Results of the phase I Transcend study show that lisocabtagene maraleucel (also known as JCAR017), an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product being developed by Juno Therapeutics, causes low incidence of all grade and severe cytokine release syndrome and neurological events and can lead to rapid and durable remission among patients with high-risk aggressive relapsed or refractory diffuse large B-cell lymphomas (DLBCL).
The standard of care for the treatment for DLBCL, curing approximately 60% of patients for more than 2 decades is called R-CHOP (a combination of rituximab (R), cyclophosphamide (C), doxorubicin hydrochloride (H), Vincristine (O; Oncovin) and Prednisone (P). However, the optimal treatment of patients who are too frail to tolerate this regimen and/or are not candidates for anthracycline therapy continues to be a concern. As a result, researchers are investigating novel treatment options.
Among the possible new treatment options is lisocabtagene maraleucel. If approved, this drug will be the third autologous CAR-T therapy to reach the market for DLBCL market following the launches of approved CAR-T drugs tisagenlecleucel (Kymriah®; Novartis) and axicabtagene ciloleucel (Yescarta®; Gilead).
Chimeric antigen receptor (CAR) T-cell Therapy
CAR T-cells are generally engineered from a patient’s own T-cells to identify target antigens and trigger an immune response. As an initial step, T cells are collected via leukapheresis and then sent to a manufacturing site where they are genetically modified with either a retroviral or lentiviral vector to express a specific CAR. After manufacturing, CAR T-cells are shipped back to the treatment center and generally administered as a single dose.[1]
In the weeks after being dosed, patients need to be monitored for life-threatening treatment-emergent side effects. But long-term follow-up after may also be required.[2]
CAR T-cell therapy involves the infusion of T-cells that have been genetically engineered to express a chimeric antigen receptor to reprogram the T-cells. These CARs combines the specificity of an antibody with the cytotoxic and memory functions of T-cells.[3][4][5][6][7]
CAR specificity comes from the extracellular domain, which is derived from the antigen-binding site of a monoclonal antibody. The intracellular domain attempts to recapitulate the normal series of events by which T-cells are activated and incorporates stimulatory and costimulatory domains to augment CAR T-cell survival and proliferation.
Meaningful activity
In clinical studies, clinically meaningful activity was noted across populations with major unmet medical needs, including uncommon histological subtypes and patients with characteristics of poor prognosis.
The study findings were published by Jeremy S. Abramson, M.D., at the Massachusetts General Hospital and Director, Jon and JoAnn Hagler Center for Lymphoma, Associate Professor of Medicine, Harvard Medical School, Boston, MA, and colleagues on 1 September 2020 in The Lancet.[8]
Lisocabtagene maraleucel
Lisocabtagene maraleucel is an investigational, autologous, CD19-directed CAR T-cell product with a 4-1BB co-stimulatory domain, which is administered as a sequential infusion of two components (CD8+ and CD4+ CAR+ T-cells) at equal target doses.
In the seamless design Transcend NHL 001 study, the study team aimed to assess the safety and activity of lisocabtagene maraleucel in a broad population of patients with relapsed or refractory large B-cell lymphomas, including lymphomas with diverse histological features and patients with aggressive disease and high-risk features. Preliminary data from the dose-finding portion of the study showed a promising risk: benefit ratio after lisocabtagene maraleucel infusion. Therefore, additional expansion cohorts were enrolled via seamless design.
In the article published in The Lancet, the Abramson and colleagues reported the results from the entire cohort with large B-cell lymphoma included in the Transcend study.
Eligible histological subgroups included diffuse large B-cell lymphoma, high-grade B-cell lymphoma with rearrangements of MYC, and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed from any indolent lymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma grade 3B.
Patients were assigned to one of three target dose levels of lisocabtagene maraleucel as they were sequentially tested in the trial (50 × 106 CAR+ T-cells one or two doses, 100 × 106 CAR+ T-cells, and 150 × 106 CAR+ T-cells), which were administered as a sequential infusion of two components (CD8+ and CD4+ CAR+ T-cells) at equal target doses.
Primary endpoints of the study were adverse events, dose-limiting toxicities, and the objective response rate assessed per Lugano criteria. The endpoints were assessed by an independent review committee in the efficacy-evaluable set comprising all patients who had confirmed PET-positive disease and received at least one dose of lisocabtagene maraleucel.
In total, 344 patients underwent leukapheresis for the manufacture of lisocabtagene maraleucel, of whom 269 patients received at least one dose. Patients had received a median of three previous lines of systemic treatment with 260 patients (97%) having had at least two lines. There were 112 patients (42%) who were aged 65 years or older, 181 patients (67%) had a chemotherapy-refractory disease, and 7 patients (3%) had secondary CNS involvement.
Median follow-up for overall survival for all 344 patients who had leukapheresis was 18.8 months (95% confidence interval [CI] 15.0–19.3).
Overall safety and activity of lisocabtagene maraleucel did not differ by dose level. The recommended target dose was 100 × 106 CAR+ T-cells (50 × 106 CD8+ and 50 × 106 CD4+ CAR+ T-cells).
Of 256 patients included in the efficacy-evaluable set, an objective response was achieved by 186 patients (73%) and a complete response (CR) by 136 patients (53%).
The most common grade 3 or worse adverse events were neutropenia in 161 patients (60%), anemia in 101 patients (37%), and thrombocytopenia in 72 patients (27%). Cytokine release syndrome and neurological events occurred in 113 patients (42%) and 80 patients (30%), respectively. Grade 3 or worse cytokine release syndrome and neurological events occurred in 6 patients (2%) and 27 patients (10%), respectively. Nine patients (6%) had dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50 × 106 CAR+ T-cells.
Abramson and colleagues wrote that since 2017, the treatment landscape in third-line or later therapy for large B-cell lymphomas has changed with approval of two CD19-directed CAR T-cell products, axicabtagene ciloleucel, and tisagenlecleucel. Both CAR T-cell treatments have shown high response rates and durable remission in patients with relapsed or refractory large B-cell lymphomas. However, severe CAR T-cell-related toxicities, including cytokine release syndrome and neurological events, have challenged clinical management of these patients.
Other studies
The Transcend study enrolled a broad range of patients with relapsed or refractory large B-cell lymphomas, compared with study populations of the previous ZUMA-1 and JULIET trials, including B-cell lymphomas with diverse histological features and patients with low creatinine clearance or poor cardiac function, and high-risk features such as CNS involvement. Additionally, patients could receive bridging therapy during the lisocabtagene maraleucel manufacturing process.
The Transcend study is the largest clinical study reported to date of CD19-directed CAR T-cell treatment for patients with relapsed or refractory large B-cell lymphomas. The study data build on those from previous studies of CAR T-cell treatment in large B-cell lymphomas.
Clinically meaningful activity was noted across various patient subgroups, with low rates of grade 3 or worse cytokine release syndrome and neurological events. These data support the use of CAR T-cell treatment in patients with multiple subtypes of large B-cell lymphoma, who have high-risk features, including older patients and those who have moderate comorbidities.
Lisocabtagene maraleucel is under further evaluation at first relapse in large B-cell lymphomas and as a treatment for other relapsed or refractory B-cell malignancies.
The study was funded by Juno Therapeutics, a Bristol-Myers Squibb company.
Clinical Trial
Study Evaluating the Safety and Pharmacokinetics of JCAR017 in B-cell Non-Hodgkin Lymphoma (TRANSCEND-NHL-001) – NCT02631044
Study Evaluating Safety and Efficacy of JCAR017 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) – NCT03331198
Reference
[1] Boyiadzis MM, Dhodapkar MV, Brentjens RJ, et al. Chimeric antigen receptor (CAR) T therapies for the treatment of hematologic malignancies: clinical perspective and significance. J Immunother Cancer. 2018;6(1):137. Published 2018 Dec 4. doi:10.1186/s40425-018-0460-5
[2] Maus MV, Levine BL. Chimeric Antigen Receptor T-Cell Therapy for the Community Oncologist. Oncologist. 2016;21(5):608-617. doi:10.1634/theoncologist.2015-0421
[3] Dotti G, Gottschalk S, Savoldo B, Brenner MK. Design and development of therapies using chimeric antigen receptor-expressing T cells. Immunol Rev. 2014;257(1):107-126. doi:10.1111/imr.12131
[4] Sadelain M, Brentjens R, Rivière I. The basic principles of chimeric antigen receptor design. Cancer Discov. 2013;3(4):388-398. doi:10.1158/2159-8290.CD-12-0548
[5] Ajina A, Maher J. Strategies to Address Chimeric Antigen Receptor Tonic Signaling. Mol Cancer Ther. 2018;17(9):1795-1815. doi:10.1158/1535-7163.MCT-17-1097
[6] Maus MV, June CH. Making Better Chimeric Antigen Receptors for Adoptive T-cell Therapy. Clin Cancer Res. 2016;22(8):1875-1884. doi:10.1158/1078-0432.CCR-15-1433
[7] Kawalekar OU, O’Connor RS, Fraietta JA, et al. Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells [published correction appears in Immunity. 2016 Mar 15;44(3):712. Snyder, Nathaniel [corrected to Snyder, Nathaniel W]; Blair, Ian [corrected to Blair, Ian A]] [published correction appears in Immunity. 2016 Mar 15;44(3):712]. Immunity. 2016;44(2):380-390. doi:10.1016/j.immuni.2016.01.021
[8] Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. The Lancet; Published online 1 September 2020. DOI: https://doi.org/10.1016/S0140-6736(20)31366-0
Featured image: Research and development at Juno Therapeutics, a Bristol-Myers Squibb company. Photo courtesy: © 2020 Juno Therapeutics, a Bristol-Myers Squibb. Used with permission.
 T-cell, causes low incidence cytokine release syndrome.){kind=link}