Leo I. Gordon MD
The CAR T-cell therapy JCAR017 induced an objective response rate (ORR) of 80%, including a complete response rate of 60% in patients with relapsed or refractory CD19-positive non-Hodgkin lymphoma, according to findings from the phase I TRANSCEND trial,
“This is an important, exciting, and possibly new paradigm for treating lymphoma but the data are still early,” explained Leo I. Gordon MD, director of the Lymphoma Program in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine.
Data presented at ASH show that severe cytokine release syndrome (CRS) has not been experienced by any of the patients enrolled in the trial, although 36% of patients had grade 1/2 CRS. Fourteen percent of patients had neurotoxicity, which had resolved in all patients evaluable for resolution.
In December 2016, the FDA granted JCAR017 a breakthrough therapy designation for aggressive large B-cell lymphoma.
In an interview with OncLive, Gordon, an investigator on the TRANSCEND study discusses the trial results and the next steps with CAR T-cell therapy in non-Hodgkin lymphoma.
OncLive: Please discuss the enrollment criteria and patient characteristics for the phase I TRANSCEND study.
Gordon: This study enrolled patients with aggressive large B-cell lymphoma, primarily DLBCL, who have refractory disease or have progressed after at least 2 lines of therapy or after autologous or allogeneic stem cell transplant. We have reported on 28 patients that were treated with JCAR017, with the median age of 63. The median number of prior therapies was 4, 82% were refractory to their last chemotherapy-containing regimen, only 46% had previously had an autologous stem cell transplant, 14% had had an allogeneic transplant, and 14% had poor performance status with an ECOG of 2. This shows the enrolled patient population is a very difficult patient population to treat with few or no options for available effective therapies.
What is the current standard treatment for these patients?
There is no standard of care in the third-line for these patients. Most patients enroll on clinical trials or receive various chemotherapy regimens that result in low rates of response and overall survival.
What was the design and efficacy of the TRANSCEND study?
It is a phase I dose escalation study of JCAR017, a 4-1BB defined-composition CAR T-cell product that is administered in a 1:1 ratio of CD4+ and CD8+ CAR T cells. After dose escalation, the trial will enroll expansion cohorts at safe and effective doses. The best overall response rate to JCAR017 in the DLBCL cohort at the first dose level was 80% with 60% achieving a complete response. Patients who were chemotherapy refractory or had very high-risk disease, including double- and triple-hit lymphoma, had similar high rates of overall and complete response. Of 19 patients who had been treated more than 3 months previously, 42% remained in response, which is very encouraging.
How was the adverse event profile?
Rates of severe toxicities were lower with JCAR017 than others have reported with anti-CD19 CAR T cells. Neurotoxicities were experienced in only 5 out of 28 (18%) patients. Of those 5 patients, 4 experienced grade 3 or 4 neurotoxicity, including seizure and encephalopathy. All patients evaluable for neurotoxicity resolution (4 of 5) had recovered and we are continuing to have patients treated on this trial. There were no deaths on study prior to progression of lymphoma.
How was the incidence of cytokine release syndrome—were there any severe cases?
There were no severe cases of cytokine release. 10 patients, about 36%, had low-grade CRS. Only 1 patient received tocilizumab and steroids for grade 2 CRS.
What are the next steps with this research?
We have escalated cell dose to investigate whether more cells will result in a higher number of complete remissions and more durable responses. Our data suggest that those patients with higher levels of CAR T cell expansion have a better chance of a longer remission, thus by escalating cell dose we hope to optimize the dose of cells. We then plan to enroll a larger cohort of patients in a phase II expansion study. Due to the low rates of CRS and neurotoxicity, we will start to investigate giving lympho-depletion and JCAR017 in the outpatient setting with close follow-up.
Are there combination regimens that will be explored with JCAR017?
A combination study of various agents combined with JCAR017 is under development, but we first have to establish a safe dose with this treatment as a monotherapy.
How does CAR T-Cell therapy compare with PD-1 inhibition in non-Hodgkin lymphoma?
In non-Hodgkin lymphoma, the response rates with checkpoint inhibitors are encouraging. However rates of complete response are low. JCAR017 contains cells that are directly targeting CD19 and have the potential to work in most patients since they do not rely on endogenous, tumor-reactive T cells. With these early studies, the rates of complete remissions with CAR T cells appears to be higher. The checkpoint inhibitors free up a patient’s own lymphocytes to attack tumor cells but they are not necessarily targeted to an epitope on the tumor cells.
Ultimately, we might need the combination with checkpoint inhibitors in some patients. Central memory T cells are enhanced with checkpoint inhibitors, and this may enable better long-term activity of CAR T cells. Theoretically, if you want to maintain CAR T cells for a long period of time, checkpoint inhibitors might allow you to do so.
Is there anything else you would like to add on JCAR017 or about CAR T-Cell therapy in general?
It's an important, exciting, and possibly new paradigm for treating lymphoma but the data are still early and in evolution. In the future we need to test whether it's better than the standard treatment in earlier lines of therapy, such as autologous stem cell transplant; it might be a bridge to transplant or it might be a replacement. The standard therapy is still either autologous or allogeneic transplant and until we have more data, this remains under investigation.