NEW ORLEANS – Modified T cells continue to show their mettle against treatment-refractory leukemias, based on study results presented at the annual meeting of the American Society of Hematology.
Among children and young adults with heavily pretreated relapsed or refractory acute lymphoblastic leukemia (ALL), chimeric antigen receptor (CAR) T cells targeted against the CD19 receptor produced complete responses in 10 of 16 patients, including 3 patients with primary, treatment-refractory ALL who had never previously been in remission, reported Dr. Daniel W. Lee III of the National Cancer Institute in Bethesda, Md.
"We were able to clear CNS [central nervous system] leukemia using CAR-T cells alone," Dr. Lee said.
Dr. Marco L. Davila
In a second study, CD19-targeted T cells induced molecular remissions in adults with B-lineage ALL refractory to chemotherapy, said Dr. Marco L. Davila from the cellular therapeutics center at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City.
The immunotherapy produced a complete response (CR) in 12 of 16 patients, and a complete molecular response (CRm) in 12.
Dr. Davila commented that CAR-T cell therapy appears to be a good therapeutic choice for relapsed/refractory B-ALL.
"Especially in light of the data that we see in indolent lymphomas, where the response rates have not been nearly as great, I would speculate that there may be something about this disease that makes it particularly well suited to the second-generation CAR-T cell therapy," he said.
In both studies, therapy with CAR-T cells served as a bridge to stem cell transplantation for several patients.
Different CAR-T flavors
Each research team used its own variation on CAR-T cell therapy. The NCI investigators collected peripheral blood mononuclear cells (PBMCs) from patients via apheresis and used a gamma retrovirus to introduce into effector cells a genetic sequence targeting the CD19 receptor on malignant cells. The NCI version also uses CD28 costimulatory signaling to boost cell-killing effects.
The patients are conditioned with fludarabine and cyclophosphamide, and the treated T-cells are reinfused into the patients 11 days after harvesting.
In the phase I study, 15 patients with relapsed or refractory ALL and 1 with diffuse large B-cell lymphoma were treated. Eight of the patients had undergone at least one hematopoietic stem cell transplant, and all had received total body irradiation. Four had previously received another form of immunotherapy. The patients had to have been at least 100 days post transplant, with no graft-vs.-host disease.
T-cell expansion and transduction was feasible in this heavily pretreated population. All but two patients had an adequate or good expression of CAR-T cells. These patients were treated nonetheless, and one went on to have a minimal-residual disease (MRD) negative response, Dr. Lee noted.
In all, 10 of the patients had complete responses: All of these patients had ALL, and three had never previously achieved a remission. The patient with non-Hodgkin’s lymphoma did not have a significant treatment response.
Of eight patients who were negative for MRD after therapy, six went on to have stem cell transplants, with no unexpected toxicities.
As in other CAR-T cell studies, the chief toxicities seen included grade 4 neutropenia lasting longer than 2 weeks in nine patients, and the cytokine-release syndrome in four patients (grade 3 in two patients and grade 4 in two patients). One patient with the cytokine-release syndrome had cardiac arrest but was successfully resuscitated.
The cytokine-release syndrome was found to be associated with interleukin-6 (IL-6) and could be ameliorated with the IL-6 blocking agent tocilizumab (Actemra). The severity of cytokine-release syndrome did not correlate with tumor burden, the researchers noted.
MSKCC Study
Dr. Davila and his colleagues used a slightly different CAR-T cell construction, also with CD28 costimulation, to treat B-ALL in adults who either had refractory or relapsed disease (MRD-positive) or who were in their first complete remission. Patients who were positive for the Philadelphia chromosome (Ph+) and those who had extramedullary disease, CNS leukemia, or were in relapse after allogeneic stem cell transplant were all eligible.
He presented data on 16 patients with B-ALL with long-term follow-up: 14 patients had a complete response, with an average time to complete response of 24.5 days.
Seven patients in the MSKCC study have gone on to allogeneic stem cell transplants; three patients in complete remission were not eligible for transplant because of medical contraindications, and one additional patient was being evaluated for transplant. There have been no post-transplant relapses to date, with the longest follow-up out to 2 years, Dr. Davila said.
As in the NCI study, the cytokine-release syndrome was a common toxicity. The investigators initially tried to manage it with steroids but found that it came at the cost of lymphotoxicity that caused a marked decline in serum T-cells. They subsequently switched to tocilizumab, which was effective at treating the syndrome without lymphotoxicity.