Table 2.

Completed and ongoing clinical trials involving adoptive Treg therapy in GVHD (ClinicalTrials.gov; search date 30 July 2021).

Study ID	Ph	Enrollment Actual/Planned	HSCT/IST	Indication	Cell Product/Dose	Outcomes	Status	Center	References
NCT01634217	I	16/16	MRD MMF/Siro, n = 2 MMF/CSA, n = 14	GVHD PPx	Expanded PB CD4 iTregs Dose-escalation 3 × 106/kg–3 × 108/kg	Final Results: 1st cohort: 100% grade 3 aGVHD 2nd cohort: 20% ≥ grade 2 aGVHD	Completed	University of Minnesota, USA	[42]
NCT02423915	I	5/5	dUCBT, n = 2 PB MUD, n = 3 MMF/Siro	GVHD PPx	Fucosylated fresh UCB CD4 tTreg 1 × 106/kg–1 × 107/kg	Final Results: 100% ≥ grade 2 aGVHD	Completed	MD Anderson, USA	[230]
NCT01660607	I/II	12/24	TCD MRD/MUD No IST, n = 5 TAC or Siro, n = 7 Remaining, n = 12	GVHD PPx	Fresh CD4 tTregs and Tcons Dose-escalation and extension 1 × 106/kg–3 × 106/kg Treg and 1 × 105/kg–3 × 107/kg Tcon	Interim Results: 1st cohort: 40% ≥ grade 2 aGVHD 2nd cohort: No GVHD (n = 7)	Recruiting	Stanford, USA	[39]
NCT01795573	I	38/48	MRD IST: unknown	GVHD PPx	Donor CD4 tTregs expanded with recipient DCs Dose: unknown	No results	Active, not recruiting	Moffitt Cancer Center, USA	N/A
2012-002685-12	I	9/9	Not specified	GVHD PPx	Fresh CD4 tTreg Up to 5 × 106/kg × once	Final Results: Safe; not designed for efficacy	Completed	University Hospital Regensburg, Germany	[231]
01/08	I	28/28	Haploidentical Without IST	GVHD PPx	Fresh PB CD4 tTregs and Tcons Dose-escalation 2 × 106/kg–4 × 106/kg Treg and 0.5 × 106/kg–2 × 106/kg Tcon	Final Results: 15% developed ≥ grade 2 aGVHD 5% developed relapse	Completed	University of Perugia, Italy	[11,206]
NCT00602693	I	11/11	dUCBT MMF/Siro	GVHD PPx	Expanded UCB CD4 tTreg Dose-escalation 3 × 106–1 × 108/kg Treg	Final Results: 9% developed ≥ grade 2 aGVHD 5% developed relapse	Completed	University of Minnesota, USA	[10]
NCT00602693	I	23/23	dUCBT	GVHD PPx	Expanded UCB CD4 tTreg Dose-escalation 0.1 × 105–30 × 105/kg Treg	Final Results: 43% ≥ grade 2 aGVHD (vs. 61% in historical control)	Completed	University of Minnesota, USA	[36]
NCT04678401	I	NA/10	Haplo Without IST	GVHD PPx	Treg enriched haplo graft NA: Treg dose	No results	Recruiting	Dana-Farber Cancer Institute, USA	N/A
NCT04013685	I	NA/84	TCD MRD/MUD Single agent IST	GVHD PPx	Engineered donor graft: TCD graft with additional infusion of Tcon and Tregs (TregGraft/Orca-T)	No results	Recruiting	Multi-center, USA	N/A
NCT01903473	II	NA/35 Treg arm, n = 10 Control, n = 25	Any	SR cGVHD	Fresh PB CD4 tTregs with sirolimus and low-dose IL-2 0.5 × 106/kg × once	No results	Recruiting	University of Liege, Belgium	N/A
NCT01937468	I	NA/25	Any	SR cGVHD	Fresh PB CD4 tTreg Dose: Unknown	No results	Active, not recruiting	Dana-Farber Cancer Institute, USA	N/A
NCT02385019	I/II	NA/22	Any	SR cGVHD	Fresh PB CD4 tTreg Dose-escalation and extension 0.5 × 106/kg–3 × 106/kg × once	No results	Unknown	IMMJLA, Portugal	N/A
NCT01911039	I	NA/20	Any	SR cGVHD	Unknown Treg Type Dose-escalation 1 × 105/kg–1.5 × 106/kg × once	No results	Unknown	Stanford University, USA	NA
NCT02749084	I/II	NA/20	Any	SR cGVHD	Multiple donor PB CD4 tTreg Dose-escalation 1.7 × 105/kg–6.6 × 106/kg monthly × 3	No results	Recruiting	Universitaria di Bologna, Italy	NA
EK 206082008	I	5/5	Any	SR cGVHD	Expanded PB CD4 tTreg Dose-escalation 5 × 105/kg–4.4 × 106/kg × once	Final Results: Clinical response in 2 pts Stable disease in 3 pts	Completed	University Hospital Carl Gustav Carus, Germany	[229]
NCT03683498	I	0/16	Any	SR cGVHD	Expanded CD4 tTreg Dose-escalation 0.5 × 106/kg–2 × 106/kg	No Results	Active, not recruiting	FPAGI, Spain	N/A
NCT01911039	I	NA/20	Any	SR cGVHD	Unknown type Dose-escalation 1 × 105/kg–1.5 × 106/kg	No Results	Unknown	Stanford University, USA	N/A
NKEBN/458-310/2008	I	2/2	MRD Single agent IST	SR aGVHD SR cGVHD	Expanded CD4 tTreg 1 × 105/kg in SR cGVHD 3 × 106/kg in SR aGVHD	Final Results: Reduced IST in cGVHD Only transient improvement in aGVHD	Completed	Medical University of Gdańsk, Poland	[198]
NCT01453140	I/II	3/15	Any	SR aGVHD	Expanded PB CD4 tTreg with cyclophosphamide and sirolimus with or without Azacitidine Unknown dose	No results	Completed	John Theurer Cancer Center, USA	N/A

Abbreviations: aGVHD: acute GVHD; cGVHD: chronic GVHD; CSA: cyclosporin; dUCBT: double umbilical cord blood transplant; GVHD: graft-versus-host disease; HSCT: hematopoietic stem cell transplantation; IST: immunosuppressive therapy; MMF: mycophenolate mofetil; MRD: matched related donor; MUD: matched unrelated donor; NA: not available; PB: peripheral blood; Siro: sirolimus; SR GVHD: steroid-refractory GVHD; TAC: tacrolimus; UCB: umbilical cord blood.