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

NCT02988258 | Suspended Phase 1 DMC

• 4 other identifiers: UCL 08/02142008-006649-18G070170308/0214
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 4

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.

Conditions

Haematological Malignancies; CMV Infection

Keywords

Ex vivo gene therapy; T cell receptor transduction; Immunotherapy; Allogeneic Haematopoietic Stem Cell Transplantation; CMV

Outcome Measures

Primary Outcomes (2)

• 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

• Evaluation of treatment toxicity according to the NCI Common Toxicity Criteria Scale (v4.03).

  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.

  5 years

• Evaluation of GvHD post CMV-TCR transduced cell infusion following allo-HSCT using standardised international criteria.

  5 years

• Evaluation of immune reconstitution post CMV-TCR transduced cell infusion following allo-HSCT.

  5 years

• Assessment of the number of CMV-TCR transduced cells that are able to persist post-infusion using quantitative real-time PCR.

  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.

  5 years

Study Arms (3)

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

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

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

Genetic: CMV-TCR transduced donor-derived T cells

Interventions

CMV-TCR transduced donor-derived T cells GENETIC

Dose escalation

Cohort 1 - 10^4 transduced cells/kg; Cohort 1a - 10^3 transduced cells/kg; Cohort 2 - 10^5 transduced cells/kg

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• University College, London: lead

Study Sites (4)

University Hospitals Birmingham NHS Foundation Trust

Birmingham, B15 2TH, United Kingdom

Location

University Hospitals Bristol NHS Foundation Trust

Bristol, BS2 8ED, United Kingdom

Location

University College London Hospital

London, NW1 2PG, United Kingdom

Location

Nottingham University Hospital

Nottingham, NG5 1PB, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 30655164 DERIVED

MeSH Terms

Conditions

Cytomegalovirus Infections

Condition Hierarchy (Ancestors)

Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections

Study Officials

• Emma Morris, Prof

  University College, London

  PRINCIPAL INVESTIGATOR

• Hans Stauss, Prof

  University College, London

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 12, 2012
• First Posted: December 9, 2016
• Study Start: July 1, 2013
• Primary Completion: August 1, 2019
• Study Completion: August 1, 2019
• Last Updated: September 12, 2018

Record last verified: 2018-09

Locations

GB (4)