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Donor-derived allogeneic T cells may cause regression of B-cell malignancies
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NEW ORLEANS — The infusion of donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells caused regression of highly treatment-resistant B-cell malignancies after allogeneic hematopoietic stem cell transplantation, according to study results presented at the ASH Annual Meeting and Exposition.
The infusions were not associated with graft-versus-host disease (GVHD), results showed.
James N. Kochenderfer
“Relapse of malignancy is a leading cause of death in patients undergoing allogeneic hematopoietic stem cell transplantation” James N. Kochenderfer, MD, of the experimental transplantation and immunology branch at NCI, said during a press conference. “B-cell malignancies persisting despite allogeneic stem cell transplantation are often treated with unmanipulated donor lymphocyte infusions. However, donor lymphocyte infusions have inconsistent efficacy and are associated with significant morbidity and mortality from GVHD.”
In the current study, Kochenderfer and colleagues genetically modified allogeneic T cells to express a chimeric antigen receptor (CAR) that targets CD19, a B-cell antigen. They obtained the T cells from healthy allogeneic HSCT donors.
The study included 10 patients; of them, four received HLA-matched unrelated donor transplants and six received HLA-matched sibling transplants. The patients were not lymphocyte-depleted at the time of the infusions.
Each patient received an infusion of anti-CD19 CAR T cells, the cell doses of which ranged from 1 x 106 T cells/kg to 10 x 106 T cells/kg. A mean of 58% of infused cells expressed the CAR.
To account for confounding effects, patients did not receive chemotherapy or anti-malignancy therapy with the infusions.
Two patients in the cohort had chronic lymphocytic leukemia (CLL) refractory to standard unmanipulated allogeneic lymphocyte infusions. Both of those patients had regressions of large malignant lymph node masses after the infusion. One achieved complete remission — which was ongoing 12 months post-infusion — and experienced complete eradication of blood B cells 9 days after the infusion.
One patient with tumor lysis syndrome and CLL that regressed in lymph nodes, bone marrow and blood 2 weeks after the anti-CD19 CAR T-cell infusion required treatment with rasburicase (Elitek, Sanofi-Aventis).
One patient with mantle cell lymphoma achieved partial remission that lasted 3 months after the infusion. One patient with diffuse large B-cell lymphoma achieved stable disease that was ongoing at 16 months.
The remaining six patients experienced short periods of stable malignancy or progressive disease.
Three of four patients with measurable blood B cells at baseline experienced specific eradication of blood B cells.
Kochenderfer and colleagues detected CAR T-cell levels from undetectable to 2.8% of peripheral blood mononuclear cells. CAR T cells persisted in the blood of patients for 1 month or less.
In ex vivo analysis, researchers also found elevated levels of the T-cell inhibitory molecule programmed cell death protein-1 on CAR-positive T cells compared with CAR-negative T cells.
Although six patients had previously developed GVHD after allogeneic HSCT, no patients developed GVHD after the cell infusion.
One patient with a history of cardiac dysfunction experienced temporary cardiac dysfunction.
Fever and hypotension were the most common toxicities. Two patients experienced grade 3 fever and two experienced grade 3 hypotension. The toxicities peaked 5 to 12 days after the cell infusion and resolved within 14 days.
Three patients who experienced toxicities also had elevated levels of serum interferon gamma.
Researchers observed no grade 4 toxicities.
“Allogeneic anti-CD19 CAR T cells have significant anti-malignancy activity when administered without prior chemotherapy,” Kochenderfer said. “There is significant patient-to-patient variation in efficacy and toxicity, but these results are scientifically interesting and promising for future development.”
For more information:
Kochenderfer JN. Abstract #151. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10; New Orleans.
Disclosure: The researchers report no relevant financial disclosures.