Infusion of Donor Lymphocytes Transduced With the Suicide Gene HSV TK in Patients With Haematological Malignancies
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||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|
- Evaluation of clinical activity in terms of immune-reconstitution, provided by the add- back of the transduced T-cells after haplo-HCT [ Time Frame: during the study ] [ Designated as safety issue: No ]
- Evaluation of the "in vivo" control of GvHD after administration of ganciclovir in patients treated with HSV-TK transduced T-cells [ Time Frame: during the study ] [ Designated as safety issue: Yes ]
- Evaluation of GvL effect [ Time Frame: during the study ] [ Designated as safety issue: No ]
- Time to relapse, time to death (evaluated by disease free survival and overall survival) [ Time Frame: during the study ] [ Designated as safety issue: Yes ]
- Incidence of infectious events (measured by number of infectious events) [ Time Frame: during the study ] [ Designated as safety issue: Yes ]
- Acute and long term toxicity related to the infusions (measured by incidence of adverse events) [ Time Frame: during the study and study follow up ] [ Designated as safety issue: Yes ]
|Study Start Date:||July 2002|
|Study Completion Date:||November 2013|
|Primary Completion Date:||December 2011 (Final data collection date for primary outcome measure)|
Infusion of genetically modified lymphocytes (1x10^6-1x10^7 c/kg): first at +21-+49 days after HSCT; in absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00423124
|Medizinische Hoschule Hannover|
|Hadassah University Hospital|
|Fondazione San Raffaele|
|Istituto Clinico Humanitas|
|London, United Kingdom|
|Principal Investigator:||Fabio Ciceri, MD||Hematology and BMT Unit, San Raffaele Scientific Institute, Milan, Italy|