Clinical Trials /

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

NCT01493453

Description:

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).

Related Conditions:
  • Non-Hodgkin Lymphoma
Recruiting Status:

Unknown status

Phase:

Phase 1

Trial Eligibility

Document

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

Title

  • Brief Title: A Phase I Study of CD19 Specific T Cells in CD19 Positive Malignancy
  • 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
  • Clinical Trial IDs

    NCT ID: NCT01493453

    ORG ID: 05_DOG05_18

    Trial Conditions

    CD19 Positive Non-Hodgkin Lymphoma

    Trial Interventions

    Drug Synonyms Arms

    Trial Purpose

    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.

    Trial Arms

    Name Type Description Interventions
    Single Arm - aCD19z cells, interleukin 2, Chemotherapy Experimental

    Eligibility Criteria

    Inclusion Criteria:

    - Patients must have histologically confirmed CD19 positive non-Hodgkin Lymphoma with
    evidence of persistent or progressive disease and poor prognosis as discussed in
    detail in section 1.5

    - Written informed consent and the ability of the patient to co-operate with study
    treatment, procedures and follow up must be ensured and documented.

    - Age equal to or greater than 18 years.

    - World Health Organisation (WHO) performance status of 0 or 1 (appendix 1).

    - Life expectancy >3months.

    - LVEF > 50% as measured by MUGA scan

    - Haematological and biochemical indices:

    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

    - Female patients of child-bearing potential are eligible, provided they have a
    negative serum or urine pregnancy test prior to enrolment and agree to use
    appropriate medically approved contraceptive precautions for four weeks prior to
    entering the trial, during the trial, and for six months afterwards.

    - Male patients must agree to use barrier method contraception during the trial and for
    six months afterwards.

    - Measurable disease as defined by RECIST criteria (appendix 3).

    Exclusion Criteria:

    - Radiotherapy, biological therapy, endocrine therapy, immunotherapy, systemic
    steroids, or chemotherapy during the previous four weeks (six weeks for nitrosoureas
    and Mitomycin-C) prior to treatment or during the course of the trial.

    - All toxic manifestations of previous treatment must have resolved. Exceptions to this
    are alopecia or certain Grade 1 toxicities which in the opinion of the Investigator
    and Trial Sponsor should not exclude the patient.

    - Participation in any other clinical trial within the previous 30 days or during the
    course of this trial.

    - Previous participation in a Gene Therapy trial.

    - Previous allogeneic transplant.

    - Patients who are high medical risks because of non-malignant systemic disease,
    including those with active infection, uncontrolled cardiac or respiratory disease,
    or other serious medical or psychiatric disorders which in the Investigator's opinion
    would not make the patient a good candidate for the clinical trial.

    - Concurrent serious infections within the 28 days prior to entry to the trial.

    - Current malignancies at other sites, with the exception of adequately treated
    cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell
    carcinoma of the skin.

    - Patients known or found to be serologically positive for Hepatitis B, C, HIV or HTLV.

    - History of autoimmune disease.

    - Evidence of CNS involvement.

    - Patients who are likely to require systemic steroids or other immunosuppressive
    therapy.

    - Pregnant and lactating women.

    - Radiotherapy to >25% skeleton.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    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

    Secondary Outcome Measures

    To assess whether aCD19z T cells in the circulation are functional

    Trial Keywords