Updated findings from early stage clinical trials exploring chimeric antigen receptor-modified T-cell therapies continue to highlight the effectiveness of these approaches for patients with non-Hodgkin lymphoma.
Stephen J. Schuster, MD
Updated findings from early stage clinical trials exploring chimeric antigen receptor (CAR)-modified T-cell therapies continue to highlight the effectiveness of these approaches for patients with non-Hodgkin lymphoma (NHL), according to findings presented at the 2015 ASH Annual Meeting.
In the first study,1 the CD19-directed CAR T-cell therapy CTL019 demonstrated an overall response rate (ORR) of 73% and 47% in patients with follicular lymphoma and diffuse large B-cell lymphoma (DLBCL), respectively. Additionally, most of the partial responses (PR) observed at 3 months had converted to complete remissions (CR) after 6 months of follow-up.
In the second study,2 up to 82% of patients with NHL responded to the anti-CD19 CAR T-cell therapy JCAR014. Specifically in those with chronic lymphocytic leukemia (CLL), the ORR with JCAR014 plus fludarabine and cyclophosphamide lymphodepletion was 100%. The CR rate in this group was 57%.
"Chimeric antigen receptor modified T cells direct against CD19 can achieve durable responses in patients with relapsed or refractory CD19-positive diffuse large B cell and follicular lymphomas," said CTL019 lead investigator Stephen Schuster, MD, associate professor, Division of Hematology/Oncology at the University of Pennsylvania, Abramson Cancer Center. "All patients who achieved a CR remain in CR."
Novartis is developing CTL019 in collaboration with the University of Pennsylvania. This therapy has received a breakthrough therapy designation from that FDA for its potential as a treatment for pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia. Juno Therapeutics is developing JCAR014, along with a host of other CD19-targeted CAR T-cell therapies.
The study exploring CTL019 enrolled 43 patients: 26 with DLBCL, 14 with follicular lymphoma, and 3 with mantle cell lymphoma (MCL). Out of those enrolled, 13 were not infused with CTL019 due to progressive disease (n = 4), CTL019 production failure (n = 6), and consent withdrawal (n = 3). A majority of the withdrawals were in the DLBCL arm.
Of the remaining patients, 15 with DLBCL, 13 with follicular lymphoma, and 2 with MCL received CTL019 at 1.0 to 5.0 e8. Patients also received lymphodepletion using a variety of methods and agents.
In the DLBCL group, the complete response rate was 40% at 6 months. At a 3-month analysis, there were 4 PRs, 3 of which converted to CRs with longer follow-up. The median progression-free survival (PFS) was 3.0 months.
In evaluable patients with follicular lymphoma (n = 11), the CR rate was 64%. There were 3 patients with a PR at 3 months who converted to a CR with longer follow-up. The median PFS was 11.9 months.
The most common grade ≥3 adverse events (AEs) seen in the trial were lymphopenia (18%), neutropenia (14%), thrombocytopenia (6%) and anemia (5%). The rates of grade ≥3 AEs of interest with CTL019 were low. Grade ≥3 cytokine release syndrome (CRS) occurred in 4% of patients, encephalitis in 1%, and delirium in 2%.
"The toxicity of this therapeutic approach appears acceptable. Cytokine release syndrome was generally grade 2, and there were no deaths," said Schuster. "We look forward to continuing this study, to further understand longer-term patient response."
For the JCAR014 study, data were assessable for 30 patients with NHL and 9 patients with CLL. Lymphodepletion therapy consisted of cyclophosphamide plus fludarabine. CAR T cells were manufactured from CD4+ and CD8+ T cells and were dosed at 2x105/kg (dose 1; n = 3), 2x106/kg (dose 2; n = 11), and 2x10/7/kg (dose 3; n = 4). Additionally, 12 patients in the NHL group and 2 in the CLL arm received various doses but did not receive lymphodepletion.
The CR rate was 33%, 64%, and 25% for dose 1, 2, and 3, respectively. Across all doses without lymphodepletion, the CR rate was 8%. The ORR rate across doses 1, 2, and 3, respectively, was 22% 82%, and 75%. Without lymphodepletion, the ORR was 50%. The median PFS with lymphodepletion was 3.1 months with doses 1 and 2 versus 1.5 months without lymphodepletion.
"CD19 CAR T-cells of defined subset composition have potent antitumor activity in refractory NHL and CLL," said lead investigator Cameron J. Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center. "Optimization of lymphodepletion improves CAR T-cell peak and persistence and clinical outcomes in NHL patients."
None of the non-lymphodepleted patients with CLL experienced a CR. The ORR in this group was 50%. In the absence of lymphodepletion, there were no occurrences of CRS or neurotoxicity versus 14% and 43%, respectively, for those in the lymphodepletion arms.
For those with NHL, severe CRS did not occur in the arms without lymphodepletion and for those treated with the lowest dose of JCAR014. In the 2x106 dose, 9% of patients experienced severe CRS. In the largest dose arm, the rate of severe CRS was 50%. Severe neurotoxicity was seen in 33%, 18%, and 67% of patients treated with dose 1, 2, and 3, respectively. In the non-lymphodepletion arm, the neurotoxicity rate was 17%.
"In conjunction with cyclophosphamide and fludarabine lymphodepletion, the defined composition strategy facilitates identification of relationships between infused CAR T-cell dose, efficacy, toxicity, and correlative biomarkers," Turtle said. "This enables the development of a more consist and safe approach for CAR T-cell immunotherapy."
A number of clinical trials continue to assess novel CAR T-cell therapies for patients with NHL. In addition to the therapies manufactured by Juno and Novartis, a host of other companies are exploring this treatment approach. At this time, none of these therapies have gained FDA approval. However, some analysts project a regulatory decision as soon as 2017.