Tregs combined with mature donor T-cells hasten immune reconstitution without triggering GvHD in HLA haploidentical transplantation

Ref ID: 18570

Author:

M. Di Ianni (1), F. Falzetti (1), A. Carotti (1), A. Terenzi (1),
E. Bonifacio (1), K. Perruccio (1), B. Del Papa (1), T. Zei (1),
L. Ruggeri (1), Y. Reisner (2), A. Velardi (1), F. Aversa (1),
M.F. Martelli (1)

Author address:

(1)University of Perugia (Perugia, IT); (2)Weizmann Institute of
Science (Rehovot, IL)

Full conference title:

Annual Meeting of the EBMT, 36th

Abstract:

Haploidentical transplantation, with extensive T cell depletion to
prevent GvHD, is associated with a high incidence of infectionrelated deaths. The key challenge is to improve immune recovery with allogeneic donor T cells without triggering GvHD. As T
regulatory cells (Tregs) controlled GvHD in preclinical studies, S75
the present phase I/II clinical trial evaluated the impact of early
infusion of donor CD4/CD25 + Tregs, followed by an inoculum
of donor mature T cells (Tcons) and positively immunoselected
CD34 + cells. Twenty-eight patients (median age 41, range 21-
60) were enrolled from September 2008 onwards; 22 had AML
(10 in CR1 at high risk, 10 in ≥ CR2 and 2 in relapse), 5 had ALL
(4 in CR1; 1 in relapse) and 1 had high grade NHL in relapse.
Conditioning was: 8Gy single fraction TBI, thiotepa (4 mg/kg x 2),
fl udarabine (40 mg/m² x 5), cyclophosphamide (35 mg/kg x 2).
All patients received immunoselected Tregs (CliniMACS,
Miltenyi Biotec) (23/28 2 x 10
6
/kg bw; 5/28 4 x 10
6
/kg bw) and
3 days later positively immunoselected CD34 + cells (median
8.2 x 10
6
/kg bw, range 5.0-19.1) together with Tcons (4/28
0.5 x 10
6
/kg bw; 17/28 1 x 10
6
/kg bw; 5/28 2 x 10
6
/kg bw; 2/28 did
not receive Tcons). CD4/CD25 + Tregs (purity 92.7±2.1) consisted of 33.6%±13.1 CD25
high
; 58.1%±6.6 CD25
int
; 5.8%±2.5
CD25
low
; 65.7%±11.8 FoxP3; 17.4%±7.2 CD127 (mean±SD). No
GvHD prophylaxis was administered. 26/28 patients engrafted.
No GvHD developed in 24/26 patients, 2 developed ≥ grade II
GvHD. Ten patients died (3 VOD, 2 fungal pneumonia, 1 bacterial sepsis, 1 CNS aspergillosis, 1 systemic toxoplasmosis,
1 adenoviral infection, 1 MOF). CD4 and CD8 counts reached,
respectively, 50/μL medianly on days 34 (range 19-63 days) and
24 (range 15-87); 100/μL medianly on days 47 (range 28-100
days) and 34 (range 19-95); 200/μL on days 70 (range 41-146
days) and 61 (range 21-95). A wide T-cell repertoire developed
rapidly with high frequencies of specifi c CD4 + and CD8 + for
opportunistic pathogens. Episodes of CMV reactivation were
signifi cantly fewer than after our “œstandard haplo” transplants.
In KIR ligand-mismatched transplants, speed of NK cell reconstitution/maturation and size of donor vs. recipient alloreactive
NK cell repertoires were preserved. In conclusion, in the setting of haploidentical transplantation infusion of Tregs makes
administration of a high dose of T cells feasible for the fi rst time.
This strategy provides a long-term protection from GvHD and
robust immune reconstitution.

Abstract Number: O383

Conference Year: 2010

Link to conference website: NULL

New link: NULL

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