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Treatment of Patients with Relapsed Or Refractory CD19+ Lymphoid Disease with T Lymphocytes Transduced by RV-SFG

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Treatment of Patients with Relapsed Or Refractory CD19+ Lymphoid Disease with T Lymphocytes Transduced by RV-SFG Open access Protocol BMJ Open: first published as 10.1136/bmjopen-2018-026644 on 19 May 2019. Downloaded from Treatment of patients with relapsed or refractory CD19+ lymphoid disease with T lymphocytes transduced by RV-SFG. CD19.CD28.4-1BBzeta retroviral vector: a unicentre phase I/II clinical trial protocol Maria-Luisa Schubert,1 Anita Schmitt,1 Leopold Sellner,1,2 Brigitte Neuber,1 Joachim Kunz,3 Patrick Wuchter,4 Alexander Kunz,1 Ulrike Gern,1 Birgit Michels,1 Susanne Hofmann,1 Angela Hückelhoven-Krauss,1 Andreas Kulozik,3 Anthony D. Ho,1,2 Carsten Müller-Tidow,1,2 Peter Dreger,1,2 Michael Schmitt1,2 To cite: Schubert M-L, ABSTRACT Strengths and limitations of this study Schmitt A, Sellner L, et al. Introduction Chimeric antigen receptor (CAR) T cells Treatment of patients with spark hope for patients with CD19+ B cell neoplasia, ► First investigator-initiated trial with CAR T cells in relapsed or refractory CD19+ including relapsed or refractory (r/r) acute lymphoblastic lymphoid disease with T Germany. leukaemia (ALL) or r/r non-Hodgkin’s lymphoma (NHL). lymphocytes transduced ► Third-generation CD19-directed CAR construct in- Published studies have mostly used second-generation by RV-SFG.CD19.CD28.4- corporating both CD28 and 4-1BB. CARs with 4-1BB or CD28 as costimulatory domains. 1BBzeta retroviral vector: a ► Broad spectrum of relapsed or refractory haema- Preclinical results of third-generation CARs incorporating unicentre phase I/II clinical tologic malignancies including acute lymphoblas- trial protocol. both elements have shown superiority concerning BMJ Open tic leukaemia, chronic lymphocytic leukaemia and 2019;9:e026644. doi:10.1136/ longevity and proliferation. The University Hospital of lymphoma (diffuse large B-cell lymphoma, follicular bmjopen-2018-026644 http://bmjopen.bmj.com/ Heidelberg is the first institution to run an investigator- lymphoma, mantle cell lymphoma), also including initiated trial (IIT) CAR T cell trial (Heidelberg Chimeric ► Prepublication history and patients after allogeneic stem cell transplantation. Antigen Receptor T cell Trial number 1 [HD-CAR-1]) in additional material for this ► CD19-negative relapses might occur after CD19- paper are available online. To Germany with third-generation CD19-directed CAR T cells. directed CAR T cell therapy. view these files, please visit Methods and analysis Adult patients with r/r ALL ► Restriction to a single centre. the journal online (http:// dx. doi. (stratum I), r/r NHL including chronic lymphocytic org/ 10. 1136/ bmjopen- 2018- leukaemia, diffuse large B-cell lymphoma, follicular 026644). lymphoma or mantle cell lymphoma (stratum II) as well as paediatric patients with r/r ALL (stratum III) will be Received 16 September 2018 Ethics and dissemination Ethical approval and approvals on September 26, 2021 by guest. Protected copyright. Revised 15 February 2019 treated with autologous T-lymphocytes transduced by from the local and federal competent authorities were Accepted 20 March 2019 third-generation RV-SFG.CD19.CD28.4-1BB zeta retroviral granted. Trial results will be reported via peer-reviewed vector (CD19.CAR T cells). The main purpose of this journals and presented at conferences and scientific study is to evaluate safety and feasibility of escalating meetings. CD19.CAR T cell doses (1–20×106 transduced cells/ Trial registration number Eudra CT 2016-004808-60; m2) after lymphodepletion with fludarabine (flu) and NCT03676504; Pre-results. cyclophosphamide (cyc). Patients will be monitored for cytokine release syndrome (CRS), neurotoxicity, i.e. CAR- © Author(s) (or their T-cell-related encephalopathy syndrome (CRES) and/or INTRODUCTION employer(s)) 2019. Re-use other toxicities (primary objectives). Secondary objectives Treatment of patients with relapsed or refrac- permitted under CC BY-NC. No include evaluation of in vivo function and survival of CD19. tory (r/r) lymphoid malignancies including commercial re-use. See rights CAR T cells and assessment of CD19.CAR T cell antitumour acute lymphoblastic leukaemia (ALL)1 or and permissions. Published by efficacy. HD-CAR-1 as a prospective, monocentric trial BMJ. chronic lymphocytic leukaemia (CLL)2–5 and aims to make CAR T cell therapy accessible to patients in For numbered affiliations see other non-Hodgkin’s lymphoma (NHL) such Europe. Currently, HD-CAR-1 is the first and only CAR T 6 end of article. cell IIT in Germany. A third-generation Good Manufacturing as diffuse large B cell lymphoma (DLBCL), 7 Practice (GMP) grade retroviral vector, a broad spectrum follicular lymphoma (FL) or mantle cell Correspondence to 8 Professor Michael Schmitt; of NHL, treatment of paediatric and adult ALL patients lymphoma (MCL) remains a challenge. For michael. schmitt@ med. uni- and inclusion of patients even after allogeneic stem cell patients with such r/r CD19-positive malig- heidelberg. de transplantation (alloSCT) make this trial unique. nancies, T cells genetically engineered to Schubert M-L, et al. BMJ Open 2019;9:e026644. doi:10.1136/bmjopen-2018-026644 1 Open access BMJ Open: first published as 10.1136/bmjopen-2018-026644 on 19 May 2019. Downloaded from express chimeric antigen receptors (CARs) have shown patients (stratum I), (2) r/r adult patients with NHL remarkable results.9 Clinical responses in up to 81%–89% (CLL, DLBCL, FL or MCL; stratum II) and (3) r/r paedi- of paediatric ALL,10 11 83%–88% of adult ALL,12 13 atric ALL patients (stratum III). 57–71% of CLL14 15 and 64%–82% of NHL16–19 have been Autologous T lymphocytes transduced with the reported for heavily pretreated patients following CAR T RV-SFG.CD19.CD28.4-1BBzeta retroviral vector (CD19. cells directed against CD19 (table 1). CAR T cells) are administered in three dose levels per CARs constitute synthetic receptors composed of three stratum: 1×106 CD19.CAR T cells/m2 (dose level 1 [D1]), domains: (1) an extracellular antigen-specific target 5×106 CD19.CAR T cells/m2 (dose level 2 [D2]), and binding domain derived from an antibody’s single-chain 20×106 CD19.CAR T cells/m2 (dose level 3 [D3]). Three variable fragment (scFv), (2) a hinge and transmem- to 16 patients per stratum leading to a maximum of brane segment and (3) intracellular domain for intracel- 48 patients will be treated in order to assess safety and lular signalling mediating activation and costimulation maximum tolerated dose of CD19.CAR T cells (figure 1). to the CAR-expressing T cell. First-generation CARs Following enrolment (exclusion and inclusion criteria contain only the tyrosine-based ζ-signal-transducing summarised in box 1), patients undergo leukapher- subunit from the TCR/CD3 receptor complex as intra- esis for collection of peripheral blood mononuclear cellular domain,20 21 whereas second-generation CARs cells (PBMCs). PBMCs are transduced with the RV-SFG. carry costimulatory domains, for example, CD28, 4-1BB CD19.CD28.4-1BBzeta retroviral vector (provided by (CD137) or OX40 (CD134) adjacent to the ζ domain. Malcolm Brenner, Baylor College of Medicine, Houston, Most widely, CD28 and 4-1BB costimulatory domains Texas, USA) after activation with anti-CD3 and anti-CD28 have been used. Both have shown to enhance CAR T cell antibodies (MACS GMP Pure, Miltenyi Biotec, Bergisch activity and signalling and to mediate complete responses Gladbach, Germany) and culturing with IL-7 (10 ng/mL) in patients with advanced CD19-positive haematologic and IL-15 (5 ng/mL) (CellGenix, Freiburg, Germany) at malignancies.16 22–24 Third-generation CARs including two the Good Manufacturing Practice (GMP) Core Facility costimulatory molecules within their constructs, that is, of the Internal Medicine V Department of the Univer- CD28 and 4-1BB, have demonstrated superior prolif- sity Hospital Heidelberg. RV-SFG.CD19.CD28.4-1BB- erative capacity, a more robust survival and antitumour zeta carries an anti-CD19 scFv derived from the FMC63 response in vitro and in vivo compared with second-gen- antibody inserted to the SFG retroviral backbone.29 The eration CARs comprising either CD28 or 4-1BB.25–27 In transmembrane domain is derived from CD28, the hinge 30 ALL and lymphoma patients co-infused with second-gen- domain from the human IgG1-CH2CH3 domain and eration and third-generation CD19-directed CARs, signifi- 4-1BB is inserted between the CD28 and CD3ζ domains cantly superior engraftment, a 23-fold higher expansion (figure 2). and prolonged in vivo persistence of third-generation All patients receive lymphodepleting chemotherapy http://bmjopen.bmj.com/ CAR T cells was reported.28 with fludarabine (flu) 30 mg/m2/day and cyclophospha- In Europe, almost all clinical CAR T cell trials are mide (cyc) 500 mg/m2/day on days −4 to −2 (ie, 3 days) industry-driven. The University Hospital of Heidelberg prior to CD19.CAR T cell infusion (defined as day 0) in is currently the first institution in Germany to run an an in-patient setting (figure 3). investigator-initiated trial (IIT) phase I/II CAR T cell CAR T cells are administered only to patients who have trial (Heidelberg Chimeric Antigen receptor T cell Trial consented to study participation and fulfil the following number 1 [HD-CAR-1]; EudraCT-No. 2016-004808-60; requirements: (1) no evidence of serious infection (active NCT03676504 ( clinicaltrials. gov); federal authority No.: infection with positive blood cultures for bacteria, fungus on September 26, 2021 by guest. Protected copyright. 3148/02; Institutional review board/Ethics Committee or virus within 48 hours of CD19.CAR T cell infusion); approval No.: AF-mu 405/2017); HD-CAR-1 clinical trial (2) adequate renal function defined as serum creati- protocol version 03; date 22 June 2018; for HD-CAR-1 nine of ≤2 x ULN or eGFR ≥30 mL/minute/1.73 m2; (3) protocol synopsis, see online supplementary file 1). no evidence of significant cardiac dysfunction; (4) no This monocentric, open-label, prospective clinical trial evidence of significant pulmonary dysfunction and (5) no initiated in September 2018 treats adult patients with acute neurological toxicity >grade 1 (with the exception r/r ALL, r/r CLL or other NHL including DLBCL, FL of peripheral neuropathy).
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