Treatment with allogeneic antiâ€“CD19 chimeric antigen receptorâ€“modified T cell therapy induced complete remissions in 30% of patients with advanced progressive B-cell malignancies without causing graft-versus-host disease.
Andre Goy, MD
Allogeneic anti—CD19 chimeric antigen receptor (CAR)—modified T cell therapy induced complete remissions (CR) in 30% of patients with advanced progressive B-cell malignancies without causing graft-versus-host disease (GVHD), according to findings from a phase I study published in the Journal of Clinical Oncology.
In the study, which was led by the National Cancer Institute, the overall response rate (ORR) with the CAR T-cell therapy was 40%, consisting of 2 partial remissions and 6 CRs. The most promising responses were experienced by patients with acute lymphoblastic leukemia (ALL), which coincides with prior experiences with CAR T-cell therapies. In this group (n = 5), 80% of patients experienced a minimal residual disease (MRD)-negative CR with the CAR T-cell therapy.
“Results of the study demonstrate that infusion of anti-CD19 CAR-T cells–targeted donor lymphocyte infusions–holds great promise in treating B-cell cancers recurring post transplantation," study co-author Andre Goy, MD, MS, chairman, John Theurer Cancer Center, and Chief, Division of Lymphoma, HackensackUMC, said in a statement. "Particularly impressive were the durable responses observed without GVH exacerbation and much less infusion-related toxicities. I believe this could play a key role in the future of allogeneic stem cell transplantation.”
The phase I dose escalation study enrolled 20 patients with CD19-positive B-cell malignancies who had received prior treatment with allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-matched sibling (n = 13) or unrelated donor (n = 7). A majority of patients had received a single prior allogeneic transplant (n = 17).
All patients received a single infusion of CAR-modified T-cells that were manufactured from the donor's T cells. A median of 67.3% of infused T-cells expressed an anti—CD19 CAR. A maximum-tolerated dose for the CAR T-cell infusion was not reached, with CAR-expressing T-cell doses ranging from 0.4 x 106 cells/kg to 8.2 x 106 cells/kg. Conditioning with chemotherapy was not administered before CAR T-cell infusion.
The average age of patients in the study was 48 years (range, 20-68). The B-cell malignancies included chronic lymphocytic leukemia (n = 5; CLL), diffuse large B-cell lymphoma (n = 4; DLBCL); mantle cell lymphoma (n = 5; MCL), Philadelphia chromosome (Ph)-negative ALL (n = 4), Ph-positive ALL (n = 1), and follicular lymphoma that had transformed to DLBCL (n = 1). Prior to the T-cell infusion, 12 patients had progressive disease, 4 had stable disease, 2 were in partial remission, and 2 were relapsing.
Six patients experienced CRs, including 4 with MRD-negative responses. The longest duration of CR was more than 30 months. Of the 2 partial remissions, 1 persisted for longer than 18 months. Overall, 8 patients had stable disease, with the longest duration of stable disease persisting for longer than 31 months following infusion. Four patients experienced progressive disease following infusion.
The absolute numbers of CAR+ T-cells in the blood was assessed using quantitative polymerase chain reaction before infusion and at multiple time points after infusion. Overall, high peak blood levels of CAR T-cells were associated with remissions (P = .001). Additionally, those with a higher CD8 to CD4 ratio were more likely to respond to therapy (P = .007).
New onset acute GVHD did not occur in any patients following CAR T-cell infusion, despite the occurrence of prior GVHD for 70% of patients. Approximately 2 years after infusion, 1 patient developed mild chronic ocular GVHD. Additionally, another patient had slowly worsening chronic mild GVHD, which existed prior to infusion and slowly worsened following treatment.
Adverse events (AEs) in the trial were similar to previous observations for CAR T-cell therapies. The most commonly observed AEs were consistent with cytokine release syndrome, including fever, tachycardia, and hypotension. Grade 3/4 AEs were experienced by 60% of patients, including an increase in serum creatine kinase in 2 patients that was associated with muscle pain (n = 2) and weakness (n = 1).
“Keep in mind that these patients had failed all standard therapies and went on to allogeneic transplant, which is considered a last-chance therapy for these patients, and continued with progressive malignancy after that,” said lead investigator James N. Kochenderfer, MD, of the NCI’s Experimental Transplantation and Immunology Branch, when he presented findings from the trial at the 2015 ASH Annual Meeting. “It’s a very, very high-risk patient population.”
A number of clinical trials from a host of companies continue to assess novel CAR T-cell therapies for patients with B-cell malignancies. However, at this time, none of these therapies have gained FDA approval.
Brudno JN, Somerville RPT, 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 [published online January 25, 2016]. J Clin Oncol. 2016:doi: 10.1200/JCO.2015.64.5929.