A Phase I/IIa study of autologous tolerogenic dendritic cells immunotherapy in kidney transplant recipients
Aurélie Moreau
(1, 2, 3)
,
Delphine Kervella
(4, 5, 6, 7, 3)
,
Laurence Bouchet-Delbos
(1, 4, 2, 3)
,
Cécile Braudeau
(1, 2)
,
Soraya Saïagh
(8, 9)
,
Pierrick Guérif
(1, 1)
,
Sophie Limou
(1, 10)
,
Anne Moreau
(4)
,
Sylvain Bercegeay
(11, 8, 12)
,
Mathias Streitz
(13, 14)
,
Birgit Sawitzki
(13)
,
Ben James
(15)
,
Paul Harden
(16)
,
David Game
(17)
,
Qizhi Tang
(18)
,
James Markmann
(19)
,
Ian S.D. Roberts
(16)
,
Edward Geissler
(20, 21, 15)
,
Brigitte Dréno
(22, 23)
,
Régis Josien
(1, 2, 3)
,
Maria-Cristina Cuturi
(4, 1, 24, 6)
,
Gilles Blancho
(4, 5, 6, 7, 3)
1
U1064 Inserm - CR2TI -
Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology
2 Team 1 - U1064 Inserm - CR2TI - Team 1 : Mononuclear phagocytes, Immunopathology, Immunovirology
3 Nantes Univ - Nantes Université
4 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
5 Team 3 - U1064 Inserm - CR2TI - Team 3 : Integrative transplantation, HLA, Immunology and genomics of kidney injury
6 ITUN - Institut de transplantation urologie-néphrologie
7 Service de Néphrologie et Immunologie Clinique [CHU de Nantes]
8 UTCG - Unité de Thérapie Cellulaire et Génique [CHU Nantes]
9 CRCI2NA - Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers
10 Nantes Univ - ECN - NANTES UNIVERSITÉ - École Centrale de Nantes
11 CRCI2NA / Eq 2 - Nuclear Oncology
12 CIC Nantes - Centre d’Investigation Clinique de Nantes
13 Charité - UniversitätsMedizin = Berlin University Medicine
14 FLI - Friedrich-Loeffler-Institut
15 University of Regensburg
16 Oxford University Hospitals NHS Trust
17 Guy's and St Thomas' Hospital [London]
18 UC San Francisco - University of California [San Francisco]
19 Massachusetts General Hospital [Boston]
20 University Hospital Regensburg
21 Fraunhofer ITEM - Fraunhofer Institute for Toxicology and Experimental Medicine
22 INCIT - Immunology and New Concepts in ImmunoTherapy
23 Service de dermatologie [Nantes]
24 LabEX IGO Immunothérapie Grand Ouest
2 Team 1 - U1064 Inserm - CR2TI - Team 1 : Mononuclear phagocytes, Immunopathology, Immunovirology
3 Nantes Univ - Nantes Université
4 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
5 Team 3 - U1064 Inserm - CR2TI - Team 3 : Integrative transplantation, HLA, Immunology and genomics of kidney injury
6 ITUN - Institut de transplantation urologie-néphrologie
7 Service de Néphrologie et Immunologie Clinique [CHU de Nantes]
8 UTCG - Unité de Thérapie Cellulaire et Génique [CHU Nantes]
9 CRCI2NA - Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers
10 Nantes Univ - ECN - NANTES UNIVERSITÉ - École Centrale de Nantes
11 CRCI2NA / Eq 2 - Nuclear Oncology
12 CIC Nantes - Centre d’Investigation Clinique de Nantes
13 Charité - UniversitätsMedizin = Berlin University Medicine
14 FLI - Friedrich-Loeffler-Institut
15 University of Regensburg
16 Oxford University Hospitals NHS Trust
17 Guy's and St Thomas' Hospital [London]
18 UC San Francisco - University of California [San Francisco]
19 Massachusetts General Hospital [Boston]
20 University Hospital Regensburg
21 Fraunhofer ITEM - Fraunhofer Institute for Toxicology and Experimental Medicine
22 INCIT - Immunology and New Concepts in ImmunoTherapy
23 Service de dermatologie [Nantes]
24 LabEX IGO Immunothérapie Grand Ouest
Delphine Kervella
- Fonction : Auteur
- PersonId : 1084350
- ORCID : 0000-0001-8069-6105
Laurence Bouchet-Delbos
- Fonction : Auteur
- PersonId : 758464
- ORCID : 0000-0002-4320-0681
Pierrick Guérif
- Fonction : Auteur
- PersonId : 1158696
Sophie Limou
- Fonction : Auteur
- PersonId : 1191789
- ORCID : 0000-0002-7702-8234
- IdRef : 146362705
Brigitte Dréno
- Fonction : Auteur
- PersonId : 918620
- ORCID : 0000-0001-5574-5825
- IdRef : 06094370X
Régis Josien
- Fonction : Auteur
- PersonId : 792085
- ORCID : 0000-0001-7900-7413
- IdRef : 075865106
Maria-Cristina Cuturi
- Fonction : Auteur
- PersonId : 1048208
- ORCID : 0000-0001-5249-7467
- IdRef : 060155396
Gilles Blancho
- Fonction : Auteur
- PersonId : 767373
- ORCID : 0000-0003-0356-5069
- IdRef : 080126626
Résumé
Kidney transplant survival is shortened by chronic rejection and side effects of standard immunosuppressive drugs. Cell-based immunotherapy with tolerogenic dendritic cells has long been recognized as a promising approach to reduce general immunosuppression. Published trials report the safety and the absence of therapy-related adverse reactions in patients treated with tolerogenic dendritic cells suffering from several inflammatory diseases. Here, we present the first phase I clinical trial results using human autologous tolerogenic dendritic cells (ATDC) in kidney transplantation. Eight patients received ATDC the day before transplantation in conjunction with standard steroids, mycophenolate mofetil and tacrolimus immunosuppression with an option to taper mycophenolate mofetil. ATDC preparations were manufactured in a Good Manufacturing Practice-compliant facility and fulfilled cell count, viability, purity and identity criteria for release. A control group of nine patients received the same standard immunosuppression, except basiliximab induction replaced ATDC therapy and mycophenolate tapering was not allowed. During the three-year follow-up, no deaths occurred and there was 100% graft survival. No significant increase of adverse events was associated with ATDC infusion. Episodes of rejection were observed in two patients from the ATDC group and one patient from the control group. However, all rejections were successfully treated by glucocorticoids. Mycophenolate was successfully reduced/stopped in five patients from the ATDC group, allowing tacrolimus monotherapy for two of them. Regarding immune monitoring, reduced CD8 T cell activation markers and increased Foxp3 expression were observed in the ATDC group. Thus, our results demonstrate ATDC administration safety in kidney-transplant recipients.