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

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.

Sex

All

Minimum age

18 Years

Maximum age

65 Years

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

• DERIVEDTendeiro 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