314 Selective Photodepletion of Recipient

314 Selective Photodepletion of Recipient-Alloreactive T-Cells
Enables Safe and Efficacious Haploidentical HSCT: Initial Results
from a Phase 2 Trial in Patients with AML, ALL, and MDS
Program: Oral and Poster Abstracts
Type: Oral
Session: 711. Cell Collection and Processing: Preclinical News
Monday, December 8, 2014: 7:15 AM
West Building, 3018-3020 (Moscone Center)
Denis-Claude Roy, MD1, Johan Maertens, MD, PhD2*, Irwin Walker, MBBS3, Silvy Lachance, MD1,
Jean Roy, MD1, Stephen Ronan Foley, MD3, Philippe Lewalle, MD, PhD4*, Dominik L.D. Selleslag, MD5,
Liesbeth De Jong, PhD6*, Jurjen H.L. Velthuis, PhD6*, Lisya Gerez, PhD6*, Karen Reitsma, PhD6*, Edwin
Wagena, PhD6* and Stephan Mielke, MD7
1Department of Hematology and Cellular Therapy Laboratory, Hôpital Maisonneuve-Rosemont,
University of Montreal, Montreal, QC, Canada
2Department of Hematology, University Hospital Gasthuisberg Leuven, Leuven, Belgium
3Department of Medicine, Juravinski Hospital and Cancer Centre, Hamilton, Canada
4Experimental Laboratory of Hematology, Institut Jules Bordet, ULB, Brussels, Belgium
5Department of Hematology, Az Sint-Jan, Brugge, Belgium
6Kiadis Pharma, Amsterdam-Duivendrecht, Netherlands
7Zentrum Innere Medizin (ZIM), Abteilung Hämatologie und Onkologie, Universitätsklinikum
Würzburg, Wurzburg, Germany
Introduction
For patients in need of a hematopoietic stem cell transplant (HSCT) but lacking an HLA matched
donor, a haploidentical family donor is a particularly appealing alternative. However, to prevent
graft-versus-host disease (GVHD), haploidentical HSCT necessitates intensive in vivo or ex vivo T-cell
depletion that results in frequent and often lethal infectious complications and/or high relapse rates,
thus decreasing overall survival. To overcome this limitation, we have developed a strategy that
photodepletes host-reactive cells from the donor T cell graft, while preserving anti-infection and
anti-leukemia reactivity.
Patients and Methods
In an open-label, multi-center phase 2 clinical trial (CR-AIR-007; NCT01794299), 12 of a planned 23
patients with high-risk hematologic malignancies were treated to date with this immunotherapy
approach consisting of donor lymphocytes selectively allodepleted of host-reactive T-cells using
photodynamic therapy (ATIR). ATIR was infused 28-32 days after haploidentical CD34-selected HSCT.
No post-transplant GVHD prophylaxis was used. These patients were compared to a control group of
28 patients treated in a previous Phase 2 study with an investigational product manufactured using a
process different from the Phase 1 trial and resulting mainly in dead and inactive cells instead of ATIR
(CR-AIR-004).
Results
Twelve patients, mean age of 45 (range 21-64), 6 females/6 males with AML (n=9) and ALL (n=3)
were treated with ATIR so far. ATIR consisted mainly of T-cells (>90%), with residual B and NK cells
(≤10%). Selective depletion of recipient-reactivity in each ATIR cell graft was assessed using a CFSEbased proliferation assay. Cell division numbers upon stimulation were analyzed using Modfit LT
software (Fig 1A), which generated a proliferation index representing viable/reactive T-cells in donor
cells (blue) and final ATIR product (green)(Fig 1B). Selective depletion of recipient-reactive T-cells
with preservation of reactivity towards 3rd party antigens and anti-CD3/CD28 was observed in all
ATIR cell grafts and used as a release criteria in the 007 study.
Figure 1: A) CFSE-dilution pattern in Modfit LT software of ATIR stimulated with 3rd party
cells. B) CFSE-based proliferation confirmed selective depletion of recipient-reactive T-cells in all
grafts (representative depiction).
Preparative regimen consisted of A) FTBI (1200 cGy; n=5) or B) melphalan (120 mg/m2; n=7), along
with thiotepa (10 mg/kg), fludarabine (30 mg/m2 x5 d) and ATG (2.5 mg/kg x4 d). Neutrophil and
platelet engraftment was achieved in all patients at a median of 12 days (range: 9-35). No patient
experienced graft rejection.
Patients (n=28) in the 004 control group, mean age of 42 (range 18-61), 13 females/15 males had
AML (n=19), ALL (n=6) or MDS (n=3). CFSE proliferation in T-cell grafts could not be assessed a
posteriori due to low cell viability. These 004 patients received the same A) FTBI- (n=14), B)
melphalan- (n= 10) based preparative regimen as 007 patients, except for 4 patients receiving single
fraction (800 cGy) TBI. Neutrophil and platelet engraftment was achieved at a median of 16 days
(range: 7-54). Three patients showed secondary graft rejection.
Two patients in study CR-AIR-007 developed acute GVHD grade I (skin only) approximately 130 days
post HSCT, which was of short duration, (18 and 41 days). Two patients died of infection and no
patient relapsed at a mean follow-up of 8 months post HSCT (range 1-14 months). In the CR-AIR-004
control group, 2 patients developed grade I, 1 patient grade II and 3 patients grade III GvHD, none of
these cases were lethal. Seventeen patients died of transplant related complications and 2 patients
of relapse/disease progression. TRM is 20% in 007 group vs 63% in the 004 control group and OS is
80% in 007 group vs 35% in the 004 control group at 9 months post-transplant (Figures 2A and 2B).
Figure 2A Kaplan Meier Transplant Related Mortality: 004 vs 007 (p=0.06)
Figure 2B Kaplan Meier Overall Survival (OS): 004 vs 007 (p=0.03)
Conclusions
These data confirm that a novel immunotherapy strategy consisting of donor lymphocytes selectively
photodepleted of alloreactive cells (ATIR) can be manufactured consistently and reproducibly.
Results to date show that ATIR is safe and does not cause any grade III/IV GvHD. Moreover,
haploidentical HSCT patients treated with ATIR demonstrate very promising TRM and OS rates when
compared to the control group.
Disclosures: Roy: Kiadis Pharma: Consultancy, Research Funding. Foley: HoffmanLaRoche: Advisory Board/Lectures Other, Honoraria; Lundbeck: Advisory Board/Lectures, Advisory
Board/Lectures Other, Honoraria; Sanofi: Advisory Board/Lectures, Advisory Board/Lectures Other,
Honoraria; Celgene: Advisory Board/Lectures, Advisory Board/Lectures Other,
Honoraria; Pfizer: Advisory Board/Lectures Other, Honoraria; Novartis: Advisory Board/Lectures
Other, Honoraria; Jansen: Advisory Board/Lectures Other, Honoraria; Alexion: Advisory
Board/Lectures, Advisory Board/Lectures Other, Honoraria; Roche Canada: Honoraria, Research
Funding, Unrestricted educational grant, Unrestricted educational grant Other. De Jong: Kiadis
Pharma: Employment. Velthuis: Kiadis Pharma: Employment.Gerez: Kiadis
Pharma: Employment. Reitsma: Kiadis Pharma: Employment. Wagena: Kiadis
Pharma: Employment.

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