Bone Marrow Transplantation | 2019
Rapid tumor regression from PD-1 inhibition after anti-CD19 chimeric antigen receptor T-cell therapy in refractory diffuse large B-cell lymphoma
Abstract
Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved by the US Food and Drug Administration for adult patients with relapsed/refractory large B-cell lymphoma after ≥2 lines of systemic therapy [1, 2]. In ZUMA-1, the pivotal study of axicel in refractory large B-cell lymphoma, with a median of 27.1 months follow-up, the objective response rate was 83%, including 58% complete responses [3]. Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in 11% and 32% of patients, respectively, and were generally reversible [3]. Significant clinical interest exists for exploring ways to augment the efficacy of CAR T-cell therapies. Programmed cell death-1 (PD-1) is expressed on antigenactivated CAR T cells [4]. In addition, checkpoint genes, including programmed death-ligand 1 (PD-L1), are upregulated in tumors of patients treated with axi-cel [5]. A recent case of a patient with primary mediastinal B-cell lymphoma (PMBCL) treated with anti-CD19 CAR T cells suggested that subsequent pembrolizumab treatment may enhance CAR Tcell activity [6]. However, as pembrolizumab demonstrated single-agent activity in PMBCL [7], it is unclear if this response resulted from direct CAR T-cell activity. This report describes a patient with rapidly progressing refractory diffuse large B-cell lymphoma (DLBCL), with strong PD-L1 expression, whose disease did not respond to axi-cel but who experienced rapid tumor regression after receiving subsequent anti-PD-1 therapy. ZUMA-1 (NCT02348216) is a multicenter, phase 1/ 2 study of axi‐cel in patients with refractory large B-cell lymphoma [3, 8, 9]. After leukapheresis and manufacturing, patients received low-dose conditioning chemotherapy (cyclophosphamide 500 mg/m and fludarabine 30 mg/m intravenously, days −5 to −3) and a single intravenous axicel infusion (target dose, 2 × 10 CAR T cells/kg, day 0). Response was assessed using International Working Group response criteria for malignant lymphoma [10]. CRS was graded per Lee et al. [11]. Neurologic events were graded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Immunohistochemistry was performed as described [8, 12]. Blood samples were analyzed for CAR T-cell and cytokine levels [13]. Each site’s institutional review board approved this study, which was conducted according to International Conference on Harmonisation Good Clinical Practice guidelines. All patients provided written informed consent. Data analyses were performed by Kite, a Gilead Company; authors had full access to data. A 43-year-old male presented with refractory germinal center DLBCL by immunohistochemistry (CD10+, MUM1−, and BCL6+). At initial diagnosis, fluorescence in situ hybridization was negative for MYC, BCL2, and BCL6 translocations. The patient was refractory to all prior therapies including first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and salvage R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) and R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin). Positron emission tomography (PET) scans at screening showed active disease in the liver, spleen, and bones. A liver biopsy confirmed persistent DLBCL. Retrospective immunohistochemical analysis * Brian T. Hill [email protected]