A Phase I Study of CD19 Specific T Cells in CD19 Positive Malignancy (CD19)
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|ClinicalTrials.gov Identifier: NCT01493453|
Recruitment Status : Unknown
Verified November 2013 by Professor Robert Hawkins, Christie Hospital NHS Foundation Trust.
Recruitment status was: Recruiting
First Posted : December 16, 2011
Last Update Posted : November 27, 2013
|Condition or disease||Intervention/treatment||Phase|
|CD19 Positive Non-Hodgkin Lymphoma||Genetic: aCD19z cells, IL2, pre conditioning Cyclophosphamide & Fludarabine||Phase 1|
CD19 is an Immunoglobulin-like 95kDa glycoprotein that is expressed on all B lymphocytes until differentiation into terminal effector cells (Tedder and Isaacs 1989). It plays an important role in regulating cell signalling thresholds and also as a costimulatory molecule for B cell receptor signalling (Tedder, et al 1997). CD19 is present on the majority of B-CLL, B-ALL, and both low and high grade non-Hodgkin lymphomas (NHL). It is rarely lost during the process of neoplastic transformation and is not expressed on haematopoetic stem cells. B cell malignancies are often highly responsive to chemotherapy, with cures possible in significant numbers of those with high grade tumours. However, improved treatments are needed for those with low grade tumours and those with high grade tumours who relapse after conventional therapy.
In recent years the introduction of Rituximab, a CD20 monoclonal antibody, into clinical practice has increased the options available for the treatment of NHL (Maloney, et al 1994). The success of Rituximab and other monoclonal antibodies has demonstrated that B cell malignancies may be particularly suitable as a target for immunotherapy. However, there are number of potential advantages of T cells engineered to express a CIR over monoclonal antibody therapies. Firstly, the possibility of in vivo T cell persistence and expansion may enable stable expression of the CIR over a prolonged period of time (Walker, et al 2000). Secondly, homing to the tumour site may mean that T cells need not rely on diffusion to achieve localisation (Balkwill 2004, Mitsuyasu, et al 2000) and thirdly following tumour recognition T cells can produce cytokines that may recruit and activate other effector cells. An alternative to CIR engineered T cells is the generation of peptide specific T cells. Lymphoma models suggest these can be effective (Armstrong, et al 2002, Armstrong, et al 2004), but to produce clinically applicable numbers of T cells is technically demanding and there is a lack of generic peptide target antigens in lymphoma.
One potential problem in the use of CIR engineered T cells in general is that tumour associated antigens are frequently expressed at low levels on normal tissues, thus providing the potential for autoimmunity. Targeting B cell malignancies with CD19 specific T cells is attractive because whilst CD19 is expressed on B cells and the majority of B cell malignancies it is not expressed on any other cell type. It is clear from clinical use of anti-CD20 antibodies that prolonged depletion of B cells (>6 months) is safe (Plosker and Figgitt 2003) and that even in patients with hereditary B cell deficiency immunoglobulin infusion restores normal health in most patients (Ochs and Smith 1996).
The Investigators have therefore propose a clinical trial using T cells expressing a CD19 targeting CIR by retroviral transduction of the CIR into activated T cells in order to target B cell malignancies.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||24 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I Study of Adoptive Transfer of Autologous Tumour Antigen-Specific T Cells With Pre-conditioning Chemotherapy and Intravenous IL2 in Patients With CD19 Positive Malignancy|
|Study Start Date :||March 2008|
|Estimated Primary Completion Date :||May 2014|
|Estimated Study Completion Date :||December 2014|
|Experimental: Single Arm - aCD19z cells, interleukin 2, Chemotherapy||
Genetic: aCD19z cells, IL2, pre conditioning Cyclophosphamide & Fludarabine
aCD19z T cells IV Day 1. The dose of aCD19z T cells will be determined by dose escalation scheme, starting at 10*9 IL2 given as 15 minute IV infusion every eight hours for up to 12 doses Cyclophosphamide (C) 15mg/kg day -7 and day -6, Fludarabine (F) 25mg/m2 day -5 to day -1.
- To asses aCD19z T cell survival and aCD19z T cell toxicity in patients, & The dose of aCD19z T cells required to give optimal survival of these cells in the circulation [ Time Frame: Week 6 ]
- To assess whether aCD19z T cells in the circulation are functional [ Time Frame: 6 weeks ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01493453
|Contact: Ian Bottomley, BA Honours||+44(0)161 9187443 ext 7443||Ian.Bottomley@christie.nhs.uk|
|The Christie NHS Foundation Trust||Recruiting|
|Manchester, United Kingdom, M20 3EE|
|Contact: Ian Emerson, BA 01619187443 email@example.com|
|Principal Investigator: Robert E Hawkins, BA, MB BS, MCRP, Phd, FRCP|
|Sub-Investigator: Fiona C Thistlethwaite, MB BChir, PhD, MRCP|