Galinpepimut-S (WT1-targeting peptide vaccine) in high-risk multiple myeloma. Final results from a Phase 2 clinical study. Koehne G, et al. EBMT 2018 slide presentation.
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It describes the androgenic nature of prostate cancer and the androgenic axis should be tackled in all phases of prostate cancer. Also a special emphasis on recent data on management of metastatic hormone sensitive prostate cancer.
Management of MSI High Solid Tumors and the impact of adding Immunotherapy upon improving survival outcome and response rate. Colorectal and Non Colorectal tumors.
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Newer biomarkers,techniques & their inclusion in 2016 WHO classification for leukaemia/lymphomas increases the responsibility of the pathologists, requiring to develop an integrated multidisciplinary approach for reporting.
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Audio and slides for this presentation are available on YouTube: http://youtu.be/6W_xoH4s-Yk
Dr. Patrick Wen, of Dana-Farber Cancer Institute's Center for Neuro-Oncology, discusses current clinical trial options for brain tumor patients and some of the new therapies available in neuro-oncology. This presentation was originally given at Dana-Farber Cancer Institute on Dec. 4, 2013.
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
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Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
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TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
The Gram stain is a fundamental technique in microbiology used to classify bacteria based on their cell wall structure. It provides a quick and simple method to distinguish between Gram-positive and Gram-negative bacteria, which have different susceptibilities to antibiotics
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...
Ebmt 2018 gps in mm koehne et al_with suppl slides_final_final_1.1.12_mar2018_copy
1. 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. 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. 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
Koehne G, et al. EBMT 2018.
4. 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.
Koehne G, et al. EBMT 2018.
IHC with WT1 monoclonal antibody 6F-H2 in MM
5. 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
Koehne G, et al. EBMT 2018.
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. 6
CD, cluster of differentiation; HLA, human leukocyte antigen; PBMCs, peripheral blood mononuclear cells; WT1, Wilms’ tumor 1.
Dao & Scheinberg, MSKCC; data on file.
Koehne G, et al. EBMT 2018.
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. 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.
Koehne G, et al. EBMT 2018.
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
8. 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. 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.
Koehne G, et al. EBMT 2018.
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. 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.
Koehne G, et al. EBMT 2018.
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. 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.
Koehne G, et al. EBMT 2018.
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. 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.
Koehne G, et al. EBMT 2018.
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. 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.
Koehne G, et al. EBMT 2018.
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. 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)
Koehne G, et al. EBMT 2018.
*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. 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.
Koehne G, et al. EBMT 2018.
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. 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)
Koehne G, et al. EBMT 2018.
Patientswithantigen-specificIRpositivity(%)
WT1 peptide
specificity
T-cell
type
100
331 427 122A WT1A WT1 all-pool
80
60
40
20
0
17. 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.
1. Kumar S, et al. Lancet Oncol. 2016;17:e328–46.
• 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)
Koehne G, et al. EBMT 2018.
18. 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.
1. Kumar S, et al. Lancet Oncol. 2016;17:e328–46.
Koehne G, et al. EBMT 2018.
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. 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
Koehne G, et al. EBMT 2018.
Conclusions (1)
20. 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
Koehne G, et al. EBMT 2018.
Conclusions (2)
22. 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.
Koehne G, et al. EBMT 2018.
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. 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).
1. Kumar S, et al. Lancet Oncol. 2016;17:e328–46.
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.
Koehne G, et al. EBMT 2018.
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