Ignite Creation Date:
2024-05-06 @ 12:06 AM
Last Modification Date:
2024-10-26 @ 10:45 AM
Study NCT ID:
NCT01493453
Status:
TERMINATED
Last Update Posted:
2023-04-19
First Post:
2011-12-14
Brief Title:
A Phase I Study of CD19 Specific T Cells in CD19 Positive Malignancy
Sponsor:
The Christie NHS Foundation Trust
Organization:
The Christie NHS Foundation Trust
Study Overview
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
Status:
TERMINATED
Status Verified Date:
2023-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Investigation into serious breach
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
CD19
Brief Summary:
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
Detailed Description:
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
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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None