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Shun Doi, PhD, President and CEOCYTLIMIC Inc.
https://www.cytlimic.com/
Innovative Cancer Vaccine:
Fruit of Integration of
AI and Immunology
BIO Asia – TaiwanSession 2 “AI for Biotech & Healthcare”July 24, 2019
➢ CTL is main player in Cancer Immunotherapy
➢ Why and How AI in Cancer Vaccine?
➢ Cancer Vaccine: History of Failure, Challenges
➢ Cytlimic approaches to overcome Challenges
✓ Optimized Shared-antigen Peptides – advent of AI
✓ Optimized Combination Adjuvants – to boost CIC
➢ CYT001: Cytlimic’s Lead vaccine for HCC
➢ Future of AI in cancer vaccine
2
Table of Contents
Development of Innovative Cancer Vaccine
CTL: Cytotoxic T Lymphocyte, CIC: Cancer-Immunity Cycle, HCC: Hepatocellular Carcinoma
© CYTLIMIC Inc. 2019 Proprietary
The Novel Prize in Physiology or Medicine 2018
Discovery of ICI (Immune-Checkpoint Inhibitors) to Release Negative Regulations to CTLs (Cytotoxic T Lymphocytes),
to let those CTLs kill cancer cells
CTLA-4 PD-1
3
© CYTLIMIC Inc. 2019 Proprietary
BUT …
CTLA-4 PD-1
The improvements in clinical responses and overall survivals by ICI alone are still limited e.g., ORR are in 20% level, except for a certain lymphoma
Combination drugs/therapies for further improvements are highly desired
Drugs/therapies that tern “Cold Tumor* to Hot” are promising as such combination
* Tumor where CTLs are not or rarely infiltrated
4
© CYTLIMIC Inc. 2019 Proprietary
Antigenpresentation
Injection of antigen peptides
Tumor cells
Killing by CTLs
CTL
CTL
Th1
CTL
IFN-γ, IL-12, etc.
IL-12etc.
Proliferation, Maturation,Migration to Tumor site
Th0IL: InterleukinIFN: InterferonTh0: Naïve T Helper CellTh1: T Helper 1 CellCTL: Cytotoxic T LymphocyteHLA: Human Leukocyte Antigen
Lymph nodes
9mer amino acids
HLA-Class Imolecule
Cancer Vaccine
Injection of antigen peptides induces Proliferation, Maturation, Migration to tumor sites of CTLs through activation via DCs,
to kill cancer cells
CTLCytotoxic T
Lymphocytes
DCDendritic Cell
Helper T cell
5
© CYTLIMIC Inc. 2019 Proprietary
Launched : anti-CTLA-4 (Ipilimumab) 2011, anti-PD-1 (Nivolumab) 2014, …
Two approaches: Accelerator and/or Releasing Brake
The initial success of ICIs makes experts recognizethe importance and power of T cells (CTLs),
in cancer therapy.
Tumor cells
SurgeryChemotherapy
Radiotherapy
CancerImmunotherapy Accelerator
ReleasingBrake
Immune-CheckpointInhibitor
Peptidevaccine
ICIpeptide
1 2
6
© CYTLIMIC Inc. 2019 Proprietary 7
NEC Headquarter Building(Tokyo)
Year Events
1990 Fundamental research in AI(Central Research Laboratories, NEC)
1998~ MHC-binding peptide prediction with AICollaboration with Prof. Keiko Udaka,Kochi University
2001~ Development of WT1 peptide vaccine
2008~ First-in-Human study of WT1 vaccine, atKochi University
2012~ Development of CYT001 vaccineCollaboration with Yamaguchi Universityand Kochi University
2016/12 Establishment of CYTLIMIC Inc.
AI approach – History in NEC
© CYTLIMIC Inc. 2019 Proprietary 8
CancerCell
Tumorcell
Antigenpeptides
How to find peptides, binding to HLA molecule, and induce anti-tumor immunity
How to find HLA binding peptides ?
HypothesisThere must be a “rule” between the binding affinity
and binding-peptide sequence.
9mer amino acids
HLA-Class Imolecule
QuestionHow to find the rule, within minimum experiments?
© CYTLIMIC Inc. 2019 Proprietary 9
STEP1: Finding the rule
Binding Tests(at Kochi Univ.)
Next test candidates
Results of the tests
Update ofRules
Sequence Affinity
ABCDEFGHI 4.5
BCDEFGHIJ 6.2
CDEFGHIJK 3.5
・ ・
・ ・
・ ・
PQRSTUVWX 8.2
QRSTUVWXY 3.3
RSTUVWXYZ 6.4
Our answer: Active Learning, an AI algorithm
MPRAPRCRAVRSLLRSHYREVLPLATFVRRLGPQGWRLVQK
GDPAAJFRALVAQCLVCVPWDARPPPAAPSFRQVSCLKELV
ARVLQRLCERGAKNVLAFGFALLDGARGGPPEAFTTSVRSYJ
LPNTVTDALRGSGAWGLLLLRRVGDDVLVHLLARCALFVLVI
APSCAYQVCGPPLYQLGAATQARPPPHASGPRRRLGCERW
NHSVREAGVPLGLPAPGARRRGGSASRSLPLPKRPRRGAAPJ
EPERTPVGQGSWAHPGRTRGPSDRGFCVVSPARPAEJEATN
LEGALSGTRHSHPSVGRQHHAGPPSTSRPPRPWDTPCPPVY
AMTKHFLYSSGDKEQLRPSFLLSSLRPSLTGARRLVETIFLGSW
MPGTPNRRLPRLPQRYWQMRPLFLELLGNHAQCPYGVLLKI・
Candidates peptides
(9 amino acids)
STEP2: Finding peptides
Antigen proteinamino acids sequence
9mer amino acids
HLA-Class ImoleculeAI
algorithm
© CYTLIMIC Inc. 2019 Proprietary 10
P RQ S T UVWX
Peptide A Peptide B Peptide C
P RQ S T UVWX
Peptide XJapanese: 85%
Caucasian: 60%
Challenges・Costs・Personalization
A single peptide can induce anti-tumorresponse in patients having different HLA types.
HLA type
Multi-HLA peptide, another advantage of AI algorithm
ConventionalVaccine
CYTLIMICVaccine
Binding peptide sequence depends on HLA type
HLA A*24:02 HLA A*02:01 HLA A*02:06
P RQ S T UVWX
P RQ S T UVWX
Human LeukocyteAntigen
© CYTLIMIC Inc. 2019 Proprietary 11
Year/month
Name Company Indication
2012/2 OTS102 Oncotherapy (J) PDAC
2012/12Tecemotide(Stimuvax)
Merck KGaA (G)(Oncothyroen)
NSCLC
2013/9 MEGE-A3 GSK (UK)MelanomaNSCLC
2016/3Rindopepimut(Rintega)
Celldex (USA) Glioblastoma
2016/11 IMA901 IMMATICS (G)Renal CellCarcinoma
2018/5 ITK-1 BrightPath (J)Prostate Cancer
Cancer Vaccine, History of failure …
No one succeeded yet in Phase III. What was wrong?
© CYTLIMIC Inc. 2019 Proprietary
Chen DS, et al. Immunity. 2013;39(1):1-10.
12
Optimized Combination Adjuvants, best boosting the
Cancer-Immunity Cycle
CYTLIMIC Bets-In-Class Vaccine Design Concept
Optimized Shared-antigen Peptides, escaping self-tolerance,
and immunogenic
© CYTLIMIC Inc. 2019 Proprietary 13
Challenges
CYTLIMIC Development Approaches
What combinationmost effectively boosts
Cancer-Immunity Cycle?
Combination of clinical-stage adjuvant
materials; Poly ICLC and LAG-3Ig
Challenge #2
How can we findOptimized Shared-antigen peptides?
(neoantigen-like*)
AI-based prediction & screening by patient‘s
samples to find cryptic* Multi-HLA peptides
Challenge #1
CYTLIMIC Development Approaches
© CYTLIMIC Inc. 2019 Proprietary
HCC Patients s
(Yamaguchi Univ. Medical School)
Phase I study:HSP70 mRNA transfected DCTherapy for unresectable or
recurrent HCC patients
Selection ofTarget Antigens- Proteome- mRNA- Histopathology
MPRAPRCRAVRSLLRSHYREVLPLATFVRRLGPQGWRLVQKGDP
AAJFRALVAQCLVCVPWDARPPPAAPSFRQVSCLKELVARVLQR
LCERGAKNVLAFGFALLDGARGGPPEAFTTSVRSYJLPNTVTDAL
RGSGAWGLLLLRRVGDDVLVHLLARCALFVLVIAPSCAYQVCGP
PLYQLGAATQARPPPHASGPRRRLGCERWNHSVREAGVPLGLP
APGARRRGGSASRSLPLPKRPRRGAAPJEPERTPVGQGSWAHPG
RTRGPSDRGFCVVSPARPAEJEATNLEGALSGTRHSHPSVGRQH
HAGPPSTSRPPRPWDTPCPPVYAMTKHFLYSSGDKEQLRPSFLLS
SLRPSLTGARRLVETIFLGSWMPGTPNRRLPRLPQRYWQMRPLFL
ELLGNHAQCPYGVLLKIMPRAPRCRAVRSLLRSHYREVLPLATFVR
RLGPQGWRLVQKGDPAAJFRALVAQCLVCVPWDARPPPAAPSF
RQVSCLKELVARVLQRLCERGAKNVLAFGFALLDGARGGPPEAFT
TSVRSYJLPNTVTDALRGSGAWGLLLLRRVGDDVLVHLLARCALF
VLVIAPS
AI-basePredictionsystem
・・・
Patients
Target HLAHLA A*24:02, 02:01, 02:06
・・・
ELISPOT assay(patients samples)
Identification ofImmunogenic
Peptide Cocktail
Screening
Use of AI-based discovery tool and Dendritic Cell therapy patient samples enables the discovery of rarely existing cryptic multi-HLA peptides
NEC
Binding assay
TargetAntigens
HLA A*24:02, 02:01, 02:06
Kochi Univ.
HSP70 Multi-HLA Class I peptideGPC3 Multi-HLA Class I peptide
Discovery of optimized shared-antigen peptides
14
© CYTLIMIC Inc. 2019 Proprietary
Peptides HLA allele
HSP70 GPC3
122 138 297 335 371 448 166 170 222
BindingAssay
24:02-5.82 -4.37 -5.21 -6.17 -5.50 -5.49 -4.70 -7.43 -5.34
02:01-4.59 -4.76 -4.33 -4.86 -4.90 -5.56 -5.31 -5.07 -6.21
02:06-5.53 -5.59 -5.58 -5.07 -5.37 -4.28 -6.14 > -3 -5.21
ELISPOTAssay
2402/(except 0201,0206)
4/5 3/6 1/2 2/2 6/7 6/7 3/5 2/2 3/5
0201/(except 2402,0206)
0/1 0/2 0/1 0/1 2/3 1/3 1/2 0/2 2/2
Other combination
1/1 0/2 0/1 0/1 1/3 0/3 0/2 1/2 1/2
Total5/7 3/10 1/4 2/4 9/13 7/13 4/9 3/6 6/9
Note:✓ PBMC of Yamaguchi HSP70 DC therapy patients (total 13 samples, Slide
14) were used to conduct ELISPOT and ELISA assays✓ Positivity criteria: Significantly higher in either ELISPOT or ELISA (ELISPOT
p<0.05, ELISA p<0.015)
Selection of optimized shared-antigen peptides
Reference: Menez-Jamet J. et al, Optimized tumor cryptic peptides: the basis for universal neo-antigen-like tumor vaccine, Ann. Transl. Med., 2016, 4(14), 266.
15
© CYTLIMIC Inc. 2019 Proprietary 16
Challenge #2 Novel combination adjuvant
Reference: Kano Y., Tamada K., Doi S. et al, Cancer Science, 2016, 107: 398-406
Peptide + IFA
Peptide + Poly IC Peptide + LAG-3Ig
Peptide + Poly IC + LAG-3Ig
* registered in Japan
DiscoveredPoly IC (TLR3, MDA5 agonist) + LAG-3Ig (MHC Class II agonist)
Tumor growth (P815 mastocytoma tumor)
Possible combinations of clinical-stage adjuvant materials (~10) weretested using tumor-bearing mouse model, to find novel synergistic pair
CYT001 – CYTLIMIC Lead Vaccine
© CYTLIMIC Inc. 2019 Proprietary
CYT001 - CYTLIMIC Peptide Vaccine
Optimized Shared-antigenMulti-HLA-reactive peptides
Optimized combination ofadjuvants in clinical-stage
Shared antigens highly expressed in various tumors
including HCC, EsC, GaC, etc.(2 patents filed)
APC activation and control of immunosuppressive mechanism
(2 patents filed)
+Poly-ICLC(Hiltonol®)
Oncovir
LAG-3Ig(IMP321)Immutep
Vial A Vial B Vial C
GPC3Class Ipeptide
HSP70Class Ipeptide
Cross-reactivity to HLA*A- 24:02, 02:01,02:06, covers 85% of Japanese andabout 60% of Caucasian*
* German: 58%, etc.Caucasian
SC injections simultaneously at both underarms and both groins
peptide Hiltonol IMP321
18
© CYTLIMIC Inc. 2019 Proprietary
Poly ICLC binds to TLR3 (Toll-Like Receptor 3)and MDA5 (Melanoma Differentiation Antigen 5)of Antigen Presenting Cells (APCs), andactivates APCs through this “danger signal”mimicking viral infection.
LAG-3Ig binds to MHC (Major HistocompatibilityComplex) Class II molecules of APCs, andactivates APCs through MHC Class II signaling.
Poly ICLC
LAG-3Ig
TLR3/MDA5 agonist
MHC Class II agonist
CancercellAdjuvants, synergistically
activates DCs
PeptidesAntigen presentation
PeptidesAntigen presentation
CTL
CTL
CD4 + T cellhelp
Proliferation, Maturation,Migration to Tumor site
HelperT cell
Pre-existingpeptide
The combination of Poly ICLC (Hiltonol, Oncovir) and LAG-3Ig (IMP321, Immutep) synergistically activates antigen-specific CTL reactions as effective combination adjuvants.
Reference: Kano Y. et al., Cancer Science, 2016, 107: 398-406
HSP70peptide
GPC3peptide
Mechanism of Action
GPC3reactive
CTL
HSP70reactive
CTL
HSP70reactive
CTL
HSP70reactive
CTL
GPC3reactive
CTL
GPC3reactive
CTLMHC Class II
receptor
MHC Class Ireceptor
DC
TLR3 MDA5
Combination adjuvants boost peptide-specific CTL reactions
Hiltonol
IP321
19
© CYTLIMIC Inc. 2019 Proprietary
Partnering for adjuvant supply
20
A pharmaceutical corporation dedicated to the development of nucleic-acid-based clinical immunotherapies for cancer and other diseases.Oncovir Hiltonol (Poly ICLC) is supplied to Cytlimic and used in Cytlimic CYT001 cancer vaccine under collaboration agreement between Oncovir and Cytlimic, to synergistically boost patient immune responses to vaccine antigens together with Immutep Efitilagimod Alpha.
https://www.oncovir.com/
A globally active biotechnology company developing LAG-3 related immunotherapeutic product. Immutep Eftilagimod Alpha (LAG-3Ig, IMP321) is supplied to Cytlimic and used in Cytlimic CYT001 cancer vaccine under collaboration agreement between Immutep and Cytlimic, to synergistically boost patient immune responses to vaccine antigens together with OncovirHiltonol.
https://www.immutep.com/
© CYTLIMIC Inc. 2019 Proprietary
Name PhaseTarget disease, patients
Study Period(Status)
Study Site(PI)
YNP01
1IIT (Specified Clinical Trial)*
jRCTs061180058
Advanced solid tumor (HCC, GI), n=17
2016/1~2019/3
(completed)
Yamaguchi Univ.(Prof. Hiroaki Nagano)
YCP02
1IIT (Specified Clinical Trial)*
jRCTs061180033
Resectable HCC(Neoadjuvant, adjuvant vaccine)n=20 (planed)
2018/1~(active,
recruiting)
Yamaguchi Univ.(Prof. Hiroaki Nagano)
CRESCENT1
1b Investigator-Initiated Clinical Trial
jRCT2031190072
Unresectable HCCn=6
2019/8~(not yet
recruiting)
Chiba Univ.(Prof. NaoyaKato)
CYT001 - Clinical Trials
* Specified Clinical Trial: Clinical trial conducted under Clinical Trial Act (Act No.16 of April 17, 2017)
21
© CYTLIMIC Inc. 2019 Proprietary
▌Study name⚫A phase I study of combination immunotherapy with HSP70 derived peptide, GPC3
derived peptide, Poly ICLC and Soluble LAG-3 for patients with advanced or metastatic solid cancer (jRCTs061180058)
▌Dose
▌Vaccination Schedule
▌Patient: 17
Level Peptides Adjuvants
HSP70 GPC3 Hiltonol IMP321
Level 1 1.0 1.0 1.4 0.25
Level 2 2.0 2.0 1.4 0.25
Level 3 2.0 2.0 1.4 1.0
(mg/injection)
Download: https://www.cytlimic.com/download/SITC_2018_poster.pdf
YNP01 trial: Study Design
22
© CYTLIMIC Inc. 2019 Proprietary
▌Endpoints⚫Primarily endpoint: Safety
⚫Secondary endpoints: Peptide-specific immune responses, biomarker response, clinical response
YNP01: Endpoints and summary of results
23
Summary
Safety All AEs related to CYT001 were Grade 1/2
Vaccine-specific immune response
88% (15/17) responded, Prompt (most responders in 1 mo.) and Strong (IFNɤ ELISPOT≧3+, in grades -/1+/2+/3+/4+/5+)
Anti-tumor response(RECIST v1.1)
DCR: 29% (5/17), SD – 5 pts., PD – 12 pts. (no CR, PR)
Tumor marker decrease: 58% (10/17)Median OS: 10.3 mo. (95% CI 5.52–20.4 mo.)Median PFS: 1.9 mo. (95% CI 1.2–3.0 mo.)Long survivor (≧ 24 mo.): 3 pts. (HCC) (HCC: 75% (3/4))
Biomarker response TIM3+/CD4 decreased in Level 3 after 1 course (p=0.012)
Sub-class analysis Longer survival in pts. with lower PD-1+/CD4, TIM3+/CD4, TIGIT+/CD8 than higher ones, respectively
© CYTLIMIC Inc. 2019 Proprietary
(1) Safety
Level 1(n=3)
Level 2(n=3)
Level 3(n=11)
irAE(Grade 1/2)
Total 2 1 7
Edema 1 0 1
Fever 0 0 2
Injection site reaction/Skin reaction
1 1 6
note: There is no irAE as Grade 3/4. (ir: immune related)
Other AE
Grade 1+2 3 4 3
Grade 3 8 7 4
note: All of Other AEs are not related to CYT001.There is no AE as Grade 4.
24
© CYTLIMIC Inc. 2019 Proprietary
Level # Patients HSP70 (%) GPC3 (%)
# Pts.
Post CTL grade >
Pre CTL grade
Level 1(Post CTL≧3+)
3 2(0)
2(0)
Level 2(Post CTL≧3+)
3 1(0)
2(0)
Level 3(Post CTL≧3+)
11 8(6)***
9(5)***
all 17
11 (65%)* 13 (76%)*
15 (88%)**
(2) Antigen-peptide specific immune response
(Notes)✓ CTL grade: -/+/2+/3+/4+/5+✓ Among 10 responses to HSP70, 8 (80%) were observed after 1 course (*)✓ Among 12 responses to GPC3, 9 (75%) were observed after 1 course (*)✓ Response to at least one of antigen-peptides (**)✓ Among responders, strong responses (ELISPOT≧3+, after 1 course) were observed only in
Level 3 (***)
25
© CYTLIMIC Inc. 2019 Proprietary
Note: Solid brown line– Level 3 pts., Dashed line– Level 1 or 2 pts.
In patients recieving Level 3 dosage, the population of TIM3+ cells in CD4+ T cells was decreased significantly, and MDSC (CD11b+CD33+HLR-DR-/PBMC) showed trend to decrease, after 1 course of treatment.
Biomarkerts tested: Proportion of CD4+T cells/ CD8+T cells/ Monocyte cells/ Tregcells (FrⅠ,Ⅱ, Ⅲ)/ MDSC (CD11b+CD33+HLA-DR-)/ Memory T cells, Exhaustion marker (PD-1, LAG-3, TIM3, TIGIT) on CD4/8+ T cells
(3) Biomarker response in PBMC
26
0
2
4
6
Pre Post
MDSCCD11b+CD33+HLA-DR-/PBMC
P=0. 132 (Level3)
0
3
6
9
12
Pre Post
TIM-3/CD4
P=0.012 (Level3)
© CYTLIMIC Inc. 2019 Proprietary
(3) Anti-tumor response (Swimmer plot)
✓Best response: SD (long-SD for > 38 months)✓Disease control rate (DCR):29%
as of 2019/7
27
© CYTLIMIC Inc. 2019 Proprietary
p=0.0399 p=0.0245 p=0.0578 p=0.2495 p=0.2374
p=0.3327 p=0.2679 p=0.5661 p=0.0317 p=0.4732
Surface marker expression on the PBMC (pre-treatment) and prognosis(Cut-off value = median value, Gehan-Wilcoxon test)
Suggesting that the overall survival of CYT001 treatment could be improved by the combination with ICI treatment.
(5) Subgroup analysis
28
PD-1/CD4 TIM-3/CD4
TIGIT/CD8
© CYTLIMIC Inc. 2019 Proprietary
▌A phase I study of combination adjuvant immunotherapy with HSP70 derived peptide, GPC3 derived peptide, Poly ICLC and Soluble LAG-3 for patients with resectable hepatocellular carcinoma (jRCTs061180033)
Treatment period (6 months)
Neoadjuvant therapy(6 injections (weekly))
Adjuvant therapy(10 injections: 4 times weekly + 6 times biweekly
-2 -1 0 1 2 3 4 12
Surgicalresection
Surgical specimen
YCP02 Study
Evaluation of recurrence
Phenotypic analysis of TIL (Tumor infiltrated Lymphocytes) using CyTOF
TIL samples
Pathological analysis to assess if the vaccine shifts “Cold tumor to Hot”
Pathological slides
29
© CYTLIMIC Inc. 2019 Proprietary
Chen DS, et al. Immunity. 2013;39(1):1-10.
30
On Interim results of YCP02 study (neoadjuvant part)
Trigger
By CYT001 neoadjuvant vaccination,✓ CTLs infiltrate into tumor sites (HCC area)✓ These CTLs recognize vaccine-target antigens✓ Infiltrated T cells (including CTLs and Helper T cells)
express PD-1 exhaustion marker(abstract only, no detail data presented yet)
© CYTLIMIC Inc. 2019 Proprietary
suppre
ssed
not-
suppre
ssed
Toward ICI-Vaccine combination trial
CTL
CTLCTL
CTL
CTL
CTL
Hot, but suppressed Cold and suppressed
Cold, and not-suppressedHot and not-suppressedNo Cancer growth
HOT COLD
Cancercell
Cancercell
Cancercell
Cancercell
Cancercell
Cancercell
Cancercell
Cancercell
Cancercell
The interim analysis results suggest that CYT001 terns “Cold
tumor to Hot”, thus the combination to anti-PD-1 drug
improves the clinical response of anti-PD-1 drug.
CytlimicVaccineVialCVialA VialB
Accelerator
CytlimicVaccineVialCVialA VialB
Accelerator
Cancercell
Cancercell
Cancercell
CancercellCTL
CTLCTL
CTL
ICICI
Brake×
ICI
Brake×
CI
31
© CYTLIMIC Inc. 2019 Proprietary
IndividualizedNeo-antigen vaccine
(Personalized vaccine)
Optimized Shared-antigenMulti-HLA peptide vaccine
(One-fit-all vaccine)
Advancing AI technologies for Cancer Vaccine
Future of AI in Cancer Vaccine (NEC)
transgene
32
© CYTLIMIC Inc. 2019 Proprietary 33
The author gratefully acknowledges the following contributors for their scientific works and supports:
- Dr. Tomoya Miyakawa*, NEC Corporation
- Prof.Dr. Keiko Udaka, Kochi Medical School
- Prof.Drs. Masaaki Oka, Hiroaki Nagano, Shoichi Hazama, and doctors and laboratory members involved in YNP01 and YCP02 studies, Yamaguchi University School of Medicine
- Prof.Dr. Koji Tamada, Dr. Daisuke Umezu, Yamaguchi University School of Medicine
- Prof.Dr. Naoya Kato, Dr. Sadahisa Ogasawara, and doctors and laboratory members involved in CRESCENT1 study, Chiba University School of Medicine
- Prof.Dr. Akira Saito, Tokyo Medical University
- Drs. Frederic Triebel, Claudia Jacoby, Immutep Limited
- Dr. Andres Salazar, Oncovir, Inc.
- Dr. Shiro Akinaga, AccuRna, Inc.
- Dr. Yoshihide Segawa, Mr. Genji Kawano, Mr. Toru Kano, CYTLILMIC Inc.
and patients participating YNP01, YCP02 and CRESCENT1 studies
Acknowledgements
* Passed away from thyroid cancer in May 2018