Autologous T cells expressing CD30 chimeric antigen receptors for relapsed or refractory Hodgkin's lymphoma: an open-label phase 1 trial

Abstract

BackgroundRelapsed or refractory Hodgkin's lymphoma is a challenge for medical oncologists because of poor overall survival. We aimed to assess the feasibility, safety, and efficacy of CD30-targeting CAR T cells in patients with progressive relapsed or refractory Hodgkin's lymphoma, in which CD30 expression is mostly positive. MethodsThis open-label, phase 1 study took place at the Chinese PLA General Hospital. Eligible patients (aged 16–80 years) had relapsed or refractory Hodgkin's lymphoma. All patients received a conditioning chemotherapy regimen at the discretion of physician, followed by the infusion of CD30-directed CAR T cells. Using escalating doses to avoid severe toxicity associated with infusion, patients received a starting dose of 3·2 × 105 CAR T cells per kg and then infused by 5-fold increments continuously for 3–5 days. After the dose-escalation infusion, no patients experienced greater than grade 3 toxicity events. We periodically monitored the expression level of CAR transgenes in peripheral blood and biopsied tumour tissues according to assigned protocol by quantitative PCR. Two-way analysis of variance (ANOVA) was used to determine the significance of the differences between means in all experiments. This trial was approved by the Institutional Review Board at the Chinese PLA General Hospital and is registered with ClinicalTrials.gov, number NCT02259556. All patients gave written informed consent before enrolment. FindingsBetween Dec 1, 2014, and Mar 1, 2015, 11 patients were enrolled. All of whom had a heavy pretreatment history (15 previous treatments, range 6–24) or multiple tumour lesions (3·3 lymph node regions involved, range 0-7; involvement of one or more extralymphatic organs), or both. The patients received a mean of 1·5×107 CAR-positive T cell per kg (SD 0·25, range 1·2–2·1) in total during infusion. Nine (82%) patients responded to the treatment: one (9%) patient maintained continuous complete remission, five (46%) patients achieved partial response, and three (27%) patients achieved stable disease. All patients experienced tolerable infusion-related febrile syndrome. One (9%) patient had 5 days of self-limiting arthralgia, myalgia, and dual knee swelling 2 weeks after cell infusion. The copy number of CAR transgene in peripheral blood peaked 3–17 days after infusion, which was accompanied by a two-times higher increase in the number of lymphocytes. Analysis of biopsied tissues revealed a highly efficient trafficking of CAR T cells into the targeted sites. InterpretationCD30-directed CAR T-cell therapy was safe, feasible, and efficient in patients with relapsed or refractory Hodgkin's lymphoma and guaranteed a large-scale patients recruitment. FundingScience and Technology Planning Project of Beijing City (No. Z151100003915076) and National Natural Science Foundation of China (Nos. 31270820, 81230061, 81121004, and 81402566).