PK/TK, PD, immunogenicity, and additional biomarkers for efficacy or safety. In this presentation, case studies will be provided to demonstrate method performance properties and their intended use for evaluation of systemically administered in vivo therapies.

Yuanxin Xu, M.D., Ph.D. has worked at Intellia Therapeutics since January 2020 as VP, Early Development & Translational Medicine. She manages bioanalysis, DMPK, and pharmacology-toxicology functions as part of Intellia ONE to advance ex vivo and in vivo CRISPR/Cas9 genome editing therapies. Previously, she had worked as Senior Director for ~ 5 years at Alnylam Pharmaceuticals and supported RNAi therapeutic development and market approvals. She was with Genzyme/Sanofi for ~ 13 years (Pr. Scientist to Senior Scientific Director) working on clinical bioanalysis. Yuanxin studied cell and organ transplantation at BioTransplant for ~ 9 years. She received her Bachelor of Medicine (MD equivalent) from Beijing Medical University (now Peking University) and Ph.D. in Biochemistry from Iowa State University.