Infusion of Donor Lymphocytes Transduced With the Suicide Gene HSV TK in Patients With Haematological Malignancies

Study Overview
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Brief Summary
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The aim of the study is to obtain immune reconsitutuion as well as reduction of infective episodes and disease relapse in patient with haematological malignancies who underwent SCT(and subsequent T lymphocytes infusions) and selectively controlling GvHD.

Detailed Description
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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.

Official Title
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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

Conditions
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Hematological Malignancies

Intervention / Treatment
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* Genetic: HSV-TK


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br> | Genetic: HSV-TK<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of clinical activity in terms of immune-reconstitution, provided by the add- back of the transduced T-cells after haplo-HCT |  | during the study | 
| Evaluation of the in vivo control of GvHD after administration of ganciclovir in patients treated with HSV-TK transduced T-cells |  | during the study | 
| Evaluation of GvL effect |  | during the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to relapse, time to death (evaluated by disease free survival and overall survival) |  | during the study | 
| Incidence of infectious events (measured by number of infectious events) |  | during the study | 
| Acute and long term toxicity related to the infusions (measured by incidence of adverse events) |  | during the study and study follow up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hematological malignancies, HSV-TK, Haploidentical HCT, GvHD, GvL