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
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
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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
United Kingdom: Medicines and Healthcare Products Regulatory Agency