Thursday May 4 09:00 – 10:30
|Catherine Bollard, MBChB, MD
Director, Program for Cell Enhancement and Technologies for Immunotherapy (CETI), Children’s National Medical Center
Professor of Pediatrics and Microbiology, Immunology and Tropical Medicine, The George Washington University
ISCT President 2016-2018
The rapidly advancing field of T cell immunotherapy is a major treatment innovation with the potential to deliver safer, more effective treatments than are currently available, for cancer as well as for life-threatening infections. One approach has been to expand antigen specific T cells as described by Helen Heslop in her overview of the virus specific T cell field, to retarget T cells to attack malignant cells by the insertion of artificial T cell receptors and gene editing strategies as presented by Chiara Bonini and strategies to direct and arm T cells by insertion of a chimeric antigen receptor (CAR) as discussed by Martin Pule. We hope that the audience will find in this Presidential Plenary session a broad overview of the most clinically promising cell therapies in this fast moving field.
Engineered T-cell Therapy, Smarter Targets and Smarter Targeting
|Martin Pule, MB BCh
Director of CAR Program & Senior Lecturer, University College London
Founder and Chief Scientific Officer, Autolus Ltd.
Chimeric antigen receptor therapy faces several challenges when moving from targeting CD19. Target antigens which are completely specific for the tumour are rare and many targets risk targeting tissues which are not as dispensable as the B-cell compartment. Targeting single antigens risks tumour escape. I will discuss some approaches that can be used to overcome these problems. Careful targeting of very particular antigens can reduce targeting of normal tissues to tolerable levels. I will also discuss alternative synthetic biology approaches which link receptors together can target patterns of antigen expression.
Virus Specific T Cells to Prevent and Treat Viral Infections After HSCT
|Helen Heslop, MD
Dan L Duncan Chair, Professor of Medicine and Pediatrics
Center for Cell and Gene Therapy,
Baylor College of Medicine, Houston Methodist Hospital and Texas Children’s Hospital
Viral infections are still a major complication during the period of immune suppression that follows allogeneic hematopoietic stem cell transplantation (HSCT). Adoptive transfer of donor-derived virus-specific cytotoxic T cells (VSTs) is a strategy to rapidly restore virus-specific immunity to prevent or treat viral diseases after HSCT. Multiple studies using different expansion or direct selection techniques have shown that donor-derived VSTs confer protection in vivo after adoptive transfer in 70% to 90% of recipients. Because a major cause of failure is lack of immunity to the infecting virus in a naïve donor, more recent studies have infused closely matched third-party VSTs and reported encouraging response rates. Current efforts are investigating broadening the applicability of this approach by simplifying manufacture and optimizing “off the shelf” approaches.
TCR Gene Editing of Memory Stem T Cells for Cancer Treatment
|Chiara Bonini, MD
Head of the Experimental Hematology Unit
San Raffaele Scientific Institute
Adoptive T cell therapy relies on the ability of T lymphocytes to recognize and destroy specific targets, on microbes or tumors, through their T cell receptors (TCR), leading to efficient killing and long-term protection against diseases. To be effective against cancer, T cells needs to be 1. Specific for cancer antigens, 2. Able to expand and persist long enough to mediate a long lasting clinical response, 3. Able to counteract the immunosuppressive tumor microenvironment.
TCR genetic engineering represents a suitable approach to generate large numbers of tumor specific T cells. The core of this approach is the transfer in patients’ T cells of genes encoding for rare tumor-specific TCR. However, the simple transfer of tumor specific TCR genes into T cells is affected by some limitations: genetically modified T cells shall express four different TCR chains, that might mispair, leading to unpredictable toxicity and to an overall dilution of the tumor specific TCR on lymphocyte surface, thus limiting the efficacy of therapeutic cellular product. To overcome these issues, we developed a TCR gene editing procedure, based on the knockout of the endogenous TCR genes by transient exposure to alfa and/or beta chain specific Zinc Finger Nucleases (ZFNs), followed by the introduction of tumor-specific TCR genes by lentiviral vectors. The TCR gene editing technology, proved safer and more effective than conventional TCR gene transfer in vitro and in animal studies, in models of acute myeloid leukemia and multiple myeloma. We developed protocols to generate high numbers of TCR edited memory stem T cells and central memory T cells, lymphocyte subsets endowed with long term persistence capacity. The immunosuppressive environment that such innovative cellular products will encounter once infused to cancer patients represents an additional challenge that will be discussed during the presentation.