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Study of Adoptive Immunotherapy With Donor-derived CMV-specific T Cells for Recipients of Allo-HSCT (CMV_TCR-001)

Primary Purpose

Haematological Malignancies, CMV Infection

Status
Suspended
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
CMV-TCR transduced donor-derived T cells
Sponsored by
University College, London
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Haematological Malignancies focused on measuring Ex vivo gene therapy, T cell receptor transduction, Immunotherapy, Allogeneic Haematopoietic Stem Cell Transplantation, CMV

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Patient Inclusion Criteria:

  • Undergoing matched sibling allogeneic HSCT for an underlying haematological malignancy with a CMV seronegative donor
  • Age ≥ 18 years and ≤ 65 years
  • HLA-A*0201 positive
  • CMV seropositive (CMV IgG detected) pre-transplant
  • Informed consent in writing and ability to co-operate with treatment and follow up.

    • Prepared to undergo additional study procedures as per study schedule
    • Patient has undergone counselling about risk
  • Serologically negative for HIV 1&2, Hep B, Hep C and syphilis
  • Female patients of child-bearing age must have a negative pregnancy test and agree to use reliable contraceptive methods for the duration of the therapy and for 6 months afterwards
  • Male patients must agree to use appropriate medically approved contraception during the trial and for six months afterwards

And to be assessed prior to CMV-specific T cell infusion (for confirmation prior to product release):

  • Donor engraftment (neutrophils > 0.5x109/l).
  • Single positive CMV PCR result (> 200 copies/ml)

Patient Exclusion Criteria:

  • Pregnant or lactating women
  • Co-existing medical problems that would place the patient at significant risk of death due to GVHD or its sequelae
  • HIV infection

And to be assessed prior to CMV-specific T cell infusion (for confirmation prior to product release):

  • Active acute GVHD > Grade I
  • Concurrent use of systemic corticosteroids
  • Organ dysfunction as measured by

    • creatinine > 200 uM/l
    • bilirubin > 50 uM/l
    • ALT > 3x upper limit of normal

Sites / Locations

  • University Hospitals Birmingham NHS Foundation Trust
  • University Hospitals Bristol NHS Foundation Trust
  • University College London Hospital
  • Nottingham University Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Cohort 1 - 10^4 transduced cells/kg

Cohort 2 - 10^5 transduced cells/kg

Cohort 1a - 10^3 transduced cells/kg

Arm Description

The first 3 patients will receive a single infusion of bulk CMV-TCR transduced donor-derived T cells on first CMV reactivation post allogeneic HSCT, at a dose of 10^4 T cells/kg recipient weight

If no cases grade III-IV GVHD in Cohort 1 the remaining patients (N=7) each receive a single infusion of bulk CMV-TCR transduced donor-derived T cells on first CMV reactivation post allogeneic HSCT, at a dose of 10^5 T cells/kg recipient weight

If 1 case grade III-IV GVHD in Cohort 1, next three patients to be treated with a single infusion of bulk CMV-TCR transduced donor-derived T cells of 1 x 10^3 T cells/kg recipient weight

Outcomes

Primary Outcome Measures

Determination of the frequency of transduced donor-derived cells expressing the CMV-specific TCR by flow cytometry.
CMV-TCR transduced cells express vbeta13 and murine constant beta chain (mCb), both of which can be easily detected by flow cytometry. The frequency of vbeta13+/mCb+ is used to calculate the efficiency of transduction of donor-derived cells.
Evaluation of treatment toxicity according to the NCI Common Toxicity Criteria Scale (v4.03).

Secondary Outcome Measures

Documentation of anti-CMV responses post CMV-TCR transduced cell infusion using quantitative PCR to determine viral copy numbers in peripheral blood.
Evaluation of GvHD post CMV-TCR transduced cell infusion following allo-HSCT using standardised international criteria.
Evaluation of immune reconstitution post CMV-TCR transduced cell infusion following allo-HSCT.
Flow cytometry and TCR repertoire analysis can be used to evaluate overall T-cell subset reconstitution.
Assessment of the number of CMV-TCR transduced cells that are able to persist post-infusion using quantitative real-time PCR.
Quantitative real-time PCR using primers specifically targeting nucleotide sequences that are only present in the introduced CMV-TCR can be used to determine the number of circulating CMV-TCR transduced cells post infusion.
Phenotypic characterisation of CMV-TCR transduced cells by flow cytometry in terms of relative expression of markers associated with cell differentiation, proliferation and intracellular cytokine production.
Flow cytometry can be used to further characterise CMV-TCR transduced cells in terms of naive/memory subsets (based on the expression of CD45RO and CD62L differentiation markers), proliferation status (assessed by Ki-67) and ability to produce cytokines (such as IFN-gamma and TNF-alpha).

Full Information

First Posted
July 12, 2012
Last Updated
September 10, 2018
Sponsor
University College, London
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1. Study Identification

Unique Protocol Identification Number
NCT02988258
Brief Title
Study of Adoptive Immunotherapy With Donor-derived CMV-specific T Cells for Recipients of Allo-HSCT
Acronym
CMV_TCR-001
Official Title
CMV TCR Gene Therapy: A Phase I Safety, Toxicity and Feasibility Study of Adoptive Immunotherapy With CMV TCR-transduced Donor-derived T Cells for Recipients of Allogeneic Haematopoietic Stem Cell Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
September 2018
Overall Recruitment Status
Suspended
Why Stopped
Protocol being re-written to allow inclusion of more patients
Study Start Date
July 2013 (undefined)
Primary Completion Date
August 2019 (Anticipated)
Study Completion Date
August 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University College, London

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The study will test the hypothesis that CMV TCR-transduced T cells, at a specific T-cell dose/kg, can generate a functional CMV immune response post-transplant, where CMV-specific donor T cells cannot be isolated by conventional means. This will be tested in the context of adult HLA-matched sibling allogeneic HSCT. In the proposed trial, an HLA-A*0201-restricted CMV pp65-specific T cell receptor (TCR) will be introduced into donor T cells via ex vivo GMP retroviral transduction. Donor T cells will be isolated from peripheral blood following a simple venesection procedure. The CMV TCR-transduced T cells will be tested for TCR expression, CMV-specific cytokine secretion and microbiological contamination before being frozen and stored at -80C. CMV seropositive transplant recipients will be tested weekly for CMV reactivation by quantitative PCR on peripheral blood. On first detection of CMV DNA > 200 copies/ml, 104 (cohort 1) or 105 (cohort 2) bulk CMV TCR-transduced T cells/kg recipient weight will be infused into the patient. Blood will be taken regularly to determine persistence and expansion of the CMV TCR-transduced T cells. Weekly CMV PCR will be continued. Patients will be examined at appropriate intervals (daily if inpatients, twice weekly in BMT clinic if outpatients) for the development of graft versus host disease (GVHD) or other potential side effects.
Detailed Description
Reactivation of the latent human herpes virus, Cytomegalovirus (CMV), post allogeneic haematopoietic stem cell transplantation (Allo-HSCT) can result in significant morbidity and mortality unless treated promptly. Anti-viral therapy is usually effective, but has serious side effects typically requiring prolonged inpatient admission, such as myelosuppression (Ganciclovir) or nephrotoxicity (Foscarnet). Cellular immunotherapy for CMV has been tested in Phase I/II trials in the UK and Europe. In these trials CMV-specific T cells were isolated from the peripheral blood of CMV seropositive donors and re-infused into recipients following CMV reactivation resulting in sustained anti-viral responses. It is clear that post-transplant recovery of CD8+ CMV-specific cytotoxic T-cells (CTL) abrogates the development of CMV-related disease. An advantage of cellular therapy for CMV reactivation is the transfer of immunological memory, which can reduce the number of subsequent reactivations. This is important, as rapidly increasing numbers of highly immunosuppressive (or T cell depleted) reduced intensity conditioning Allo-HSCTs are being performed in the UK. These approaches reduce the toxicity of transplantation in older patients with more co-morbidities. Reduced intensity allogeneic transplants are currently part of the UK MRC AML15 trial and are to be recommended in the proposed MRC/ECOG UKALL14 study and again in UK MRC AML17. In addition, a number of NCRN approved UK multicentre extended Phase II studies have recently started using reduced intensity Allo-HSCT in various lymphoma subtypes. Transplant recipients with CMV seronegative donors cannot benefit from currently available cellular immunotherapy approaches due to the lack of CMV-specific memory T cells in these donors. At present, there is no reliable strategy to isolate virus specific T cells from uninfected naïve individuals, as the precursor frequency is low or absent and the in vitro priming of T-cell responses is inefficient. T-cell receptor (TCR) gene transfer offers a strategy to produce antigen-specific T cells independent of precursor frequency and without the need for T-cell priming. As approximately 50% of adult individuals have been previously infected with CMV, there are significant numbers of CMV 'mismatched' Allo-HSCT performed, where the donor is CMV seronegative and the recipient CMV seropositive. The proposed study will test the feasibility of generating donor-derived CMV-specific T cells via the ex vivo introduction of a CMV-specific T cell receptor using a GMP grade retroviral vector.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Haematological Malignancies, CMV Infection
Keywords
Ex vivo gene therapy, T cell receptor transduction, Immunotherapy, Allogeneic Haematopoietic Stem Cell Transplantation, CMV

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
10 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1 - 10^4 transduced cells/kg
Arm Type
Experimental
Arm Description
The first 3 patients will receive a single infusion of bulk CMV-TCR transduced donor-derived T cells on first CMV reactivation post allogeneic HSCT, at a dose of 10^4 T cells/kg recipient weight
Arm Title
Cohort 2 - 10^5 transduced cells/kg
Arm Type
Experimental
Arm Description
If no cases grade III-IV GVHD in Cohort 1 the remaining patients (N=7) each receive a single infusion of bulk CMV-TCR transduced donor-derived T cells on first CMV reactivation post allogeneic HSCT, at a dose of 10^5 T cells/kg recipient weight
Arm Title
Cohort 1a - 10^3 transduced cells/kg
Arm Type
Experimental
Arm Description
If 1 case grade III-IV GVHD in Cohort 1, next three patients to be treated with a single infusion of bulk CMV-TCR transduced donor-derived T cells of 1 x 10^3 T cells/kg recipient weight
Intervention Type
Genetic
Intervention Name(s)
CMV-TCR transduced donor-derived T cells
Intervention Description
Dose escalation
Primary Outcome Measure Information:
Title
Determination of the frequency of transduced donor-derived cells expressing the CMV-specific TCR by flow cytometry.
Description
CMV-TCR transduced cells express vbeta13 and murine constant beta chain (mCb), both of which can be easily detected by flow cytometry. The frequency of vbeta13+/mCb+ is used to calculate the efficiency of transduction of donor-derived cells.
Time Frame
5 years
Title
Evaluation of treatment toxicity according to the NCI Common Toxicity Criteria Scale (v4.03).
Time Frame
5 years
Secondary Outcome Measure Information:
Title
Documentation of anti-CMV responses post CMV-TCR transduced cell infusion using quantitative PCR to determine viral copy numbers in peripheral blood.
Time Frame
5 years
Title
Evaluation of GvHD post CMV-TCR transduced cell infusion following allo-HSCT using standardised international criteria.
Time Frame
5 years
Title
Evaluation of immune reconstitution post CMV-TCR transduced cell infusion following allo-HSCT.
Description
Flow cytometry and TCR repertoire analysis can be used to evaluate overall T-cell subset reconstitution.
Time Frame
5 years
Title
Assessment of the number of CMV-TCR transduced cells that are able to persist post-infusion using quantitative real-time PCR.
Description
Quantitative real-time PCR using primers specifically targeting nucleotide sequences that are only present in the introduced CMV-TCR can be used to determine the number of circulating CMV-TCR transduced cells post infusion.
Time Frame
5 years
Title
Phenotypic characterisation of CMV-TCR transduced cells by flow cytometry in terms of relative expression of markers associated with cell differentiation, proliferation and intracellular cytokine production.
Description
Flow cytometry can be used to further characterise CMV-TCR transduced cells in terms of naive/memory subsets (based on the expression of CD45RO and CD62L differentiation markers), proliferation status (assessed by Ki-67) and ability to produce cytokines (such as IFN-gamma and TNF-alpha).
Time Frame
5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Patient Inclusion Criteria: Undergoing matched sibling allogeneic HSCT for an underlying haematological malignancy with a CMV seronegative donor Age ≥ 18 years and ≤ 65 years HLA-A*0201 positive CMV seropositive (CMV IgG detected) pre-transplant Informed consent in writing and ability to co-operate with treatment and follow up. Prepared to undergo additional study procedures as per study schedule Patient has undergone counselling about risk Serologically negative for HIV 1&2, Hep B, Hep C and syphilis Female patients of child-bearing age must have a negative pregnancy test and agree to use reliable contraceptive methods for the duration of the therapy and for 6 months afterwards Male patients must agree to use appropriate medically approved contraception during the trial and for six months afterwards And to be assessed prior to CMV-specific T cell infusion (for confirmation prior to product release): Donor engraftment (neutrophils > 0.5x109/l). Single positive CMV PCR result (> 200 copies/ml) Patient Exclusion Criteria: Pregnant or lactating women Co-existing medical problems that would place the patient at significant risk of death due to GVHD or its sequelae HIV infection And to be assessed prior to CMV-specific T cell infusion (for confirmation prior to product release): Active acute GVHD > Grade I Concurrent use of systemic corticosteroids Organ dysfunction as measured by creatinine > 200 uM/l bilirubin > 50 uM/l ALT > 3x upper limit of normal
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Emma Morris, Prof
Organizational Affiliation
University College, London
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Hans Stauss, Prof
Organizational Affiliation
University College, London
Official's Role
Study Chair
Facility Information:
Facility Name
University Hospitals Birmingham NHS Foundation Trust
City
Birmingham
ZIP/Postal Code
B15 2TH
Country
United Kingdom
Facility Name
University Hospitals Bristol NHS Foundation Trust
City
Bristol
ZIP/Postal Code
BS2 8ED
Country
United Kingdom
Facility Name
University College London Hospital
City
London
ZIP/Postal Code
NW1 2PG
Country
United Kingdom
Facility Name
Nottingham University Hospital
City
Nottingham
ZIP/Postal Code
NG5 1PB
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
30655164
Citation
Tendeiro Rego R, Morris EC, Lowdell MW. T-cell receptor gene-modified cells: past promises, present methodologies and future challenges. Cytotherapy. 2019 Mar;21(3):341-357. doi: 10.1016/j.jcyt.2018.12.002. Epub 2019 Jan 14.
Results Reference
derived

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Study of Adoptive Immunotherapy With Donor-derived CMV-specific T Cells for Recipients of Allo-HSCT

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