Gene Editing Leads to Successful Outcome for Pediatric ALL Patient


Waseem Qasim, MBBS, PhD, and his team began researching a novel strategy to enable “off-the-shelf”’ therapy with mismatched donor chimeric antigen receptor (CAR)19 T cells.

A chance of a lifetime or a chance at a lifetime is a matter of perspective. Depending on whether one looks at the opportunity presented to the researchers or the very young patient and her family who needed immediate results, this chance led to a positive outcome.

Waseem Qasim, MBBS, PhD, Professor of Cell and Gene Therapy at the Institute of Child Health, Uiniversity College London and Consultant in Paediatric Immunology/BMT at the Great Ormond Street Hospital for Children, London, and his team began researching a novel strategy to enable “off-the-shelf”’ therapy with mismatched donor chimeric antigen receptor (CAR)19 T cells. 

Dr. Qasim presented his research results at the American Society of Hematology's 57th Annual Meeting on December 5, 2015, in Orlando, Fla.

A very young patient had been diagnosed with an aggressive form of acute lymphoblastic leukemia (ALL) at the tender age of 3 months old.  By 11 months, the patient presented with high-risk, CD19-positive infant ALL (t(11;19) rearrangement) relapsed in the bone marrow 3 months after a myeloablative 8/10 mismatched unrelated donor transplant. After careful consideration with a medical ethics team and desperate to help their baby survive, her parents, along with her hematology team, agreed to try an approach that had only been used in mouse model studies.

The investigators manufactured a bank of donor T cells under Good Manufacturing Practice conditions from Cellectis Biopharmaceuticals for final stage validation studies using a third generation self-inactivating lentiviral vector encoding a 4g7 CAR19 (CD19 scFv- 41BB- CD3ζ) linked to RQR8, an abbreviated sort/suicide gene encoding both CD34 and CD20 epitopes. Cells were then electroporated with two pairs of transcription activator-like effector nucleases (TALEN) mRNA for multiplex targeting of both the T-cell receptor alpha constant chain locus, and the CD52 gene locus. Following ex-vivo expansion, cells still expressing TCR were depleted using CliniMacs alpha/beta TCR depletion, yielding a T-cell product with <1% TCR expression, 85% of which expressed CAR19, and 64% becoming CD52-negative.

This case was complicated by several variables. For example, leukemic blasts expressed CD19, but were CD52-negative. Her disease progressed (70% blasts in bone marrow) despite treatment with the monoclonal antibody blinatumomab (Blincyto), and the researchers were unable to generate CAR19 T cells. The patient received cytoreduction with vincristine, dexamethasone, and asparaginase followed by lymphodepleting conditioning with fludarabine 90mg/m2, cyclophosphamide 1.5g/m2, and alemtuzumab (Lemtrada) 1mg/kg. Prior to infusing the patient with the UCART19 cells, the bone marrow showed persisting disease (0.5% FISH-positive). She received a single dose (4.5x106/kg) of UCART19 T cells and did not experience significant toxicity.

To date, the designer immune cells have shown to be effective, and the patient is growing and recovering. A watchful hematology team will continue to monitor the patient, as she is not completely in remission, but this has been a positive outcome for both the family and pediatric cancer field.





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