Clinical Trials Logo

Clinical Trial Details — Status: Suspended

Administrative data

NCT number NCT02988258
Other study ID # UCL 08/0214
Secondary ID 2008-006649-18G0
Status Suspended
Phase Phase 1
First received
Last updated
Start date July 2013
Est. completion date August 2019

Study information

Verified date September 2018
Source University College, London
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Suspended
Enrollment 10
Est. completion date August 2019
Est. primary completion date August 2019
Accepts healthy volunteers No
Gender All
Age group 18 Years to 65 Years
Eligibility 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

Study Design


Intervention

Genetic:
CMV-TCR transduced donor-derived T cells
Dose escalation

Locations

Country Name City State
United Kingdom University Hospitals Birmingham NHS Foundation Trust Birmingham
United Kingdom University Hospitals Bristol NHS Foundation Trust Bristol
United Kingdom University College London Hospital London
United Kingdom Nottingham University Hospital Nottingham

Sponsors (1)

Lead Sponsor Collaborator
University College, London

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Primary 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. 5 years
Primary Evaluation of treatment toxicity according to the NCI Common Toxicity Criteria Scale (v4.03). 5 years
Secondary Documentation of anti-CMV responses post CMV-TCR transduced cell infusion using quantitative PCR to determine viral copy numbers in peripheral blood. 5 years
Secondary Evaluation of GvHD post CMV-TCR transduced cell infusion following allo-HSCT using standardised international criteria. 5 years
Secondary 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. 5 years
Secondary 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. 5 years
Secondary 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). 5 years
See also
  Status Clinical Trial Phase
Completed NCT03067155 - CMV Specific T Cell Therapy After Allogeneic Stem Cell Transplantation. Phase 2
Completed NCT02324244 - CMV Intensive Care Units N/A
Enrolling by invitation NCT06263218 - Real-world CMV Outcomes Among Kidney Transplant Recipients in Brazil
Recruiting NCT04934527 - Association of T Gamma Delta-CD16+ Cells and Anti-CMV Immunoglobulins in the Prevention of CMV Infection Phase 2
Not yet recruiting NCT06075927 - Multivirus-specific T Cells in the Treatment of Refractory CMV and/or EBV Infection After Allo-HSCT Phase 1/Phase 2
Not yet recruiting NCT06341686 - Evaluation of the Prophylactic Use of Letermovir in Kidney Transplant Recipients at Risk of Cytomegalovirus Infection Phase 3
Recruiting NCT02136797 - Trial of Third Party Donor Derived CMVpp65 Specific T-cells for The Treatment of CMV Infection or Persistent CMV Viremia After Allogeneic Hematopoietic Stem Cell Transplantation Phase 2
Terminated NCT02843880 - Prediction of Cytomegalovirus (CMV) Reactivation in Intensive Care Unit (ICU) by Immunological Study N/A
Recruiting NCT04278547 - Multicenter Clinical Trial to Evaluate the Efficacy of a Preventive Strategy Against CMV Infection in Heart Transplant Patients, Based on the Specific T Cells Response Phase 4
Recruiting NCT06021210 - Letermovir for the Prevention of CMV Infection in HSCT Recipients Based on the Outcome of mNGS Phase 2
Active, not recruiting NCT01633476 - CMV Modulation of the Immune System in ANCA-associated Vasculitis Phase 2
Recruiting NCT04017962 - A Study of the Drug Letermovir (LTV) as Prevention for Recurrent of Cytomegalovirus (CMV) Infection Phase 2
Recruiting NCT03159364 - Antigen-specific Cytotoxic T Cells in the Treatment of Opportunistic Infections Phase 1/Phase 2
Recruiting NCT05089838 - CMV-TCR-T Cells for Refractory CMV Infection After HSCT Phase 1
Enrolling by invitation NCT05656599 - Immune Reconstitution to CMV After HSCT: Impact of Clinical Factors and Therapy Strategies
Completed NCT02985775 - Preemptive Therapy With CMV-specific T Cells Infusion to Prevent Refractory CMV Infection Post Transplantation Phase 1/Phase 2
Recruiting NCT02083731 - MSC for Treatment of CMV Infection Phase 2
Recruiting NCT02779439 - Partially HLA-matched Third Party Antigen Specific T-cells for Infection Post-stem Cell or Solid Organ Transplantation Phase 1
Recruiting NCT03798301 - Treatment of Cytomegalovirus (CMV) Infections With Viral-Specific T Cells Phase 1
Completed NCT02550639 - Prospective, Randomized Study for Predicting Human Cytomegalovirus (hCMV) Infection Based on Baseline hCMV Specific T-cell Response in Kidney Transplant Phase 4