Phase IIa Trial of Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) in Patients with Relapsed or Refractory CD19+ Lymphomas
Authors: Schuster Stephen J. , Svoboda Jakub , Dwivedy Nasta Sunita , Porter David L. , Chong Elise A. , Mahnke Yolanda , Lacey Simon F. , Melenhorst J. Joseph , Chew Anne , Shah Gaurav , Hasskarl Jens , Litchman Manuel , Wasik Mariusz A. , Landsburg Daniel J. , Mato Anthony R. , Garfall Alfred L. , Frey Noelle V. , Marcucci Katherine T. , Shea Joanne , McConville Holly , Zheng Zhaohui , Levine Bruce L. , June Carl H. 
Published: November 2019

Abstract
BACKGROUND: Autologous T cells genetically modified to express a chimeric antigen receptor consisting of an external anti-CD19 single chain antibody domain with CD3ζ and 4-1BB signaling domains (CTL019 cells) can mediate potent anti-tumor effects in patients (pts) with relapsed or refractory chronic lymphocytic and acute lymphoblastic leukemias. We are conducting a phase IIa clinical trial to evaluate the safety and efficacy of CTL019 cells in pts with relapsed or refractory CD19+ non-Hodgkin lymphomas (NHL).
METHODS: 30 evaluable pts are planned for analysis, including at least 8 with follicular lymphoma (FL), 8 with diffuse large B cell lymphoma (DLBCL), and 8 with mantle cell lymphoma. Eligible pts have CD19+ NHL with no available curative treatment options, a limited prognosis of several months to <2 years anticipated survival, and responsive or stable disease with most recent therapy. Pts with FL have progression of lymphoma within 2 years after second or higher line of therapy (not including single agent monoclonal antibody therapy); DLBCL pts have residual disease after primary therapy and are not eligible for autologous stem cell transplant (ASCT) or have relapsed or residual disease after ASCT. After steady state apheresis to collect peripheral blood leukocytes, pts receive lymphodepleting chemotherapy based on disease burden, histology, and past therapies. One to 4 days after chemotherapy, pts receive a single dose of CTL019 cells by intravenous infusion; total CTL019 target dose is 5 x 108 cells. Peripheral blood and marrow samples are collected for immunophenotypic, cytokine, and molecular studies at pre-specified times after T cell infusion. Initial tumor response assessment is performed 3 months after T cell infusion using International Working Group response criteria. Enrollment started in February 2014; data reported here are through July 30, 2014.
RESULTS: To date, 23 pts (DLBCL 16; FL 7) have enrolled. The median age is 56 years (range: 25-77), male: female ratio is 14:9, median number of prior therapies is 4 (range: 1-8), and number of pts with prior ASCT is 9 (39%). Ann Arbor stages at enrollment are: stage IV 11 pts (48%); stage III 5 pts (22%); stage II 5 pts (22%); stage IE 2 pts (8%); 5 pts (22%) had bone marrow involvement. LDH was increased in 17 pts (74%). Three pts (DLBCL 2 pts; FL 1 pt) were removed from the trial before therapy due to progressive disease. As of July 30, 2014, 14 pts have received CTL019 T cell infusions. Pre-infusion chemotherapy regimens were EPOCH (1 pt); cyclophosphamide (7 pt); bendamustine (5 pts); cyclophosphamide-fludarabine (1 pt). Median CTL019 T cell dose is 5.8 x 106 cells / kg (range: 3.7 – 8.9 x 106). In vivo expansion of CTL019 cells was brisk; the median peak CTL019% of CD3+ cells in peripheral blood was 6.1% (range: 0.7-43.1%) for all patients, 17.3% (range: 3.9-43.1) for responders, and 4.95% (range: 0.7-7.3) for non-responders. Peak CTL019 cell expansion generally occurred around 7 days after T cell infusion. All patients developed fever following T cell infusion, attributed to cytokine release syndrome (CRS). Severity of CRS according to our novel grading scale (reported separately) was: 12 pts grade 2; 1 pt grade 3; 1 pt grade 4. One pt received steroids and tocilizumab for grade 4 CRS. CRS occurred within the first week of T cell infusion in all pts. Neurologic toxicity was observed in 2 pts (1 pt with grade 3 encephalopathy that resolved with corticosteroids; 1 pt with grade 3 dysarthria and grade 3 ataxia). There was no treatment-related mortality. Eight pts are evaluable for response (DLBCL 6; FL 2). Overall response rate at 3 months is 50% with 3 complete responses (DLBCL 2 pts; FL 1 pt) and 1 partial response (FL); 4 pts with DLBCL had progressive disease before or at initial response assessment.
CONCLUSIONS: In this ongoing trial of CTL019 cells in relapsed or refractory NHL, 4 of the first 8 evaluable pts responded to therapy. These early results demonstrate that CTL019 cells can be prepared from previously treated pts with active NHL, can undergo robust in-vivo expansion, and can induce complete responses in pts with advanced, relapsed or refractory DLBCL and FL. Longer follow up will define toxicities, durability of response, and clinical benefit, as well as guide further development of this promising new therapeutic approach.

Disclosures
Schuster: Novartis: Research Funding. Porter:Novartis: Patents & Royalties, Research Funding; Genentech (spouse employment): Employment. Mahnke:Novartis: Research Funding. Lacey:Novartis: Research Funding. Chew:Novartis: Patents & Royalties, Research Funding. Shah:Novartis: Employment. Hasskarl:Novartis: Employment. Litchman:Novartis: Employment. Frey:Novartis: Research Funding. Zheng:Novartis: Patents & Royalties, Research Funding. Levine:Novartis: Patents & Royalties, Research Funding. June:Novartis: Patents & Royalties, Research Funding.