A Phase I Study of CD19 Specific T Cells in CD19 Positive Malignancy

Overview

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.