ORLANDO – A single infusion of donor-derived chimeric antigen receptor (CAR)-modified T cells targeting CD19 achieved remission in 9 of 20 patients with B-cell malignancies that progressed after allogeneic stem cell transplant, a study shows.
The seven complete remissions and two partial remissions occurred without any chemotherapy and without causing acute graft-versus-host disease (GVHD).
Dr. James Kochenderfer
The experimental anti-CD 19 CAR T-cells seem particularly effective against acute lymphoid leukemia (ALL) and chronic lymphocytic leukemia (CLL), but responses also occurred in lymphoma, Dr. James Kochenderfer of the Center for Cancer Research, National Cancer Institute, in Bethesda, Md., reported at the annual meeting of the American Society of Hematology.
B-cell malignancies that persist after transplantation are often treated with unmanipulated donor lymphocytes, but these infusions are often ineffective and associated with significant morbidity and mortality from GVHD.
To improve on this approach, 20 patients were infused with T cells obtained from the original stem cell donor and transduced with a CD19-directed CAR that was encoded by a gamma-retroviral vector and included a CD28 co-stimulatory domain. The highest dose reached in the phase I study was 107 total cell/kg. Production of the anti-CD19 CAR T cells took only eight days for each patient, Dr. Kochenderfer said at a press briefing.
The patients had received at least one standard donor-leukocyte infusion, had to have minimal or no GVHD, and could not be receiving systemic immunosuppressive drugs.
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The highest response rates were in ALL, where four of five patients obtained complete remission (CR) with no detectable minimal residual disease by multi-color flow cytometry, Dr. Kochenderfer said. Two of these patients later relapsed, one is in ongoing CR at 18 months, and one went on to a second allogeneic transplant and continues in complete remission.
The longest ongoing CR at 36 months occurred in a patient treated for CLL. Another patient achieved a partial remission (PR) ongoing at 18 months, two patients progressed, and one has stable disease.
In five patients treated for Mantle cell lymphoma, there is one CR ongoing at 31 months, one PR, and three stable diseases.
Three of the five patients treated for diffuse large B-cell lymphoma experienced stable disease, one progressive disease, and one obtained a CR, but is no longer evaluable because she received other therapies for chronic GVHD. Dr. Kochenderfer went on describe an impressive response in this patient, who had large lymphoma masses at the back of her head and in her eye socket before infusion.
“Amazingly, the tumor masses completely disappeared within five days of CAR T-cell infusion,” he said.
Patients with high tumor burdens, however, experienced severe cytokine-release syndrome with fever, tachycardia, and hypertension that was treated with the interleukin-6 receptor antagonist tocilizumab (Actemra).
Only one case of mild aphasia occurred, which contrasts with other CAR T-cell therapies where neurotoxicity is common, Dr. Kochenderfer said.
One patient had continued worsening of pre-existing chronic GVHD after CAR T-cell therapy, and one patient developed very mild chronic eye GVHD more than a year after infusion.
The press corps was not fully convinced by the findings, however, asking Dr. Kochenderfer why they should be excited by the 40% remission rate when other CAR T-cell therapies have yielded remission rates as high as 90%.
Dr. Kochenderfer pointed out that four of the five ALL patients (80%) achieved a MRD-negative complete response, which compares favorably with other protocols. The remaining patients had far more advanced, treatment-resident disease of varying histologies than evaluated in other trials and, unlike most trials, all patients had received an allogeneic transplant. Further, the investigators used no chemotherapy whatsoever, whereas other CAR T-cells trials have used chemotherapy, sometimes in huge does, he said.