Clinical Grade Adenovirus Specific T Cells for Immunotherapy After Allogeneic Stem Cell Transplantation (CTL-ADV)

Study Overview
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Brief Summary
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Fourteen patients will be included for infusion of adenovirus-specific T-cells generated by a clinical grade IFN-γ based immunomagnetic isolation from a leukapheresis from their original donor or a haploidentical donor, in case of Umbilical cord blood transplantation, in the event of refractory ADV infection or disease.

Detailed Description
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Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) has improved over the last decades. However, after HSCT and especially with matched unrelated, cord blood or haploidentical donors, patients often experience a deep immunodeficiency, increasing susceptibility to viral infections. Among them, adenovirus (ADV) systemic infection, often refractory to antiviral treatment, is associated with a high mortality rate up to 50% (even more in children). Viremia monitoring after HSCT has contributed to improve survival allowing the implementation of a pre-emptive anti-viral treatment before any appearance of clinical signs of ADV disease. Nevertheless, no anti-viral drug is authorized for ADV infections, although intravenous (IV) cidofovir seemed to be, up to now, the most efficient. However, nephrotoxicity, especially tubular dysfunction, is often described, requiring hydratation and uroprotection with probenecid and limiting the treatment period. Meanwhile, adoptive transfer of ADV-specific T cells, prepared with an immunomagnetic clinical grade technology, is becoming an alternative treatment that has already proved feasible, safe and helpful in viral clearance and immune reconstitution related to an in vivo expansion of ADV-specific T cells leading to clinical improvement (Feuchtinger et al, 2006, 2015; Qazim et al, 2013). Our team proposes a multicenter Phase I/II clinical trial with ADV-specific T cells where 14 patients, with refractory ADV infection or disease after unrelated Peripheral blood or umbilical cord blood HSCT, are included.

Official Title
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Generation of Clinical Grade Adenovirus Specific T Cells for Adoptive Immunotherapy After Allogeneic Stem Cell Transplantation : Clinical Trial

Conditions
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Adenovirus Infection

Intervention / Treatment
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* Other: Infusion of ADV specific T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Study Population : adults or children Allogeneic hematopoietic stem cell (bone marrow and peripheral blood stem cell, umbilical cord blood (UCB)) sibling or matched unrelated donors 10/10 or 9/10 ((M)MUD) or haploidentical donor in case of UCB transplantation Within 18 months after HSCT, occurrence of: - An adenovirus infection without clinical symptoms (except fever with unknown origin) definitively due to this infection, after treatment failure during at least 2 weeks with Cidofovir (5 mg/kg/week). To determine ADV infection, 2 consecutive viremia performed at 4 days interval must be higher than viral threshold of 500 copies/mL (with significant increase between these 2 analysis and at least 0, 5 log when the first viremia is equal to 500 cp/mL). Probable or definitive adenovirus infection after Cidofovir treatment failure, 5 mg/kg/week (according to Wisconsin's criteria) and/or renal toxicity or major intolerance to anti-viral drug and/or in case Cidofovir is not available in France Acute or Chronic GVHD with acute form grade II or less, controlled after 2 lines of treatment at the most. Or controlled Chronic GVHD - Life expectancy > 1 month at the time of inclusion Exclusion Criteria: Graft failure Derogatory HSCT Acute or Chronic GVHD in acute form with grade > II, uncontrolled after 2 lines of immunosuppressive agents. Patients with grade > III clinical or biological toxicities (according to OMS classification) Chronic GVHD uncontrolled Immediate life-threatening Patients have not signed informed consent

Ages Eligible for Study
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Minimum Age: 6 Months

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Infusion of ADV specific T cells<br>This one arm study consists in ADV-specific T cell infusion after HSCT from a (M)MUD or, for the first time, from a haploidentical donor for patients having undergone previous UCB transplantation, in the event of refractory ADV infection or disease. Specific anti-ADV immune reconstitution was observed in all patients, and viral load clearance in all but one. | Other: Infusion of ADV specific T cells<br>* Cell engineering<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Graft Versus Hot Disease (GVHD) grade >2 | No occurrence of acute Graft Versus Hot Disease (GVHD) grade >2 and/or extensive chronic GVHD and no reactivation or worsening of acute or chronic GVHD during the first month following infusion. | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Follow-up of ADV viral load | Follow-up of ADV viral load by quantitative Polymerase Chain Reaction (PCR) : Decrease > 0.5 Log | 90 days | 
| Follow-up of anti-ADV immune response | Follow-up of anti-ADV immune response in the recipient (developing a specific immune response based on in vivo CTL expansion evaluated by IFN ELISPOT or intracellular cytokine staining). | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adenovirus