CAR T-Cells Active in Resistant B-Cell Disease

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ORLANDO — Patients with treatment-resistant B-cell malignancies achieved durable accomplish responses to genetically engineered donor T-cells administered after post-transplant progression, results of a petite, ongoing clinical trial showcased.

Eight of twenty patients had disease remission following treatment with allogeneic T-cells modified by the addition of anti-CD19 chimeric antigen receptor (CAR). Remissions have persisted for as long as thirty six months, some of which are ongoing. The protocol omits use of chemotherapy.

The treatment led to sometimes-severe cytokine release syndrome, which was manageable with conventional treatment. No patient developed graft-versus-host-disease (GVHD), James Kochenderfer, MD, of the National Cancer Institute in Bethesda, Md., reported here at the American Society of Hematology (ASH) meeting.

“We’ve treated patients with very advanced malignancies,” Kochenderfer said during an ASH press briefing. “Many of these patients had failed all standard therapies and went on to allogeneic stem-cell transplant, which is considered a last-chance therapy for these patients, and continued to have progressive disease after that. It is a very high-risk patient population.”

The treatment has been particularly effective in patients with refractory acute lymphoblastic leukemia (ALL), as four of five patients achieved accomplish remissions, he added. Some patients with high tumor burdens developed severe cytokine release syndrome, which was manageable with conventional interventions.

Malignant relapse remains a major cause of mortality in patients who fall under allogeneic stem-cell transplantation. For B-cell malignancies that persist despite stem-cell transplantation, patients often receive unmanipulated donor lymphocyte infusions (DLI), which have consistent efficacy and a risk of significant morbidity and mortality related to GVHD, Kochenderfer noted.

In an effort to improve post-transplant treatment of B-cell malignancies, some clinical research groups have begun to evaluate infusions of allogeneic T-cells genetically modified to express a CAR that targets the CD19 antigen on B-cells. Kochenderfer reported findings from an initial clinical practice with CAR-modified T-cells.

The twenty patients enrolled thus far included five each with ALL, CLL, mantle-cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). Eligibility criteria included any CD19-positive B-cell malignancy persisting after allogeneic stem cell transplant and at least one standard DLI, minimal or no GVHD, and no systemic immunosuppressive therapy.

Patients receive a single infusion of anti-CD19-CAR-transduced T-cells, obtained from the original transplant donor, without chemotherapy. Kochenderfer said the transduction process requires eight days to accomplish.

Patients in all four disease groups have responded to the treatment. The best results have occurred in patients with ALL, as four of five achieved minimum residual disease (MRD)-negative accomplish responses. Two patients subsequently relapsed, one has an ongoing finish response at eighteen months, and one underwent a 2nd allogeneic transplant while in finish remission.

Of the five patients with CLL, one had a accomplish response, one had a partial response, and two had stable disease. The finish and partial responses are ongoing at thirty six and eighteen months, respectively. One patient with MCL achieved a accomplish response, one achieved a partial response, and one had stable disease as best response. The finish response was ongoing at thirty one months.

In the DLBCL subgroup, one patient had a accomplish response and three had stable disease. Stable disease was ongoing in one patient.

Some patients have had rapid and dramatic resolution of tumors in response to the CAR T-cell infusion. Describing one patient with DLBCL and large tumors in the cranium and eye socket, Kochenderfer said, “Amazingly, the tumor masses disappeared fully within five days of CAR T-cell infusion.

“This patient had some chronic GVHD before we gave the CAR T-cells. The GVHD continued to worsen before and after the CAR T-cells, and she went on to get other therapy for GVHD, and she proceeds in remission thirteen months after the CAR T-cell infusion.”

Focusing on advances in gene therapy for hematologic diseases, the press briefing included reports on five ongoing studies, the largest being the one reported by Kochenderfer. Briefing moderator George Daley, MD, PhD, of Boston Children’s Hospital, said the puny numbers of patients treated to date with CAR T-cells and other gene-therapy strategies do not detract from the results, which have been positive more often than not.

“The fact that there’s now clinical proof of principle for gene therapy, in a multiplicity of diseases, is truly remarkably arousing,” said Daley. “Having observed the wheel for thirty years and not being a direct participant but an observer, I find the data remarkably reassuring, despite the petite numbers.”

Kochenderfer disclosed a relevant relationship with Bluebird Bio. Co-authors disclosed relevant relationships with Celgene, Allos, Biogen Idec, Genentech, Millennium, Gilead, Kite Pharma, and CRADA inbetween Surgery Branch-NCI and Kite Pharma.

Daley disclosed relevant relationships with True North Therapeutics, Raze Therapeutics, Ocata, Therapeutics, MPM Capital, Solasia, Epizyme and Verastem.

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