Autologous Cytomegalovirus (CMV) Specific CD8+ T Cells as Treatment for CMV Reactivation

Study Overview
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Brief Summary
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The investigators will assess whether the infusion of autologous CMV-specific T-cells at the time of CMV reactivation posttransplant will prevent worsening of CMV virus reactivation posttransplant to a level that warrants therapy with antiviral drugs (objectively assessed by looking at CMV virus copy number).

Detailed Description
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Allogeneic Hematopoietic Stem Cell transplantation (allo-SCT) remains the only curative approach for a number of patients with hematological malignancies. However, the use of allo-SCT can expose patients to prolonged periods of immunosupression during which time viral infections can be a significant cause of morbidity and mortality. Human cytomegalovirus (CMV) infection and reactivation still represents one of the most important and lifethreatening complications in immunocompromised patients. Prophylaxis or early treatment with antiviral drugs after CMV reactivation have reduced the mortality related to this complication. However, the antiviral drugs have many side-effects and are costly. Furthermore, CMV infection refractory to antiviral treatment after alloSCT is associated with a high mortality. A number of studies have shown the efficacy of selecting Tcells against the virus from the donor and infusing them into the recipient (adoptive transfer of immunity) to prevent or treat CMV reactivation. However this approach relies on the donor having preexisitng immunity to CMV (50% of the healthy population is CMV seronegative and therefore have no preexisting immunity against CMV). We propose an alternative approach to collect CMV specific Tcells from the seropositive recipient prior to transplantation; the autologous CMV specific T cells will then be infused back into the recipient at the time of CMV reactivation post-transplant. This approach is especially relevant where the donor is CMV seronegative or unavailable or following the use of cord blood transplant where there is no memory T cell response to CMV.

Official Title
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Adoptive Transfer of Autologous CMV Specific CD8+ T Cells After Allogeneic Stem Cell Transplantationas Treatment for CMV Reactivation: A Phase I/II Clinical Trial.

Conditions
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CMV Reactivation, Allogeneic Stem Cell Transplantation, Autologous CMV Specific CD8+ T Cells

Intervention / Treatment
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* Procedure: Lymphopheresis
* Procedure: CMV specific lymphocyte infusion
* Procedure: Peripheral blood for CMV DNA PCR
* Procedure: Haematology/Blood chemistry


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have received an allogeneic stem cell transplant from any donor, as treatment for a haematological malignancy. HLAA0201 positive at one allele CMV seropositive The patient must be willing and capable of donating lymphocytes for CMVspecific CD8+ T cell selection using apheresis techniques The patient must be in complete remission with no evidence of circulating blasts or other malignant cells Patient must be fit to undergo leukapheresis Patients must have signed an informed consent form before undergoing LP prior to alloSCT Indications for infusion of autologous CMV specific CD8+ Tcells: Therapeutic: CMV disease following allogeneic stem cell transplantation Preemptive: CMV reactivation (by CMV DNA PCR) autologous CMV specific CD8+ T-cells must be infused into the patient no later than 72 following CMV reactivation. Steroids should be withdrawn at least 1 week before the infusion of CMVspecific CD8+ T-cell Patients must have signed an informed consent form before the infusion of autologous CMV specific CD8+ T-cells Exclusion Criteria: Patient CMV seronegative No informed consent Patient positive at the time of LP for one of the following infectious agents: HIV, HBV, HCV,Syphilis, HTLV 1 and 2 Patient with circulating leukemic blasts at the time of LP Exclusion criteria for infusion of autologous CMV specific CD8+ T cells: Severe GvHD (grade IIII-V) requiring full dose immunosuppressive treatment

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

| Intervention/Treatment |
| --- |
|Procedure: Lymphopheresis|Lymphopheresis|
|Procedure: CMV specific lymphocyte infusion|CMV specific lymphocyte infusion|
|Procedure: Peripheral blood for CMV DNA PCR|Peripheral blood for CMV DNA PCR|
|Procedure: Haematology/Blood chemistry|Haematology/Blood chemistry analysis, Collection of blood for ancillary laboratory tests.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to adoptive transfer of autologous CMV-specific CD8+ T-cells | Response to CMV-specific CD8+ T-cells administration will be measured and defined as a CMV DNA PCR< 50 copies. | Up to three years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The occurrence of subsequent CMV reactivations | The occurrence of subsequent CMV reactivations. | Up to three years | 
| Rate of complete response | The rate of complete response will be analyzed and compared to patients treated with anti-viral drugs only. | Up to three years | 
| Rate of early complete response | The rate of early complete response will be analyzed and compared to patients treated with anti-viral drugs only. | Up to three years | 
| Rate of subsequent CMV reactivation | The rate of subsequent CMV reactivation will be analyzed and compared to patients treated with anti-viral drugs only. | Up to three years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CMV, cytomegalovirus, autologous, leukemia, hematological malignancies, stem cell transplantation, CMV reactivation, adoptive therapy