Orca-T, a Precision Treg-Engineered Donor Product, in Myeloablative HLA-Matched Transplantation Prevents Acute and Chronic GVHD with Less ...
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Orca-T, a Precision Treg-Engineered Donor Product, in Myeloablative HLA-Matched Transplantation Prevents
Acute and Chronic GVHD with Less Immunosuppression in an Early Multicenter Experience
Everett H. Meyer1, Rasmus Hoeg2, Anna Moroz3, Bryan J. Xie1, Hsin-Hsu Wu1, Rahul Pawar1, Kartoosh Heydari1, David B.
Miklos1, Parveen Shiraz1, Lori Muffly1, Sally Arai1, Laura Johnston1, Robert Lowsky1, Andrew R. Rezvani1, Judith A. Shizuru1, Wen-
Kai Weng1, Nathaniel Fernhoff7, Gerhard Bauer2, Arpita Gandhi3, James Scott McClellan7, Bronwen E. Shaw4, Caspian Oliai6,
Joseph P. McGuirk5, Mehrdad Abedi2 and Robert S. Negrin1
1Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA
| 2Hematology/Oncology, University of California, Davis, Sacramento, CA | 3Oregon Health Sciences University, Portland, OR |
4CIBMTR (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI | 5Department of Blood and Bone Marrow Transplant, The University of Kansas Medical Center,
ASCT 2021 | SLIDE 1
Kansas City, KS | 6University of California, Los Angeles, Los Angeles, CA | 7Orca Bio, Menlo Park, CA
Conflicts of interest
Everett Meyer, MD, PhD
Co-founder, scientific advisor
Co-founder, scientific advisor
Scientific Advisory Board
Scientific Advisory Board
Sponsored Research Support
ASCT 2021 | SLIDE 2
Regulatory T cells (Tregs) in hematopoietic stem cell transplantation
Conventional Transplant
Day -2: Collection of
Donor Cells
Conventional
Graft
CD4+CD25+CD127loFoxP3+
Day 0: Infusion
into Patient
Eddinger et al. Nature Medicine 2003 Sep;9(9):1144-50. | Trzonkowski et al. Clin Immunol. 2009 Oct;133(1):22-6.
Di Ianni M, et al. Blood. 2011;117(14):3921–3928. | Brunstein, et al. Blood 2016 Feb 127 (8):1044-51. | Kellner H, et al.
Oncotarget 2018 Nov 2;9(86):35611-35622.
ASCT 2021 | SLIDE 3
Regulatory T cells (Tregs) in hematopoietic stem cell transplantation
Conventional Transplant High-prec. Orca-T
Day -2: Collection of Day -2: Collection of
Donor Cells Donor Cells
Cell
Processing Tcons
Conventional Day +2
Graft
Day 0
Tregs &
HSPCs
Day 0: Infusion Infusion into
into Patient Patient
Eddinger et al. Nature Medicine 2003 Sep;9(9):1144-50. | Trzonkowski et al. Clin Immunol. 2009 Oct;133(1):22-6.
Di Ianni M, et al. Blood. 2011;117(14):3921–3928. | Brunstein, et al. Blood 2016 Feb 127 (8):1044-51. | Kellner H, et al.
Oncotarget 2018 Nov 2;9(86):35611-35622.
ASCT 2021 | SLIDE 4
Clinical protocol Orca-T
SOC
MA Conditioning Post-Transplant
Day-10 to Day-2: Days +1, +3, +6, +11: Methotrexate prophylaxis
MA Conditioning
Day 0: Infusion of Apheresis Product
(cell dose: 10e8 – 10e9 Tcells/kg)
Day -1: Tacrolimus
Orca-T
MA Conditioning Post-Transplant
Day-10 to Day-2: Start Day +3: Single-agent Tacrolimus
MA Conditioning (4-6 ng/mL target)
Day +2: Infusion of Tcon
(cell dose: 3e6 Tcells/kg)
Day 0: Infusion of HSPCs and Treg
(cell dose: 3e6 Treg/kg)
Meyer, E. H., Laport, G., et al. JCI INSIGHT. 2019; 4 (10)
ASCT 2021 | SLIDE 5Clinical protocol Orca-T Eligible Patients High risk, MRD+, active disease Leukemia, lymphoma, MDS, MPN Myelodysplastic syndrome KPS >70 Age
Patient demographics Orca-T and SOC control cohort
SOC Control
Orca-T*
Cohort
Cohort size 50 144
Median age (range) 47 (20-65) 48 (20-64)
% Male 52% 49%
Race White 60% 44%
African American 2% 2%
Asian 14% 19%
Unspecified 26% 30%
Primary Disease % AML 42% 39% #
ALL 28% 26%
CML 4% 6% #
B-cell lymphoma 2% 8% #
MDS/MF 16% 19% # * subjects with ≥ 30
days f/u. Data from
Other 8% 2% NCT04013685 and
(E.g. mixed phenotype acute leukemia)
NCT01660607
Graft source HLA-matched siblings/URD 62%/38% 56%/44%
% with active leukemia at time of transplant 23% 21% #
these numbers have
Median f/u (days) 223 days (30 – 1561 days) 886 days (55-1783) been edited post TCT
ASCT 2021 | SLIDE 7Orca-T manufacturing and supply
Vein-to-vein times of less than 72 hours across the continental US
Orca Bio GMP Orca Bio mfg platform
• Manufacturing and logistics carried out by
Clinical center Orca Bio
• 12+ participating clinical sites in the
NMDP Apheresis Centers continental US across 3 studies
• Product sourced from MRD and MUDs
• Consistent vein-to-vein time of less than 72
hours
• No manufacturing nor logistic failures to
date (100+ patients treated across all
studies)
ASCT 2021 | SLIDE 8Orca-T manufacturing and supply
Central manufacturing with consistent quality and
performance to date
CD34 Treg Cell Doses %Treg Purity
20 4 100
cell dose (million cells/kg)
cell dose (million cells/kg)
15 3 95
% CD45+ cells
10 2 90
5 1 85
0 0 80
Treg Cell Dose Treg % Purity
HSPC DP Cell Dose Treg
HSPC (by CD45+ Treg
Moxi count) Surface Stain
(by CD45+ Moxi count)
(in millions of cells/kg) (in millions of cells/kg)
ASCT 2021 | SLIDE 9More rapid engraftment and hospital discharge with Orca-T
200
**** 100 **** 160 **
120
80
30 80
60
60
50 50
20
Days
Days
40 40
Days
30 30
10 20 20
10 10
0 0 0
Orca-T Standard of Care Orca-T Standard of Care Orca-T Standard of Care
Time to Neutrophil Engraftment (Days) Time to Platelet Engraftment (Days) Time from Day 0 to Hospital Discharge (Days)
Median 12 vs 14 days; pReduction of acute GVHD with Orca-T
Grade ≥2 Acute GVHD
Percent with Grade ³ 2 aGVHD
40 Standard of Care
Orca-T
Grade Steroid Secondary
Organ Stage
30 30% (MAGIC) response response
GI tract 3 3 Responsive n/a
20
Resp. to
GI tract 3 3 Unresponsive
ruxolitinib
10 10%
Liver 1 2 Responsive n/a
GI tract 1 2 Responsive n/a
0
50
100
0
Days
ASCT 2021 | SLIDE 11Reduction of Chronic GVHD with Orca-T
Percent with Extensive cGVHD Chronic GVHD
Standard of Care
50
Orca-T
46%
40
30
20 Severity (NIH Steroid
Organ
Consensus) response
10
Skin and Moderate Responsive
3% soft tissue
0
100
200
300
400
0
Days
ASCT 2021 | SLIDE 12Orca-T plus single-agent GVHD PPX is well-tolerated
Infectious Complications seen with Orca-T plus single agent PPX
(n=50)
CMV
No reactivation n=36 (72%)
Low level viremia n=8 (16%)
Required treatment n=6 (12%)
Other infections
• EBV reactivation n=8 (1 requiring therapy) • URI (Adenovirus) n=3
• BK viruria/viremia n=4 • HHV-6 n=2
• Rhinovirus n=1 • COVID-19 -
• C. Difficile n=4 • Fungal infections -
• Bacteriemia n=7 • Pneumonia -
• Norovirus n=1
Only minimal complications with Orca-T
• 18% (n=9) of patients have experienced serious adverse events
• 10% of patients with SOS/VOD
• No deaths due to infection to date
ASCT 2021 | SLIDE 13No treatment-related mortality noted with Orca-T to date
Treatment-Related Mortality
25 Standard of Care
20 Orca-T
15
TRM
11%
10
5
0%
0
0 100 200 300 400
Days
ASCT 2021 | SLIDE 14Profound improvement in GVHD-free relapse-free survival (GRFS)
with Orca-T
Standard of Care
Orca-T
100
75%
GRFS (%)
50
31%
0
0 100 200 300 400
Days
GVHD event: Grade 3 or greater acute and
moderate to severe chronic GVHD
ASCT 2021 | SLIDE 15Disease status pre- and post-transplant in Orca-T patients
Deceased
Active/refractory
disease/PR
CR, MRD+
Orca-T retains GvT effect
CR, MRD- • Despite markedly reduced GVHD rates
with Orca-T, early data suggests that GvT
effect is preserved
• Patients at relapse or with at least 180
days of follow up.
Pre-Orca-T Day 90 Day 180 Day 356
ASCT 2021 | SLIDE 16Donor chimerism at day +30 and day +90
% of Donor Chimerism in Patients Received TregGRAFT + Tacrolimus as a Single Agent
PPX on Day +30 and Day +90
100
80
% donor chimerism
%60of Donor Chimerism in Patients Received TregGRAFT + Tacrolimus as a Single Agent
PPX on Day +30 and Day +90
40
100
DAY 30
20 DAY 90
80 Achieved full donor
chimerism on later
time points
or chimerism
0
Whole blood CD15 CD3
60
ASCT 2021 | SLIDE 17 Day 30 n=10; Day 90 n=13Orca-T presentation summary
Graft versus Host Disease Treatment Related Mortalities
GVHD Orca-T demonstrates significantly TRM No TRMs with Orca-T observed to
reduced GVHD date
GVHD relapse-free survival Mfg and Logistics Scalability
GRFS 1-yr GRFS more than doubled with Orca-T is scaled across the continental
Orca-T compared to standard of care US with vein-to-vein times < 72 hours
ASCT 2021 | SLIDE 18Acknowledgments
Robert Negrin, MD | Steve Devine, MD | Anna Moroz, MD, PhD |
Lori Muffly, MD | Parveen Shiraz, MD | David Miklos, MD, PhD |
Kailey Zaffran | Anna Hoppe | John Petersen | NMDP Apheresis
center staff and couriers | Jennifer McAtee | Leah Schroer | Michelle
Chin | Kelly Chyan | Khanh Nguyen | Heraa Hashmi | Stanford Cell
Therapy Lab & Apheresis staff | Emily Schwab | Leslie Mellor | UC
Davis Cell Therapy Lab & Apheresis staff | Mindi Yost | Marietta
Wadley | OHSU Cell Therapy Lab & Apheresis staff | Jeff Roesgen |
Nichola Fell | KUMC Cell Therapy Lab & Apheresis staff | Joshua
Sasine, MD | Caspian Oliai, MD | Bruck Habtemariam | Carla Petro |
UCLA Cell Therapy Lab & Apheresis staff | Be The Match Biotherapies
| Kevin Sheehan | Randy Amstrong | Orca Bio Mfg & Ops | Kate
Bickett | Hollie Pisseri | Virginia Sullivan | Marina Becker |
Jeroen Bekaert, PhD | Ivan Dimov, PhD
AMY STRELZER MANASEVIT
RESEARCH PROGRAM
ASCT 2021 | SLIDE 19? Questions
ASCT 2021 | SLIDE 20You can also read
