LONDON Researchers at Great Ormond Street Hospital in London have published full details of how two girls with treatment-resistant leukemia were cured using Cellectis SA's non-matching donor CAR-T cells.
The two cases are a significant endorsement of Cellectis' push to develop cryopreserved cancer cell immunotherapies that will be available off-the-shelf and suitable for any recipient.
That promises greater flexibility and lower costs than the other CAR-T cell products currently in development, which involve engineering a patient's own T-cells to target the CD19 antigen on B-cells.
The publication in Science Translational Medicine comes just a few weeks after Paris-based Cellectis filed an investigational new drug application with the FDA to conduct the first U.S clinical trial of an allogeneic CAR-T cell therapy. If approved, the study will start later in 2017.
In order for T cells from any donor to be suitable for universal application, they must not only be transduced to express anti-CD19 antigens, but also be gene-edited so that they are not rejected by the recipient.
In collaboration with scientists at University College London, Cellectis has devised a method for simultaneously editing transduced T cells to disrupt T-cell receptor expression, thus reducing the risk of graft-vs.-host disease, and also to delete the CD52 receptor in order to render the CAR-T cells insensitive to the CD52-targeting antibody alemtuzumab.
The latter modification makes it possible to administer alemtuzumab to the patient in order to suppress host-mediated rejection of the non-matching CAR-T cells.
The editing is done with transcription activator-like effector nuclease (Talen), a technique Cellectis has been honing over two decades.
In the report, the researchers said they are able to manipulate the cells at high efficiency. They produced a bank of universal CAR19 (UCART19) T cells from a single female donor. Expression of CAR19 occurred in 85 percent of cells and more than 64 percent had depleted T-cell receptor and CD52 receptor expression. After further processing, only 0.7 percent of cells had detectable T-cell receptors.
Both of the girls, who were treated on a compassionate use basis with cells that had been prepared for phase I trials, had relapsed after chemotherapy and stem cell transplants (SCT).
In the case of the first child to be treated, there were no infusion-related toxicities and unlike autologous CAR-T therapy, there was no evidence of cytokine release or neurotoxicity. She did develop graft-vs-host disease (GVHD) but this was limited to her skin and bone marrow, in contrast to the usual widespread manifestation of this immune reaction.
After several weeks she went into remission, allowing her to have a second SCT. The girl remains well 18 months after treatment and has a normal lymphocyte profile.
The second child had been diagnosed at 4 weeks old with a congenital leukemia. She received a SCT from a non-related matched donor but relapsed and was treated with UCART19 at the age of 16 months.
She also had GVHD on her skin, but it was mild and responded to a topical steroid. Immediately after transfusion of UCART19, the child experienced a period of unusual irritability, which the researchers attribute to transient neurotoxicity caused by the transplanted cells.
Although the cases have been reported separately at two medical conferences, it is good to see the full details published in a peer reviewed journal, said Julianne Smith, vice president of CAR-T development at Cellectis. "We think it's a great paper; it validates our approach," she told BioWorld Today.
Before these first two cases, commentators said the cells would have no activity, or would be immediately rejected, Smith noted. Now she believes it is possible to leapfrog autologous CAR-T products, even given they are further advanced in clinical development. "The allogeneic approach really is a game-changer in the market," she said.
For the two children treated at Great Ormond Street, it was not possible to raise sufficient CD19 cells to generate an autologous CAR-T cell population. This issue also limits the use of autologous treatments in heavily pre-treated elderly patients.
"The fact that allogeneic cells are easily accessible to all patients is the advantage. Some patients are not able to be treated with their own cells," Smith said.
In addition, the use of donor cells makes it far easier to produce a consistent, pharmaceutical quality product. T-cells are not a single lineage but come in phenotypic subsets, each with different properties. As a result, one of the problems with autologous CAR-T therapies is having any control over, or consistency in, the composition from patient to patient.
The lead author of the Science Translational Medicine paper, Waseem Qasim, is now overseeing a formal 10-patient pediatric phase I trial of UCART19, sponsored by Cellectis' collaboration partner, Servier SA. That began in June 2016 and is due to complete in July 2019.
A second phase I, which will recruit 12 adults, began at King's College London in August 2016. The product is being developed in partnership with Pfizer Inc., which took U.S rights in December 2015, when details of the first girl to be treated due were presented at the American Society of Hematology annual conference. (See BioWorld Today, Nov. 20, 2015.)
Cellectis is now lining up to start the U.S. phase I trial of its wholly owned UCART123 in acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm.
The application for an IND followed a public hearing at the NIH Recombinant DNA Advisory Committee on Dec. 14, when the product received unanimous approval.