A Phase I Study of CD19 Specific T Cells in CD19 Positive Malignancy
|First Received Date ICMJE||December 14, 2011|
|Last Updated Date||December 15, 2011|
|Start Date ICMJE||March 2008|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures ICMJE
||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 ] [ Designated as safety issue: Yes ]|
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT01493453 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||To assess whether aCD19z T cells in the circulation are functional [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]|
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||A Phase I Study of CD19 Specific T Cells in CD19 Positive Malignancy|
|Official Title ICMJE||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|
In particular circumstances T cells can be an effective treatment for malignant disease, for example, donor lymphocyte infusions following allogeneic transplants or treatment of EBV related lymphomas post allograft. However, many common cancers are poorly recognised by the immune system in part because of a lack of suitable T cell targets and in part because of defects in antigen presentation by tumours (Garrido, et al 1997). Genetically modified T cells engineered to express chimeric immune receptors (CIRs) on their cell surface can bypass the need for MHC presentation and thus represent an attractive approach to immunotherapy (Gross, et al 1989).
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 ICMJE||Interventional|
|Study Phase||Phase 1|
|Study Design ICMJE||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Condition ICMJE||CD19 Positive Non-Hodgkin Lymphoma|
|Intervention ICMJE||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.
|Study Arm (s)||Experimental: Single Arm - aCD19z cells, interleukin 2, Chemotherapy
Intervention: Genetic: aCD19z cells, IL2, pre conditioning Cyclophosphamide & Fludarabine
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Suspended|
|Estimated Enrollment ICMJE||24|
|Completion Date||Not Provided|
|Primary Completion Date||Not Provided|
|Eligibility Criteria ICMJE||
Haemoglobin (Hb)≥ 10.0 g/dl neutrophils ≥ 1.0 x 109/L platelets (Plts)≥ 100 x 109/L
Any of the following abnormal baseline liver function tests:
serum bilirubin ≤ 1.5 x upper limit of normal (ULN) alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) and /or alkaline phosphatase (ALP)≤ 5 x ULN Serum creatinine ≤ 0.14 mmol/L
|Ages||18 Years and older|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Location Countries ICMJE||United Kingdom|
|NCT Number ICMJE||NCT01493453|
|Other Study ID Numbers ICMJE||05_DOG05_18|
|Has Data Monitoring Committee||Yes|
|Responsible Party||Not Provided|
|Study Sponsor ICMJE||Christie Hospital NHS Foundation Trust|
|Collaborators ICMJE||Not Provided|
|Investigators ICMJE||Not Provided|
|Information Provided By||Christie Hospital NHS Foundation Trust|
|Verification Date||June 2009|
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