Autologous EBV-Specific T Cells (CMD-003): Early Results from a Multicenter, Multinational Phase 2 Trial for Treatment of EBV-Associated NK/T-Cell Lymphoma

Abstract Introduction: Extranodal NK/T-cell lymphoma (ENKTL) is a rare lymphoma that is highly associated with EBV expression and an aggressive course in advanced stages. Standard treatment for advanced disease involves multiagent asparaginase based regimens. However, this treatment is often toxic and relapses are common; hence there is an unmet medical need. We are presenting early results from a global phase 2 open label study, CITADEL (NCT01948180), that investigates the safety and efficacy of autologous EBV-specific T cells (CMD-003) for the treatment of aggressive ENKTL. Methods: In this trial, approximately 35 patients with relapsed ENKTL will be enrolled and treated with the cell product, CMD-003. Patients must have relapsed after or be intolerant of asparaginase-based chemotherapy. The study is being conducted at sites in France, South Korea, the UK and the US. The cell product is manufactured at the time of relapse or at any time in high risk patients. To prepare the product, 200 mL of whole blood are collected from the patient and the product is manufactured at a central facility using EBV peptide stimulation in the presence of antigen presenting cells and cytokines to yield ex-vivo expanded EBV-specific T cells. Patients receive 2x107 CD3+ cells/m2 via intravenous infusion on Day 1 and Day 15 with the option to receive 3 additional doses over a 6-month period. The primary endpoint is overall response rate (ORR) by Lugano criteria, as assessed by an independent review committee. The CITADEL study utilizes a Simon two-stage (minimax) design. In Stage I, 2 or more responses are required for the study to continue to Stage II. For Stages I and II combined, 5 or more responses are required to support the conclusion that a true response rate of 30% cannot be ruled out. Results: As of 31 July 2017, 11 patients with relapsed/refractory ENKTL have been enrolled and administered CMD-003, either as adjuvant therapy for patients without measurable disease at baseline (n=3) or as treatment for patients with measurable active disease (n=8). Manufacturing success rate is 70% under current release specifications. Two serious adverse events (lymphoma pain and hyperbilirubinemia) were observed that were possibly related to CMD-003. There have been 12 non-serious product-related adverse events of mild to moderate severity observed in 4 patients. No cytokine release syndrome or neurotoxicity events have occurred. Of the 3 patients with non-measurable disease who received CMD-003, 1 remained in remission with follow up for 6 months before receiving allogenic hematopoietic stem cell transplantation, while 2 subsequently progressed. Of the 8 patients with measurable disease who received CMD-003, 6 patients were evaluable for the 8-week follow up imaging by PET-CT and 2 patients withdrew early due to progressive disease. In the predefined evaluable disease population, the ORR is 50% (3/6) and the disease control rate [complete response (CR) + partial response (PR) + stable disease (SD)] is 67% (4/6). Including all patients with measurable disease the ORR is 37.5% (3/8). One evaluable patient had a CR (6.0 months), 2 had PRs (3.5 and 2.2+ months), 1 patient had SD (ongoing) and 2 patients had tumor progression. We monitored peripheral blood EBV DNA measured by both whole blood and plasma PCR. EBV DNA levels tended to be greater in the whole blood assay. In 6 patients, whole blood EBV DNA levels rose with initial cell infusion, followed by a decline with continued treatment. These 6 patients included all patients with disease control (1 CR, 2 PR and 1 SD), 1 patient with progressive disease and 1 patient with non-measurable baseline disease. Whole blood EBV DNA declined to non-detectable levels in the patients with CR and SD. All patients with disease control remain alive. For all 11 patients, the median overall survival (OS) has not been reached at a median follow up 10 months. Based on independent data safety monitoring committee review of the ORR data, the study can now progress to Stage II. Conclusions : In the CITADEL trial, we have observed preliminary indications of activity and safety after administration of autologous EBV-specific T cells in patients with relapsed ENKTL. The clinical trial is ongoing and accruing patients. Download : Download high-res image (63KB) Download : Download full-size image Disclosures Kim: JJ Kyowa-Kirin: Research Funding; Mundipharma: Research Funding; Takeda: Research Funding; Donga: Research Funding; Novartis: Research Funding; Celltrion, Inc: Consultancy, Honoraria; Roche: Research Funding. Ruan: Cell Medica: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Jacobsen: Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Brammer: Celgene: Research Funding. Radford: ADC Therapeutics: Research Funding; AztraZeneca: Equity Ownership; GlaxoSmithKline: Equity Ownership; Novartis: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Budde: Mustang Therapeutics: Research Funding; Merck: Research Funding, Speakers Bureau; Amgen: Research Funding; KITE Pharmaceutical: Speakers Bureau; Precision Biosciences: Consultancy. Salles: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria; Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bollard: Neximmune: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellectis: Membership on an entity's Board of Directors or advisory committees; Torque: Membership on an entity's Board of Directors or advisory committees. Jaccard: Amgen: Honoraria; Celgene: Honoraria, Other: Travel expenses, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding. Inman: Cell Medica, Inc: Employment. Murray: Cell Medica, Inc: Employment. Gunter: Cell Medica, Inc: Employment. Lee: Cell Medica, Inc: Consultancy. Rooney: Bellicum: Patents & Royalties; Tessa Therapeutics: Research Funding; Marker: Equity Ownership; Viracyte: Equity Ownership; Cell Medica, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: antigen-specific T-cell manufacturing; CellGenix: Consultancy, Membership on an entity's Board of Directors or advisory committees. Heslop: Cell Medica: Patents & Royalties: EBV specific T cells, Research Funding; Celgene: Research Funding; Marker Therapeutics: Equity Ownership; Viracyte: Equity Ownership.