Engineered T-Cells Led to Tumor Regression in Resistant CLL

James N. Kochenderfer, MD

Results of a small clinical study showed that in patients with posttransplant relapsed B-cell malignancies, treatment with engineered donor T cells led to substantial tumor regression.

Three of 10 patients had disease regression following a single infusion of chimeric antigen receptor (CAR)—transduced T cells targeting CD19. No patient developed graft-versus-host disease (GVHD) after the infusion, although efficacy and toxicity varied considerably from patient to patient, James N. Kochenderfer, MD, reported at the 2013 Annual Meeting of the American Society of Hematology meeting in New Orleans, Louisville.

“Allogeneic anti-CD19 CAR T cells have significant antimalignancy activity when administered without prior chemotherapy,” said Kochenderfer, a translational researcher in the Experimental Transplantation and Immunology Branch of the National Cancer Institute in Bethesda, Maryland.

“Allogeneic anti-CD19 CAR T cells caused regressions of malignancy in patients who were not lymphocyte depleted. Malignancies that were resistant to standard donor lymphocyte infusions regressed after administration of allogeneic anti-CD19 CAR T cells.”

Progressive disease after allogeneic hematopoietic stem cell transplantation is a leading cause of death among patients with B-cell malignancies. Patients have few effective options, as donor lymphocyte infusions have inconsistent efficacy and significant risk of morbidity and mortality resulting from GVHD.

Many B-cell malignancies express CD19, providing a rationale for therapy targeting the cells with anti-CD19 therapy. The rationale led to development of a strategy to use donor allogeneic T cells genetically modified to express an anti-CD19 CAR.

Treatment consisted of a single infusion of anti-CD19-CAR-transduced T cells with no additional therapy, including chemotherapy. Donor T cells were obtained from the original transplant donors.

Thus far, 10 patients have been treated in the ongoing program. Four patients received HLA-matched transplants from unrelated donors and six received HLA-matched transplants from sibling donors. Infusion doses ranged from 1 x 10⁶to 10 x 10⁶anti-CD19-CAR T cells, and an average of 58% of cells expressed the CAR.

The three patients with substantial disease regression included two patients with chronic lymphocytic leukemia (CLL) resistant to standard allogeneic donor-lymphocyte infusions. Following treatment with the engineered anti-CD19 T-cells, both patients had regression of large malignant lymph node masses.

One of the two patients obtained a complete remission that is ongoing after a year of follow-up, said Kochenderfer. The other patient with CLL had disease regression in bone marrow, blood, and lymph nodes, and subsequently developed tumor lysis syndrome, which responded to treatment with rasburicase. A patient with mantle-cell lymphoma obtained a partial remission.

Additionally, a patient with diffuse large B-cell lymphoma attained stable disease that persisted beyond 11 months.

Toxicity was manageable and consisted primarily of fever, hypotension, and B-cell depletion. In six of the 10 patients, the absence of GVHD contrasted with prior episodes of the condition following allogeneic stem-cell transplants. One patient with a history of cardiac dysfunction had transient cardiac dysfunction after the anti-CD19 CAR T-cell infusion.

Illustrating the difficulty of the patient population, Kochenderfer described a patient whose CLL was diagnosed in 1996. The patient received multiple lines chemotherapy, two matched-sibling allogeneic transplants, and an unrelated-donor transplant in 2009. Additionally, the patient underwent multiple lines of chemotherapy for posttransplantation relapse and received five unrelated donor-lymphocyte infusions.

“The patient had regression of adenopathy, leading to complete remission, after infusion of allogeneic anti-CD19 CAR T-cells,” said Kochenderfer.

Imaging studies before and 9 months after the infusion showed complete resolution of a large abdominal mass and other smaller tumors.

During the discussion that followed his presentation, Kochenderfer said the research has not yet progressed to the state that would indicate how widely the anti-CD19 CAR T-cell therapy might apply to the treatment of malignancies. However, the results to date have sparked interest in evaluating the technique in a variety of hematologic malignancies and in some solid tumors.

Kochenderfer JN, Dudley ME, Carpenter RO, et al. Donor-derived anti-CD19 chimeric-antigen-receptor-expressing T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Presented at: 55th ASH Annual Meeting; December 7-10, 2013; New Orleans, LA. Abstract 151.

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