While allogeneic hematopoietic cell transplantation (alloHCT) is used in patients with advanced B-cell malignancies, it is not universally effective, and many relapse afterward. Donor lymphocyte infusions (DLIs) of un-manipulated allogeneic lymphocytes from the transplant donor may be used to treat B-cell malignancies that recur following alloHCT. Given the risk of graft-versus-host disease (GVHD), and the limited efficacy of DLI, patients with B-cell malignancies who progress after alloHCT need more treatment options.
In a study published in the Journal of Clinical Oncology, Jennifer N. Brudno, MD, from the National Cancer Institute, and colleagues found that allogeneic anti-CD19 chimeric antigen receptor (CAR) T cells can effectively treat these patients, inducing a complete remission (CR) in 30 percent of patients with advanced progressive B-cell malignancies without causing GVHD.
“Anti-CD19 CAR T cells can cause lasting remissions in a subset of patients with progressive B-cell malignancies after allogeneic stem cell transplantation,” James Kochenderfer, MD, investigator in the Experimental Transplantation and Immunology Branch of the National Institutes of Health and corresponding author on the study, told ASH Clinical News. “The fact that the CAR T cells caused remissions without chemotherapy clearly demonstrates the anti-malignancy activity of the CAR T cells.”
The phase I dose-escalation study included 20 patients treated between August 2010 and February 2015. Patients had measurable CD19+ B-cell malignancies including:
- chronic lymphocytic leukemia (CLL; n=5)
- diffuse large B-cell lymphoma (DLBCL; n=4)
- mantle cell lymphoma (MCL; n=5)
- Philadelphia chromosome (Ph)-negative ALL (n=4)
- Ph-positive ALL (n=1)
- follicular lymphoma (FL) that had transformed to DLBCL (n=1)
Patients had previously undergone human leukocyte antigen-matched sibling (n=13) or unrelated donor alloHCT (n=7). Chemotherapy and antibody therapies had to be stopped two weeks prior to CAR19 T-cell infusion. Disease stage was determined at least two weeks after the last therapy before CAR T-cell infusions, and patients were excluded if they had evidence of acute GVHD > grade 1 or moderate or severe chronic GVHD.
Patients received a median of four post-transplant lines of therapy prior to enrollment (range = 1-24), and at least two months elapsed between the most recent DLI and CAR19 T-cell infusion.
Subjects received a single infusion of CAR19 T cells obtained from the alloHCT donor’s T cells, and dose-escalation followed a standard, phase I, 3+3 design. Patients did not receive conditioning with chemotherapy prior to infusion.
Following CAR19 T-cell therapy, the overall response rate (ORR) was 40 percent, with eight patients achieving remission: six CRs and two partial remissions. Patients with acute lymphocytic leukemia (ALL) experienced the highest response rate, with four of five patients obtaining minimal residual disease-negative CR. The longest ongoing CR was reached in a patient with chronic lymphocytic leukemia (30 months), and, of the two partial remissions, one persisted for longer than 18 months. Eight patients had stable disease, with the longest duration of stable disease persisting for longer than 31 months following infusion.
“Many of the patients who obtained remission after CAR19 T-cell infusions did not obtain remission after standard DLIs that contained higher T-cell doses, which demonstrates that in some cases, CAR19 T-cell infusion is superior to standard DLI at eradicating malignancy,” Dr. Brudno and colleagues observed.
Peak blood CAR T-cell levels (measured by quantitative polymerase chain reaction) were higher among those who achieved remission compared with those who did not (p=0.001), “indicating that increasing the peak blood levels of CAR19 T cells in vivo is an important goal for future research,” the authors explained. Programmed cell death protein-1 (PD-1) expression, an inhibitory receptor expressed on T cells, was significantly elevated on CAR T cells after infusion, suggesting that administering PD-1 antagonists after CAR19 T-cell infusion might improve the rates of remission.
The researchers reported no findings of new-onset acute GVHD following CAR T-cell infusion, despite 14 patients (70%) having had a history of GVHD sometime after alloHCT and prior to enrollment. GVHD occurred in only two patients on the trial: A case of mild chronic ocular GVHD developed approximately two years after CAR19 T-cell infusion and a case of slowly worsening chronic mild GVHD.
The most commonly reported adverse events (AEs) included fever, tachycardia, and hypotension, which was similar to other trials assessing CAR T cells, the authors noted. Sixty percent of patients experienced grade 3/4 AEs, including an increase in serum creatine kinase in two patients that was associated with muscle pain and weakness.
Though the study is limited by its small sample size, Dr. Brudno and co-authors concluded that the findings “point toward a promising future when CAR T-cell therapy will be commonly used in transplant regimens to specifically target malignancy-associated antigens. CAR T cells could be administered as planned infusions along with or soon after stem cell infusions. Genetically targeted T cells will be an integral part of allogeneic transplant protocols to separate graft-versus-malignancy activity from GVHD.”
Follow-up is also limited, and the study had no comparison group.
Brudno JN, Somerville RP, Shi V, et al. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J Clin Oncol. 2016;34:1112-21.