First Trial With Universal CAR-T Treatment in Pediatric Leukemia Reports Success

“Off-the-shelf” chimeric antigen receptor (CAR)-T cells, also known as universal donor cells, were used in 2 young infants with relapsed, refractory acute lymphoblastic leukemia (ALL) resulted in molecular remission in 28 days in both infants.

The process of leukapheresis—using the patient’s own T cells, modifying them, and then expanding them in vitro, before infusing them back into the patient—can be very cumbersome and time consuming. It is also complicated by the fact that heavily treated patients, particularly the younger patients, may not be the most ideal candidates to yield a good “product” of T cells. While using nonmatched donors is an option, it can create immune-related complications such as graft-versus-host disease.

With this in mind, researchers used a gene-editing tool, transcription activator-like effector nuclease (TALEN), to modify the expression of the CD52 gene in CD19 CAR-T cells, also known as CAR19, from a healthy female donor. TALEN was simultaneously used to disrupt the cell surface expression of the αβ T-cell receptor. Following quality control checks, the cells were infused into 2 infants who had relapsed refractory CD19+CD52− B-ALL and had previously failed a hematopoietic allogenic stem cell transplant (ASCT) and some other experimental treatments.

The first treatment in June 2015 was in an 11-month infant who had a bone marrow relapse 3 months after receiving fludarabine, treosulfan, thiotepa, and ATG in combination with an ASCT from an unrelated male donor. She was administered a single infusion of CAR19+ TCR− T cells. There was no evidence of immediate infusion-related toxicity or cytokine release syndrome, which are typically observed with CAR-T treatment. Continuous monitoring showed sustained cytogenetic and molecular remission from 6-weeks onwards, with persistence and expansion of the donor cells observed. A month after eradication of donor cells from the infant’s blood and transplantation, the patient was in complete remission.

In December 2015, the authors treated a 16-month infant with a similar protocol. This patient had received a matched unrelated donor stem cell transplant (SCT) after conditioning with treosulfan, fludarabine, thiotepa, and ATG in January 2015. She relapsed in 10 months, at which point she received a single dose of CAR19+ TCR− T cells (4.0 × 106/kg). A second ASCT followed within 10 weeks of the infusion, and the child was confirmed to be in remission 1 year after therapy.

The authors believe this technology has immense potential as a “bridge” to allow a successful SCT and marked remissions in patients with leukemia.

Companies like Juno Therapeutics and Kite Pharma, have built their model on modifying T cells derived from the patient’s own immune system, and the “off-the-shelf” model could create tremendous competition in the space.

Reference

Qasim W, Zhan H, Samarasinghe S, et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci Trans Med. 2017;9(374). doi: 10.1126/scitranslmed.aaj2013.