Chimeric antigen receptor-modified T-cell therapies continue to demonstrate promising signs of efficacy for patients with hematologic malignancies, including those with acute lymphoblastic leukemia and non-Hodgkin lymphoma.
Stephan Grupp, MD, PhD
Chimeric antigen receptor (CAR)-modified T-cell therapies continue to demonstrate promising signs of efficacy for patients with hematologic malignancies, including those with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL), according to data from several early phase trials.
For patients with ALL, CD19-targeted CAR-modified T-cells have demonstrated complete response (CR) rates ranging from 90% to 100%.1,2 Additionally, for those with NHL, the CR rates are approximately 60% for patients treated with anti—CD19 CAR T cell therapies.4,5 Moreover, studies are beginning to identify effective management techniques for cytokine release syndrome (CRS), which is an indicator of effectiveness for this class of medication.
There are currently a number of therapies in development, including CTL019, which is furthest along in development and has received a breakthrough therapy designation from that FDA for its potential as a treatment for pediatric and adult patients with relapsed/refractory ALL. This therapy has been assessed across numerous settings, including ALL, NHL, and multiple myeloma.In a phase II study exploring CTL019,1 which is being developed by the University of Pennsylvania and Novartis, 59 patients with CD19-positive ALL received treatment with the modified T-cells at a median 4.3x106 cells/kg over 1 to 3 days. One week prior to treatment with CTL019, a majority of patients received lymphodepleting chemotherapy.
In this study, CTL019 demonstrated a 93% CR rate in pediatric patients with relapsed/refractory ALL. After a median follow-up of 12 months, 79% of patients enrolled in the trial remained alive. Additionally, the relapse-free survival rate was 76% and 55% at 6 and 12 months, respectively.
Of those who responded, 6 went on to receive subsequent stem cell transplantation and 18 patients remained in CR for more than 1 year. There were no relapses past the 1-year mark.
“This clinical trial of CTL019 is the largest study of a CAR-T therapy in pediatric patients with relapsed or refractory acute lymphoblastic leukemia, and it is helping us better understand the therapy's potential to achieve durable responses in this patient population,” said lead investigator Stephan Grupp, MD, PhD, the Yetta Deitch Novotny Professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.
Overall, 88% of patients experienced grade 1 to 4 CRS with CTL019. The severity of CRS was related to tumor burden and coincided with response. Overall, 27% of patients with CRS developed hemodynamic or respiratory instability that was reversed by IL-6 receptor antagonist.
“With each child we treat as part of this trial, we learn more about the potential of CTL019 to help patients whose cancers cannot be controlled with conventional therapies,” said Grupp. “The response rate and durability we are seeing are unprecedented, and gives us hope that personalized cellular therapies will be a powerful key to long-term control of this difficult cancer.”
In a second trial,2 which was conducted by the National Cancer Institute (NCI) and Kite Pharma, a CD19 CAR T-cell therapy showed a 100% CR rate in 9 patients with primary refractory ALL and for 5 patients with CNS ALL. All patients who achieved a CR also tested negative for minimal residual disease (MRD). Those with Philadelphia chromosome-positive and downs syndrome-related ALL experienced an MRD-negative CR rate of 60% and 67%, respectively.
All patients responding with primary refractory ALL went on to receive a stem cell transplant. At the time of the analysis, all patients remained alive and 88.9% remained disease-free (range 5-28 months). A response was not seen for patients with MLL rearranged ALL (n = 2).
“There was a 60% complete response rate in this ultra-high risk ALL population and a 100% MRD-negative response rate in primary refractory and CNS leukemia," said lead investigator Daniel W. Lee III, MD, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute. “This treatment was a bridge to transplant in refractory patients.”
An early intervention algorithm developed by the NCI was utilized to prevent CRS. Under this grade-driven system, those with grade 1 CRS received vigilant supportive care. For grade 2 CRS, if the patient had extensive comorbidities or an older age, and for those with grade 3 or 4 CRS, tocilizumab was initiated with or without corticosteroids along with supportive care.
Using this system, there were no grade 3 incidences of CRS and 1 grade 4 event (4%). Overall, there were no severe or permanent neurologic toxicities and no neurocognitive declines, in patients responding to therapy. “Institution of the grade-driven algorithm reduces life-threatening CRS,” said Lee.In a study exploring CTL019,3 43 patients were enrolled with a variety of NHL subtypes, including 26 with diffuse large B-cell lymphoma (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.
Overall, CTL019 demonstrated an overall response rate (ORR) of 73% and 47% in patients with follicular lymphoma and DLBCL, respectively. In the DLBCL group, the CR 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.
“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.”
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 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.”
In a second study, which assessed the anti—CD19 CAR T-cell therapy JCAR014,4 data were assessable for 30 patients with NHL and 9 patients with chronic lymphocytic leukemia (CLL). Lymphodepletion therapy consisted of cyclophosphamide plus fludarabine.
In this study, up to 82% of patients with NHL responded to JCAR014. Specifically in those with CLL, the ORR with JCAR014 plus fludarabine and cyclophosphamide lymphodepletion was 100%. The CR rate in this group was 57%. In patients with CLL who did not received lymphodepletion, the CR rate was 0%. The ORR in this group was 50%.
“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.”
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 across subtypes of NHL, severe CRS did not occur in the arms without lymphodepletion and for those treated with the lowest dose of JCAR014.
“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.Data have been published in The New England Journal of Medicine (NEJM) showing the efficacy of CTL019 in refractory multiple myeloma.5 Traditionally, CD19 has not been considered a target for treatments in multiple myeloma, due to low levels of expression on dominant cells. However, researchers hypothesized that CD19-positivity on minor subsets and very low levels of CD19 expression on the dominant cells could be ample to elicit responses.
In the ongoing study, patients received high-dose melphalan with autologous stem cell transplantation (ASCT) followed 12 to 14 days later by an infusion of 1 to 5x107 cells of CTL019. One patient in this study experienced an exceptional response to therapy, which was published in NEJM.
The single-patient case study followed a 48 year-old female with a complex karyotype, t(4;15), TP53 deletion, and +1q. She had received 10 prior therapies after being diagnosed at the age of 43, including vorinostat, elotuzumab, proteasome inhibitors, and immunomodulatory agents.
Treatment with CTL019 caused a rapid decline in immunoglobulin and by day 130 she met the criteria for a stringent CR. Moreover, 12 months after ASCT, there was no evidence of monoclonal immunoglobulin and no clinical signs or symptoms of multiple myeloma (MRD-negativity). No significant toxicities were observed with CTL019, and the patient did not develop cytokine release syndrome.