Haematological MalignanciesPhase 1CMV_TCR-001NCT02988258
Study of Adoptive Immunotherapy With Donor-derived CMV-specific T Cells for Recipients of Allo-HSCT
A Phase 1 study testing CMV-TCR transduced donor-derived T cells in people with Haematological Malignancies and CMV Infection, run by University College, London at 4 sites in United Kingdom.
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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Haematological Malignancies, CMV Infection
- What is being tested?
- CMV-TCR transduced donor-derived T cells
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 4 sitesUnited Kingdom
- Study dates
- Jul 2013to Aug 2019
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
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
Trial locations and contacts
4 sites in 1 country.
United Kingdom4 sites
University Hospitals Birmingham NHS Foundation Trust
Birmingham, B15 2TH
University Hospitals Bristol NHS Foundation Trust
Bristol, BS2 8ED
University College London Hospital
London, NW1 2PG
Nottingham University Hospital
Nottingham, NG5 1PB
About this study
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
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.
Read the 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.
- Conditions
- Haematological Malignancies, CMV Infection
- Being tested
- CMV-TCR transduced donor-derived T cells
- Keywords
- Ex vivo gene therapy, T cell receptor transduction, Immunotherapy, Allogeneic Haematopoietic Stem Cell Transplantation, CMV
- Medical subject headings
- Cytomegalovirus Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CMV-TCR transduced donor-derived T cellsGenetic
Dose escalation
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1 - 10^4 transduced cells/kg | Experimental | 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 Receives: Genetic: CMV-TCR transduced donor-derived T cells |
| Cohort 2 - 10^5 transduced cells/kg | Experimental | 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 Receives: Genetic: CMV-TCR transduced donor-derived T cells |
| Cohort 1a - 10^3 transduced cells/kg | Experimental | 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 Receives: Genetic: CMV-TCR transduced donor-derived T cells |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 5 years
Evaluation of treatment toxicity according to the NCI Common Toxicity Criteria Scale (v4.03).
Measured: 5 years
Secondary outcomes (5)
Documentation of anti-CMV responses post CMV-TCR transduced cell infusion using quantitative PCR to determine viral copy numbers in peripheral blood.
Measured: 5 years
Evaluation of GvHD post CMV-TCR transduced cell infusion following allo-HSCT using standardised international criteria.
Measured: 5 years
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.
Measured: 5 years
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.
Measured: 5 years
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).
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Dec 2016 (estimated)
- Study startJul 2013
- Primary completionAug 2019 (estimated)
- Study completionAug 2019 (estimated)
Why it stopped: Protocol being re-written to allow inclusion of more patients
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Haematological MalignanciesStudies of the same condition, open and under way.
- More trials run by University College, LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 10 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University College, London
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Emma Morris, Prof, Principal investigator, University College, LondonHans Stauss, Prof, Study chair, University College, London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02988258
- Sponsor's protocol ID
- UCL 08/0214
- Other IDs
- 2008-006649-18, G0701703, 08/0214, 2008
- Acronym
- CMV_TCR-001
- Status last verified
- Sep 2018
- First submitted
- 12 Jul 2012
- Last updated
- 12 Sep 2018
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
Publications
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.
PubMed 30655164
Study at a glance
From the registry record, last updated by the sponsor on 12 Sep 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02988258
- Acronym / sponsor ID
- CMV_TCR-001 / UCL 08/0214
- Conditions
- Haematological Malignancies, CMV Infection
- Keywords
- Ex vivo gene therapy, T cell receptor transduction, Immunotherapy, Allogeneic Haematopoietic Stem Cell Transplantation, CMV
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- SuspendedReason stopped: Protocol being re-written to allow inclusion of more patients
- Enrolment
- 10 participants (estimated)
- Lead sponsor
- University College, LondonUniversity, hospital or other
- Study start
- Jul 2013
- Primary completion
- Aug 2019 (estimated)
- Study completion
- Aug 2019 (estimated)
- First posted
- 9 Dec 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Cohort 1 - 10^4 transduced cells/kg | Experimental | Genetic: CMV-TCR transduced donor-derived T cellsThe 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 |
| Cohort 2 - 10^5 transduced cells/kg | Experimental | Genetic: CMV-TCR transduced donor-derived T cellsIf 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 |
| Cohort 1a - 10^3 transduced cells/kg | Experimental | Genetic: CMV-TCR transduced donor-derived T cellsIf 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 |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CMV-TCR transduced donor-derived T cellsDose escalation | Genetic | Cohort 1 - 10^4 transduced cells/kg, Cohort 1a - 10^3 transduced cells/kg, Cohort 2 - 10^5 transduced cells/kg |
Primary outcome
Determination of the frequency of transduced donor-derived cells expressing the CMV-specific TCR by flow cytometry.
Time frame: 5 years
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).
Time frame: 5 years
5 secondary outcomes
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
Evaluation of GvHD post CMV-TCR transduced cell infusion following allo-HSCT using standardised international criteria.
Time frame: 5 years
Evaluation of immune reconstitution post CMV-TCR transduced cell infusion following allo-HSCT.
Time frame: 5 years
Assessment of the number of CMV-TCR transduced cells that are able to persist post-infusion using quantitative real-time PCR.
Time frame: 5 years
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.
Time frame: 5 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Sep 2018.
- Derived from this study: PubMed 30655164Tendeiro 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.
- Individual participant dataSharing planned: Undecided
Related trials for Haematological Malignancies
RecruitingObservational study
Adapted Boxing and Photography in Haematology: Body Image and Self-Esteem
Haematological Cancer
Not yet recruitingObservational study
variaTIon in Referral Thresholds in the Chronic Lymphocytic LeukaEmia Pathway
Chronic Lymphocytic Leukemia, Haematological Malignancy
Recruiting
Proof of Concept to Assess the Feasibility of a Decentralised Pathway Coordinated by the Advanced Practice Nurse for Patients Receiving Oral Treatment for Cancer or Malignant Haemopathy (ACCELER PLATFORM)
Solid Cancer, Haematological Malignancies
RecruitingPhase 2/3
DETERMINE Trial Treatment Arm 07: Dabrafenib in Combination With Trametinib in Adult, Paediatric and Teenage/Young Adult Patients With BRAF V600 Mutation-Positive Cancers.
Haematological Malignancy, Malignant Neoplasm
RecruitingPhase 2/3
DETERMINE (Determining Extended Therapeutic Indications for Existing Drugs in Rare Molecularly Defined Indications Using a National Evaluation Platform Trial) - Master Screening Protocol
Haematological Malignancy, Solid Tumour
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Emma Morris, Prof principal investigator
University College, London
Hans Stauss, Prof study chair
University College, London
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing CMV-TCR transduced donor-derived T cells in people with Haematological Malignancies and CMV Infection, run by University College, London at 4 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: paused, as of the sponsor's last update on 12 Sep 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Determination of the frequency of transduced donor-derived cells expressing the CMV-specific TCR by flow cytometry. (time frame: 5 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02988258, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Sep 2018.