UPDATED: CAR-T Therapy in Leukemia
Curator: Larry H. Bernstein, MD, FCAP
UPDATED 3/15/2020
UCART19: First in Man Proof of Concept to be Presented at 2015 ASH Annual Meeting
An infant in London with an aggressive leukemia has been given TALEN-edited immune cells, a treatment that appears to have put her disease into remission, the Wall Street Journal reports.
The infant, Layla, had relapsed acute lymphoblastic leukemia against which conventional treatment was ineffective. The Journal notes that an experimental treatment called CAR in which patients’ T cells are removed and engineered to better find and eliminate leukemia cells had shown some success in trials. But Layla didn’t have enough of her own immune cells to use.
Instead, clinicians from Great Ormond Street and University College London researchers along with Cellectis turned to T cells from a healthy donor that they edited using TALENs so they didn’t attack the girl’s body as well as so they wouldn’t be attacked by the leukemia drugs then given to the girl.
Weeks after the cells were given to Layla, the Journal reports, she went into remission.
First Clinical Application of Talen Engineered Universal CAR19 T Cells in B-ALL
Gene Therapy and Transfer
Program: Oral and Poster Abstracts
Session: 801. Gene Therapy and Transfer:
Poster I Saturday, December 5, 2015, 5:30 PM-7:30 PM
Hall A, Level 2 (Orange County Convention Center)
Waseem Qasim, MBBS PHD1*, Persis Jal Amrolia2*, Sujith Samarasinghe, MD, PhD3*, Sara Ghorashian, MD, PhD, FRCPath1*, Hong Zhan, PhD4*, Sian Stafford, PHD1*, Katie Butler, PHD1*, Gul Ahsan5*, Kimberly Gilmour5*, Stuart Adams, PHD5*, Danielle Pinner5*, Robert Chiesa5*, Steve Chatters, PHD5*, Sue Swift, PHD1*, Nicholas Goulden, MD, PhD3, Karl Peggs, MBBChir, MRCP, FRCPath6*, Adrian J Thrasher, MD, PhD1*, Paul Veys2* and Martin Pule, PhD7*
1 INSTITUTE OF CHILD HEALTH, UCL, London, United Kingdom
2 Bone Marrow Transplantation Department, Great Ormond Street Hospital, London, United Kingdom
3 Department of Haematology, Great Ormond Street Hospital For Children, London, United Kingdom
4 Institute of Child Health / Molecular and Cellular Immunology Unit, University College London, London, United Kingdom
5 GREAT ORMOND STREET HOSPITAL, London, United Kingdom
6 CANCER INSTITUTE, UCL, London, United Kingdom
7 Cancer Institute, University College London, London, United Kingdom
UPDATED 3/15/2020
An article by Jennifer Couzin-Frankel in Science discusses safety profile of early CRISPR gene editing trials in a set of cancer patients. Two women and one man, all in their 60’s (one with sarcoma and the other two with multiple myeloma received CRISPR altered chimeric antigen receptor T cells (CAR-T) and tolerated the therapy quite well. The study was led by University of Pennsylvania’s Carl June, M.D., who said the primary goal of the trial was designed to determine safety, not efficacy.
However the trial also wanted to answer a conundrum which was evident from early CAR-T therapies: that not all patients showed complete response and some who showed initial response could show a relapse. Therefore the investigators attempted to use CRISPR to knockout certain genes while hoping to prevent the off target effects that is sometimes seen with CRISPR gene-editing (note the problems with some of the Vertex/ CRISPR Therapeutics trials).
The trial criteria were very specific. Patients tumor cells had to express the protein NY-ESO-1, to which the investigators would target in the engineered T-cells and to boost the immune response they also CRISPRed out the PD-1 protein in the engineered T-cells, thereby releasing the engineered CAR-T from immune block. Fortunately any off target effects, which were small, decreased to minimal over time and CRSPR-edited cells lasted for 9 months versus only 2 months for conventional CAR-T. However it appears at this point, due to limited number of patients, although very safe, therapeutic response was limited.
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