Ebmt 2018 gps in mm koehne et al_with suppl slides_final_final_1.1.12_mar2018_copy

www.ebmt.org#EBMT18
Clinical benefit after galinpepimut-S (GPS), a Wilms’ tumor 1
(WT1) immunotherapeutic, correlates with antigen-specific
immune responses in high-risk multiple myeloma:
Complete analysis of the Phase 2 GPS maintenance study
G. Koehne, MD, PhD1,2, S. Devlin, PhD2, N. Korde, MD3, S. Mailankody, MBBS3, H. Landau, MD3,
D. Chung, MD, PhD4, S. Giralt, MD4, N. Sarlis, MD, PhD5, and O. Landgren, MD, PhD3
1Dept. of BMT and Hem. Oncology, Miami Cancer Institute, Miami, FL, USA; 2Dept. of Epidemiology – Biostatistics, 3Myeloma Service, 4BMT Service,
Memorial Sloan Kettering Cancer Center, New York, NY, USA; 5Sellas Life Sciences Group, Inc., New York, NY, USA
Lisbon, 19/03/2018

2
• G. Koehne is a consultant to Sellas Life Sciences Group, Inc.
• Support for this study was provided by Leo A. Guthart and Kathryn Medina Research Fund
in Multiple Myeloma, and Sellas Life Sciences Group, Inc.
Disclosures
Koehne G, et al. EBMT 2018.

3
• The WT1 protein is a zinc finger transcription factor
– A true oncogene, with roles in cell proliferation, differentiation, apoptosis, and organ development
– National Cancer Institute top-ranked antigen for anticancer immunotherapy1
• WT1 overexpression in MM cells by IHC, and formation of peptide fragment (RMFPNAPYL)/
HLA-A*0201 complex on the MM–T-cell engagement interface in HLA-A*0201+ patients2
• WT1-specific IRs following donor lymphocyte infusion post–CD34(+)-selected allografts in MM
patients3
• Encouraging clinical and preliminary IR results in patients with MM immunized with GPS, a
first-in-class WT1-targeting heteroclitic peptide vaccine, following ASCT, previously reported in
a Phase 2 study, along with absence of high-grade systemic adverse events4–7
ASCT, autologous stem cell transplantation; CD, cluster of differentiation; GPS, galinpepimut-S; HLA, human leukocyte antigen; IHC, immunohistochemistry; IR, immune response; MM, multiple myeloma; WT1, Wilms’ tumor 1.
1. Cheever MA, et al. Clin Cancer Res. 2009;15:5323–37. 2. Koehne G, et al. ASH 2015. Abstr. 98. 3. Tyler EM, et al. Blood. 2013;121:308–17. 4. Koehne G, et al. EBMT 2017. Abstr. O094. 5. Koehne G, et al. ASCO 2017.
Abstr. 8016. 6. Koehne G, et al. EHA 2017. Abstr. E1252. 7. Koehne G, et al. SOHO 2017. Abstr. MM–252.
WT1 gene product in MM

4
WT1 (red)/CD138 (brown) co-staining of BM biopsy
WT1 (red) staining of kidney biopsy CD138 (brown) staining of BM biopsy
BM, bone marrow; CD, cluster of differentiation; IHC, immunohistochemistry; MM, multiple myeloma; WT1, Wilms’ tumor 1.
Tyler EM, et al. Blood. 2013;121:308–17.
IHC with WT1 monoclonal antibody 6F-H2 in MM

5
CD, cluster of differentiation; HLA, human leukocyte antigen; mAb, monoclonal antibody; MHC, major histocompatibility complex; TCR, T-cell receptor; WT1, Wilms’ tumor 1.
Rafiq S, et al. Leukemia. 2017;31:1788–97.
TCR
MHC class I
(HLA-A, -B, -C)
Malignant
plasma cell
TCR-like
anti-WT1 mAb
(ESK1)
WT1 peptide
Cytotoxic
CD8+ T cell
WT1 peptides are presented efficiently via an MHC/antigen
complex to the TCR
Demonstrated by successful targeting of WT1 by TCR-like mAbs (ESK1)

6
CD, cluster of differentiation; HLA, human leukocyte antigen; PBMCs, peripheral blood mononuclear cells; WT1, Wilms’ tumor 1.
Dao & Scheinberg, MSKCC; data on file.
Binding of anti-WT1 monoclonal antibody ESK1 to PBMCs
from healthy donors
• Gated cells are listed on the
y-axis (single representative
of 16 samples)
ESK1 Isotype control mAb
CD33CD19CD3
HLA-A02+ HLA-A02–
100
80
60
40
20
0
1 10 100 1000 10000
100
80
60
40
20
0
1 10 100 1000 10000
100
80
60
40
20
0
1 10 100 1000 10000
100
80
60
40
20
0
1 10 100 1000 10000
100
80
60
40
20
0
1 10 100 1000 10000
100
80
60
40
20
0
1 10 100 1000 10000
Normal

7
Ab, antibody; APC, allophycocyanin; BMMC, bone marrow mononuclear cell; CD, cluster of differentiation; FITC, fluorescein isothiocyanate; HLA, human leukocyte antigen; hIgG, human immunoglobulin G; MM, multiple
myeloma.
Koehne & Scheinberg, MSKCC; data on file.
ESK1 staining of MM BMMCs of a patient with plasma cell
leukemia
• BB7: mouse Ab
against HLA-A02
ESK1 FITC-A
102
103
104
105
0
0 102
103
104
105
3.14
0.966
95.8
0.0805
0.0382
3.7
0.573
95.7
APC-A
FITC-A
102
103
104
105
0
0 102
103
104
105
Percentageofmax
APC-A
40
60
80
100
0
20
0 102
103
104
105
40
60
80
100
0
20
0 102
103
104
105
Sample
Specimen_001_pt 1 hlgG.fcs
Specimen_001_pt 1 ESK.fcs
Median: APC-A
86.5
9257
Percentageofmax
FITC-A
Sample
Specimen_001_pt 1 mIso.fcs
Specimen_001_pt 1 BB7.fcs
Median: FITC-A
182
25549
hIgG
CD38 CD38APC-A

8Koehne G, et al. EBMT 2018.
Heteroclitic technology-based cancer immunogens/
vaccines
• GPS is a mixture of 2 native and 2
synthetic WT1 peptide sequences:
the heteroclitic peptides – bearing
point mutations (*) – were created
to stimulate both CD4+ and CD8+
T-cell responses
• Heteroclitic peptides
– Have higher affinity for HLA,
– Are prone to break tolerance,
and
– Generate a response to the
native peptide sequence (of
the cognate target antigen)
expressed by cancer cells
APC, antigen-presenting cell; CD, cluster of differentiation; CTL, cytotoxic T lymphocyte; GPS, galinpepimut-S; HLA, human leukocyte antigen; TCR: T-cell receptor; WT1, Wilms’ tumor 1.
Krug LM, et al. Cancer Immunol Immunother. 2010;59:1467–79. May RJ, et al. Clin Cancer Res. 2007;13:4547–55. Pinilla-Ibarz J, et al. Leukemia. 2006;20:2025–33.
TCR in T cells:
Recognizes and kills cancer cells expressing WT1
GPS administration
Heteroclitic peptide
(WT1 fragment)
Naive CD8+
cell
CTL
ActivationNative peptide
Malignant plasmacyte
APC

9
Broad specificity across
multiple HLA types and
potential application to
~20 types of malignancies
Heteroclitic peptide increases
immune response and mitigates
tolerance, while maintaining
antigenicity profile
• Also strengthens MHC class I and II
binding for optimal recognition of the
corresponding native peptide sequence
Production of both CD4+ and CD8+
WT1-specific activated cells
Multivalent immunogen –
4 peptide chains:
Two of the 4 peptides are
heteroclitic – bearing point
mutations (*)
Elicits multi-epitope, broad
cross-reactivity along the
full length of the WT1 protein
Activity predicated upon
overcoming barriers of adverse/
immunosuppressive TME
• Monotherapy studies are in the setting
of complete remission/MRD
*Mutated (heteroclitic) peptides – whereby Tyr (Y) replaces Arg (R), R being in the native sequence.
CD, cluster of differentiation; GPS, galinpepimut-S; HLA, human leukocyte antigen; MHC, major histocompatibility complex; MRD, minimal residual disease; TME, tumor microenvironment; WT1, Wilms’ tumor 1.
1. Maslak PG, et al. Blood Adv. 2018;2:224–34. 2. Maslak PG, et al. Blood. 2010;116:171–9. 3. Krug LM, et al. Cancer Immunol Immunother. 2010;59:1467–79. 4. Pinilla-Ibarz J, et al. Leukemia. 2006;20:2025–33. 5. Gomez-
Nunez M, et al. Leuk Res. 2006;30:1293–8. 6. May RJ, et al. Clin Cancer Res. 2007;13:4547–55.
GPS: Differentiated WT1 vaccine immunotherapeutic1–6
Peptide sequences (position)
WT1-A1:
*YMFPNAPYL (126–134) 9-mer
427 long:
RSDELVRHHNMHQRNMTKL
(427–445) 19-mer
331 long:
PGCNKRYFKLSHLQMHSRKHTG
(331–352) 22-mer
122A1 long:
SGQA*YMFPNAPYLPSCLES
(122–140) 19-mer

10
Phase 2 study of GPS in MM: Key features and
GPS administration schedule
*HR CG included the following aberrations: -13/del[13q], -17/del[17p], t[4;14], t[14;16], t[14;20], hypodiploidy [<45 chromosomes, excluding -Y], and Chr 1 aberrations [+1, -1, t(1;x)], per IMWG risk classification.1
**One patient was maintained with bortezomib instead.
ASCT, autologous stem cell transplantation; Chr, chromosome; correl., correlative translational studies (serially assessed results, incl. IR, CG, MRD, WT1 expression by RT-PCR, and select molecular markers); GPS,
galinpepimut-S; HR CG, high-risk cytogenetics; ICS, intracellular cytokine staining; IFNy, interferon gamma; IMWG, International Myeloma Working Group; IR, immune response (WT1-specific T-cell responses, assessed by ICS
for IFNy); MM, multiple myeloma; MRD, minimal residual disease; pts, patients; RT-PCR, reverse transcription polymerase chain reaction; s.c., subcutaneous; WT1, Wilms’ tumor 1.
1. Sonneveld P, et al. Blood. 2016;127:2955–62.
N = 19 (evaluable)
• 15/19 pts HR CG*,1
at baseline
• 18/19 pts at least
MRD+ post-ASCT
Study number:
NCT01827137
MSK 12-288
• GPS biweekly s.c. administration (dose
of 200 μg for each of the 4 peptides)
• First GPS administration within 22 days
of ASCT
• 6 doses over 10 weeks
• GPS monthly s.c. administration (dose
of 200 μg for each of the 4 peptides)
• 6 additional doses
Lenalidomide maintenance (10 mg daily)**
Starting on day 100 post-ASCT
Clinical/correl.
IR assessment
at baseline
Clinical/correl.
assessment
Clinical/correl. and IR assessment
2–4 weeks post-6th GPS dose
(week 12–14)
Clinical/correl. and IR assessment
2–4 weeks post-12th GPS dose
(week 60–62)

11
Efficacy endpoints: Updated results
ASCT, autologous stem cell transplantation; CR, complete response; GPS, galinpepimut-S; IMWG, International Myeloma Working Group; MRD, minimal residual disease; NR, not reached; OS, overall survival; PD, progressive
disease; PFS, progression-free survival; PR, partial response; SD, stable disease; VGPR, very good partial response.
1. Kumar S, et al. Lancet Oncol. 2016;17:e328–46.
Median follow-up among survivors: 20 months
(range: 7–34 months)
OS and PFS
Eventprobability
Time from ASCT (months)
OS, N = 19
PFS, N = 19
Median OS has not been reached to date
Current median PFS: 23.6 months (15.2–NR)
CR and VGPR
PR and SD
PD
Therapeutic response*,1 over time
No. of
evaluable
patients N = 19** N = 19** N = 16# N = 15† N = 11‡
Post-induction
Pre-ASCT
Post-GPS × 6 Post-GPS × 12 12 months
Post-ASCT
18 months
Post-ASCT
Responsecategory(%)
*CR/VGPR, PR/SD, and PD, per IMWG criteria.1
**Eighteen of 19 patients had MRD or worse at post-induction and pre-ASCT.
#Progressed at previous assessment (n = 1) and had not received full course of GPS by the time of analyses (n = 2).
†Progressed or died at previous assessment (n = 2) and had not received full course of GPS by the time of analyses (n = 2).
‡Progressed or died at previous assessment (n = 2), had not received full course of GPS by the time of analyses (n = 2),
withdrew consent (n = 1), and had not yet undergone response assessment by the time of analyses (n = 3).

12
PFS of MM Patients with High-Risk Cytogenetics^
GPS + Lenalidomide vs. Thalidomide +/- Bortezomib Maintenance*
^ Defined per IMWG risk classification (Sonneveld P, et al. Blood. 2016;127:2955–62); * After induction therapy followed by melphalan conditioning and successful ASCT
** Median time period from induction therapy initiation to ASCT = 5.5 mo in the first-line setting; ASCT: autologous stem cell transplant; Len: lenalidomide; Vel: (Velcade®; bortezomib); MM: multiple myeloma; Thal: thalidomide
Historical control K-M curve from Rosinol L, et al. Blood. 2012;120:1589-1596; Juxtaposition of results is shown for illustrative purposes only.
PFS = 12.6 mo
(estimated from time of ASCT)
PFS = 18.1 mo
(from initiation of induction Rx)
PETHEMA 2005-001110-41
Thal +/- Velcade maintenance
GPS MSK study
GPS + Len
maintenance
PFS = 23.6 mo
(from time of ASCT)
PFS = 29.1 mo
(from initiation of induction Rx)
Difference in PFS = 11 mo
(1.87-fold higher with GPS+Len)
Time from initiation of induction Rx (months; mo)
EventProbability
GPS + Len
N = 68
Thal +/- Vel
**
N=19
0 10 20 30 40

13
WT1-specific T-cell IRs over time: Methodology
APC, allophycocyanin; CD, cluster of differentiation; FACS, fluorescence-activated cell sorting; FITC, fluorescein isothiocyanate; FSC-A, forward side scatter area; GPS, galinpepimut-S; IFNγ, interferon gamma; IR, immune
response; PBMC, peripheral blood mononuclear cell; PE, phycoerythrin; PerCP, peridinin-chlorophyll-protein; WT1, Wilms’ tumor 1.
6 WT1
individual peptides
• 2 natives (of GPS mixture)
• 2 heteroclitics (of GPS mixture) and their
native counterparts (set of 4)
“All-pool” WT1
peptides
• 113 partially overlapping 15-mers along
the entire WT1 protein
WT1 peptides +
brefeldin A
• Fix cells
• Permeabilize
• Stain
PBMC
sample FACS with gating to CD8+ and CD4+ T cells
Plotting against post-incubation production of IFNγ
Readout:
Absolute frequency
of T cells of interest
Host IR
tested against
Surrogate marker of cross-epitope reactivity
(akin to “epitope spreading”)
FSC-A
CD3 APC
CD4PerCP
IFNγ FITC
CD8PE
IFNγ FITC
Q1
0
Q2
0
Q4
52.0
Q3
48.0
CD3+
44.6
Q9
35.2
Q10
0.048
Q12
64.2
Q11
0.61
Q5
62.5
Q6
0.65
Q8
36.8
Q7
0.074

14
Induction of antigen-specific IRs (CD8/CD4) by GPS:
T-cell frequencies over time (complete study database)
1Q submedian-
to-median
intervals*
At baseline
Post-GPS
(6 or 12 doses)
Median values
3Q submedian
values (upper
boundary of 3Q
of the IQR)
*Interval between the median value and the upper boundary of the 1Q of the IQR; shown as thin vertical colored bars.
1Q, 1st quartile; 3Q, 3rd quartile; CD, cluster of differentiation; GPS, galinpepimut-S; IQR, interquartile range; IR , immune response; mo, months; WT1, Wilms’ tumor 1.
AbsoluteT-lymphocyte
frequencies(cells/mL)–logscale
106
105
104
103
102
10
0
0 6 12
CD4
0 6 12
CD8
0 6 12
CD4
0 6 12
CD8
0 6 12
CD4
0 6 12
CD8
0 6 12
CD4
0 6 12
CD8
0 6 12
CD4
0 6 12
CD8
0 6 12
CD4
0 6 12
CD8
0 6 12
CD4
0 6 12
CD8
331 427 122A
Native
122A1
Heteroclitic
WT1A
Native
WT1A1
Heteroclitic
WT1 – all pools
Native All-pool 15-mers
Time post-GPS (mo)
T-cell type
WT1 peptide
specificity

15
Absolute number and percentage of patients with IR
positivity (CD8/CD4) over time
*Out of the 6 pts who were IR+ at baseline, only 2 had presence of reactive CD8+ cells (at a low level, <200 cells/mL), while all 6 pts had detectable presence of reactive CD4+ cells (2 at a low level,<200 cells/mL).
**All 4 pts who were IR+ to “all-pool” antigens had only detectable CD4+ cells; no CD8+ baseline reactivity was seen.
#Approximately equal frequency of CD4 and CD8 IR positivity.
ASCT, autologous stem cell transplantation; CD, cluster of differentiation; GPS, galinpepimut-S; IR, immune response; pts, patients; WT1, Wilms’ tumor 1.
Against any of the WT1 antigenic variants of GPS Against “all-pool” WT1 fragments
(cross-epitope reactivity)
Timepoint Baseline
(pre-ASCT; N = 15)
Post-GPS × 6
(N = 15)
Post-GPS ×
12
(N = 12)
Baseline
(pre-ASCT; N = 15)
Post-GPS × 12
(N = 12)
Patients, N (%) 6 (40)* 9 (60) 12 (100) 4 (27)** 9 (75)#

16
Rates of antigen-specific IR positivity (CD8/CD4) at the
time of completion of GPS therapy
Note: Completion of GPS therapy was achieved after 12 GPS doses.
CD, cluster of differentiation; GPS, galinpepimut-S; IR, immune response; WT1, Wilms’ tumor 1.
• IR+ rates for:
– The 4 peptides in GPS
▪ CD4 OR CD8: 72%–91%
– The “all-pool” peptides
▪ CD4 OR CD8: 75%
• Up to 64% of patients
demonstrated IR positivity
(CD4/CD8) against >1 WT1
peptide (multivalent IRs)
Patientswithantigen-specificIRpositivity(%)
WT1 peptide
specificity
T-cell
type
100
331 427 122A WT1A WT1 all-pool
80
60
40
20
0

17
Exploratory correlations between IR positivity and clinical
response (achievement of CR/VGPR) at the time of
completion of GPS therapy
Note: CR/VGPR was assessed per IMWG criteria1 at the time of completion of GPS therapy (after 12 doses of GPS). Varying number of patients were evaluable for each pair of these exploratory correlative analyses.
CD, cluster of differentiation; CR, complete response; GPS, galinpepimut-S; IMWG, International Myeloma Working Group; IR, immune response; VGPR, very good partial response.
• Rate of IR positivity in patients who achieved CR/VGPR
– 81.8% demonstrated prior CD8 IR+ (N = 9)
– 100% demonstrated prior CD4 IR+ (N = 11)
• Rate of achievement of CR/VGPR in patients who maintained IR positivity (relative rates of >50%
denote strong association)
– 54.6% – if CD4 IR+ was maintained to any of the 4 native GPS peptides (N = 11)
– 44.0% – if CD8 IR+ was maintained to any of the 4 native GPS peptides (N = 9)
– 62.5% – if CD4 IR+ was maintained to “all-pool” peptides (N = 8)
– 57.1% – if CD8 IR+ was maintained to “all-pool” peptides (N = 7)

18
MM patients exhibiting multivalent IRs (CD8/CD4) were
more prone to achieve clinical response (CR/VGPR) at the
time of completion of GPS therapy
Note: CR/VGPR was assessed per IMWG criteria1 after 12 doses of GPS (completion of GPS therapy). Varying number of patients were evaluable for each pair of these exploratory analyses; hence, the rates shown cannot be
added across subgroups.
CD, cluster of differentiation; CR, complete response; GPS, galinpepimut-S; IMWG, International Myeloma Working Group; IR, immune response; MM, multiple myeloma; VGPR, very good partial response; WT1, Wilms’ tumor 1.
No. of native WT1 peptides
for which IR positivity was
maintained by 12 GPS
vaccinations
1 2 3 4
100
80
60
40
20
0
CD4 IR CD8 IR
1 2 3 4
100
80
60
40
20
0
RateofachievementofCR/VGPR
(patientsineachindividualsubgroup,%)

19
ASCT, autologous stem cell transplantation; CD, cluster of differentiation; GPS, galinpepimut-S; HLA, human leukocyte antigen; IR, immune response; MM, multiple myeloma; PFS, progression-free survival; WT1, Wilms’ tumor 1.
• Administration of the WT1 heteroclitic peptide mixture immunizer GPS in a Phase 2 study of
19 high-risk patients with MM has shown an excellent safety profile and a promising median
PFS of 23.6 months (post-ASCT in first line) in a particularly challenging setting
• Impressive, time-dependent, and robust CD8 or CD4 IRs specific for the 4 WT1 peptides
within GPS, as well as the 2 native counterpart peptides, were confirmed in up to 91% of
patients across HLA allele types
– Multivalent IRs emerged in up to 64% of patients
Conclusions (1)

20
CD, cluster of differentiation; CR, complete response; GPS, galinpepimut-S; IMWG, International Myeloma Working Group; IR, immune response; MM, multiple myeloma; VGPR, very good partial response; WT1, Wilms’ tumor 1.
• Multifunctional cross-epitope T-cell reactivity was observed in 75% of patients to antigenic
epitopes against which hosts were not specifically immunized, in a pattern akin to antigen
cross-reactivity
• A strong and bidirectional association was observed between achievement of CR/VGPR
clinical status (per IMWG criteria) and frequency as well as potency of IRs at the time of
completion of all planned vaccination boosters; this effect was more notable for CD4+ T-cell
responses or IR multivalency
• These data suggest a distinctive link between clinical and immune responses, which has not
been previously described for a peptide vaccine in MM. The results offer mechanistic
underpinnings for immune activation against WT1 in patients with aggressive MM, and point
to the urgent need for further testing of the putative antimyeloma activity of GPS in more
extensive clinical studies
Conclusions (2)

21
Questions?
GuentherK@baptisthealth.net

22
*Mutated (heteroclitic) peptides.
APC, antigen-presenting cell; CD, cluster of differentiation; GPS, galinpepimut-S; i-PS: immuno-proteasome; MHC, major histocompatibility complex; s.c., subcutaneous; tc-PS: tumor cell proteasome; WT1, Wilms’ tumor 1.
Based on information in: 1. Oka Y, et al. Sci World J. 2007;7:649–65. 2. Oka Y, et al. Oncol Res Treat. 2017;40:682–90.
GPS: Mechanism of action
Tumor cell
B cell
CD4
T cell
CD8
T cell
CD8
and CD4
T cells
WT1 peptides in the
GPS mixture
(administered s.c.)
WT1 protein
APC
Immunologically-meditated
cell killing and antitumor effect
MHC I
i-PS
MHC II
Tumor cell
tc-PS
* *

23
Notes: a. A total N = 12 patients were evaluable for each pair of these exploratory correlative analyses.
b. Aggregate potency of IR against WT1 peptides was arbitrarily derived as follows: the “per patient average” of absolute T-cell frequencies against any of the 4 antigens was first calculated, and then the median value of those
averages was derived and used to divide IRs into high vs low potency subgroups of equal patient numbers.
c. CR/VGPR and PR/SD were assessed per IMWG criteria1 at the time of completion of GPS therapy (after 12 doses of GPS).
CD, cluster of differentiation; CR, complete response; GPS, galinpepimut-S; H, high; IMWG, International Myeloma Working Group; IR, immune response; L, low; PR, partial response; SD, stable disease; VGPR, very good
partial response; WT1, Wilms’ tumor 1.
Clinical response category (CR/VGPR vs. less) at the time
of completion of GPS therapy is associated with CD4 IR
potency (high vs. low)
Rateofachievementofaspecificclinical
responsecategory(patients,%)
80
70
60
50
40
30
20
10
0
100
Aggregate IR
CD4
L H
Aggregate IR
CD8
*
L H
Aggregate IR
CD4 or CD8
*
L H
“All-pool” IR
CD4
L H
“All-pool” IR
CD8
*
L H
“All-pool” IR
CD4 or CD8
L H
PR and SD
CR and VGPR

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