A Phase I-II Study: Infusion of Donor Lymphocytes Transduced With the Suicide Gene HSV TK, After Transplantation of Allogeneic T-depleted Stem Cells From a Haploidentical Donor in Patients With Haematological Malignancies
18 Years
N/A
Both
Hematological Malignancies
Trial Information
A Phase I-II Study: Infusion of Donor Lymphocytes Transduced With the Suicide Gene HSV TK, After Transplantation of Allogeneic T-depleted Stem Cells From a Haploidentical Donor in Patients With Haematological Malignancies
Delayed immune-reconstitution remains one of the main limitation of haploidentical stem cell
transplantation. The risk of severe infections remains high for several months and CD4+
reconstitution could take more than 10 months. The low number of lymphocytes infused with
the graft, the degree of HLA disparity, and a reduced thymic function in adults and
differences in host/donor antigen presenting cells are contributing causes.
The infusions of HSV-TK engineered lymphocytes may represent a significant therapeutic
improvement in haploidentical haplo-HCT, because it remarkably may enhance both GvL
activity, thus reducing the occurrence of disease relapse, and post-transplant immune
reconstitution in the absence of chronic immune suppression, thus decreasing the rate of
both post-transplant opportunistic infections and transplant-related mortality. Furthermore,
the efficient control of GvHD achieved via the suicide mechanism allows also the multiple
infusion of HSV-TK-treated donor lymphocytes, when needed, that might further improve
post-transplant host immune reconstitution, and, eventually, survival in patients receiving
haplo-HCT. Finally, this therapeutic approach, which allows the safe infusion of escalating
doses of donor lymphocytes, can become a valuable option for all candidates, including
patients with advanced disease and older age.
The proposed clinical trial represents an innovative therapeutic treatment for patients
affected by hematological malignancies, who have undergone haploidentical stem cell
transplantation.
Inclusion Criteria:
- Patients >=18 years old affected by hematological malignancies at high risk of
relapse based on disease progression or presence of negative prognostic factors, who
have received a HCT from donor HLA mismatched (haploidentical) for 2 or 3 loci
- Engraftment documented by >500 neutrophils/µl for three consecutive days in the
absence of growth factors
- Mixed chimerism or full donor chimerism confirmed
- AML in 1st or 2nd relapse or primary refractory
- High-risk AML in 1st or subsequent remission
- RAEB and RAEB-T
- CML in 2nd chronic phase, blast crisis or accelerated phase
- Poor prognosis ALL in 1st or subsequent remission
- High grade lymphomas in 3rd or subsequent remission
- Multiple myeloma in advanced stage relapsing or progressing after high dose
chemotherapy
- Absence of fully HLA matched or one HLA locus mismatched family donor
- Stable clinical conditions and life expectancy >3 months
- PS Karnofsky >70
- Written donor/patient informed consent
Exclusion Criteria:
- Infection with cytomegalovirus being treated with ganciclovir
- Presence of GvHD grade > I that requires systemic immunosuppressive therapy (at
baseline)
- Ongoing systemic immunosuppressive therapy
- Ongoing acyclovir administration
- Administration after haplo-HCT of G-CSF and cyclosporine A
- CD3+ lymphocytes >100/µl before day +42 after haplo-HCT
- Life-threatening condition or complication other than their basic disease
- CNS disease
- Pregnant or lactating women
Type of Study:
Interventional
Study Design:
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Evaluation of clinical activity in terms of immune-reconstitution, provided by the add- back of the transduced T-cells after haplo-HCT
Outcome Time Frame:
during the study
Safety Issue:
No
Principal Investigator
Fabio Ciceri, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Hematology and BMT Unit, San Raffaele Scientific Institute, Milan, Italy
Authority:
Italy: National Institute of Health
Study ID:
TK007
NCT ID:
NCT00423124
Start Date:
July 2002
Completion Date:
March 2013
Related Keywords:
- Hematological Malignancies
- Hematological malignancies
- HSV-TK
- Haploidentical HCT
- GvHD
- GvL
- Neoplasms
- Suicide
- Hematologic Neoplasms
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