Donor-derived Anti-CD19 CAR T cells Show Promise Against Post-transplant B-cell Malignancies
NEW ORLEANS—Genetically modified donor-derived anti-CD19 chimeric antigen receptor (CAR)-expressing T-cell infusions were followed by regression of B-cell malignancies that had persisted after allogeneic hematopoietic stem cell transplantation (alloHSCT), according to research reported at the 55th American Society of Hematology Annual Meeting and Exposition.
“The results show for the first time that small numbers of donor-derived allogeneic anti-CD19-CAR T cells can cause regression of highly treatment-resistant B-cell malignancies after alloHSCT without causing GVHD,” reported James Kochenderfer, MD, of the National Cancer Institute's Experimental Transplantation and Immunology Branch in Bethesda, MD, and coauthors. “Malignancies that were resistant to standard DLIs (donor lymphocyte infusions) regressed after anti-CD19-CAR T cell infusions.”
Progressive B-cell malignancy is a leading cause of death among patients who undergo alloHSCT, the authors noted.
The authors enrolled 10 patients who were not lymphocyte-depleted to receive allogeneic T cells that had been genetically modified to express a CAR that targets the B-cell antigen CD19. Of the 10 patients, four had received human leukocyte antigen (HLA)-matched unrelated donor (URD) transplants and six had received HLA-matched sibling transplants, the coauthors reported.
Patients were administered a single infusion of the modified anti-CD19-CAR T cells, with doses ranging from 1x106 to 10x106 T cells/kg, and an average of 58% of infused cells expressing the CD19-targeting CAR. Patients were not administered chemotherapy or other treatment with the infusions.
Three patients with chronic lymphoblastic leukemia (CLL) refractory to standard DLIs “had regressions of large malignant lymph node masses after infusion of allogeneic anti-CD19-CAR T cells,” Dr. Kochenderfer noted. “One of these CLL patients obtained a complete remission that is ongoing 12 months after treatment…This patient also had complete eradication of blood B cells within 9 days after her CAR-T-cell infusion.”
Another patient experienced tumor lysis syndrome necessitating rasburicase treatment. “His CLL dramatically regressed in lymph nodes, bone marrow, and blood within 2 weeks of his anti-CD19-CAR-T-cell infusion.”
Six other patients “all had short periods of stable malignancy or progressive disease” after infusions, Dr. Kochenderfer said.
“We detected cells containing the anti-CD19-CAR gene in the blood of eight of 10 patients,” the coauthors reported. “The peak blood levels of CAR T cells varied from undetectable to 2.8% of peripheral blood mononuclear cells. The persistence of the CAR T cells in the blood of patients was limited to 1 month or less. When we assessed T cells from the blood of patients ex vivo, we found elevated levels of the T-cell inhibitory molecule programmed cell death protein-1 (PD-1) on CAR-positive T cells compared to CAR-negative T cells.”
Even though six of 10 participants had a history of previous GVHD, no patients developed GVHD after the anti-CD19-CAR T-cell infusions. Toxicities included fever and hypotension, peaking 5 to 12 days after infusion, and resolved within 14 days, the coauthors reported. Two patients suffered grade 3 fevers, and two had grade 3 hypotension. Serum interferon gamma elevations were noted in three patients at the time of post-infusion toxicity.
Future goals for developing this approach include “enhancing the persistence of anti-CD19-CAR T cells and reducing toxicities,” the coauthors noted. “Infusion of allogeneic T cells genetically modified to recognize malignancy-associated antigens is a promising approach for treating residual malignancy after alloHSCT.”