Clinical trial NCT02851576: Clinical Grade Adenovirus Specific T Cells for Immunotherapy After Allogeneic Stem Cell Transplantation (CTL-ADV)
Official title: Generation of Clinical Grade Adenovirus Specific T Cells for Adoptive Immunotherapy After Allogeneic Stem Cell Transplantation : Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Adenovirus Infection
Keywords: Adenovirus
Lead sponsor: Central Hospital, Nancy, France
Sponsor class: OTHER
First posted: 2016-08-01
Enrollment: 14
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Graft Versus Hot Disease (GVHD) grade >2
timeFrame: 1 month
Secondary outcomes:
measure: Follow-up of ADV viral load
timeFrame: 90 days
measure: Follow-up of anti-ADV immune response
timeFrame: 90 days
Other outcomes:
Locations:
city: Vandœuvre-Lès-Nancy
country: France
facility: Centre Hospitalier Universitaire de Nancy
Study officials:
affiliation: Central Hospital, Nancy, France
name: Cécile POCHON, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Bordeaux
name: Laurence CLEMENT, Doctor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Aissi-Rothe L, Decot V, Venard V, Jeulin H, Salmon A, Clement L, Kennel A, Mathieu C, Dalle JH, Rauser G, Cambouris C, de Carvalho M, Stoltz JF, Bordigoni P, Bensoussan D. Rapid generation of full clinical-grade human antiadenovirus cytotoxic T cells for adoptive immunotherapy. J Immunother. 2010 May;33(4):414-24. doi: 10.1097/CJI.0b013e3181cc263b.
citation: Feucht J, Opherk K, Lang P, Kayser S, Hartl L, Bethge W, Matthes-Martin S, Bader P, Albert MH, Maecker-Kolhoff B, Greil J, Einsele H, Schlegel PG, Schuster FR, Kremens B, Rossig C, Gruhn B, Handgretinger R, Feuchtinger T. Adoptive T-cell therapy with hexon-specific Th1 cells as a treatment of refractory adenovirus infection after HSCT. Blood. 2015 Mar 19;125(12):1986-94. doi: 10.1182/blood-2014-06-573725. Epub 2015 Jan 23.
citation: Feuchtinger T, Matthes-Martin S, Richard C, Lion T, Fuhrer M, Hamprecht K, Handgretinger R, Peters C, Schuster FR, Beck R, Schumm M, Lotfi R, Jahn G, Lang P. Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation. Br J Haematol. 2006 Jul;134(1):64-76. doi: 10.1111/j.1365-2141.2006.06108.x.
citation: Qian C, Campidelli A, Wang Y, Cai H, Venard V, Jeulin H, Dalle JH, Pochon C, D'aveni M, Bruno B, Paillard C, Vigouroux S, Jubert C, Ceballos P, Marie-Cardine A, Galambrun C, Cholle C, Clerc Urmes I, Petitpain N, De Carvalho Bittencourt M, Decot V, Reppel L, Salmon A, Clement L, Bensoussan D. Curative or pre-emptive adenovirus-specific T cell transfer from matched unrelated or third party haploidentical donors after HSCT, including UCB transplantations: a successful phase I/II multicenter clinical trial. J Hematol Oncol. 2017 May 8;10(1):102. doi: 10.1186/s13045-017-0469-0.