basics of immuno-oncologyaacr cancer progress report 2014 phase iii trial: ipilimumab/gp100 vs...
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Basics of Immuno-Oncology
2016. 6. 25
Kyong Hwa Park MD, PhD
Oncology/Hematology
Korea University Hospital
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Contents
• Immune microenvironment in cancer
• Immunologic therapeutics in Oncology
- Cytokines
- Vaccines
- Immune checkpoint Inhibitors – a new breakthrough
- Cell-based treatment
• Rational Application of Immunotherapeutics - Biomarkers
- Combination strategy
- Immune monitoring
• Summary & Future directions
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Coley’s Toxins
• William Coley (New York surgeon) began intratumoral injections of live or inactivated bacteria (1891)
• Stimulate antibacterial phagocytes that might kill bystander tumour cells
Nature Reviews Cancer 9, 361-371 (May 2009)
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Science 25 March 2011
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Cellular Immunity in Tumor microenvironment
Mast cells
T cells N1 neutrophils
M1 macrophage
NK cells
B cells
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Chronic Inflammation directs Th2 Immunity
Primary tumor-derived factors
Successful metastatic outgrowth
Immune-mediated dormancy/Elimination
Cancer Res October 1, 2013 73; 5852
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CD4+ Treg Immune Regulation
Front. Immunol., 18 November 2013
Targeting DCs
Metabolic disruption
Competition
Cytolysis of Teff Inhibitory cytokines
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Tumor Reprogramed Myeloid Cells
Nature Reviews Immunology 12, 253-268
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Immune Contexture
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Pages et al, NEJM, 2005
Immunity can Impact Disease Outcome: Role of Th1 CD4+ T Cells
Galon et al, Science, 2006
Factors Predicting Outcome:
Th1 TEM
Central Dense
>400 samples
75 samples
Th1 Signature: IFN
J Galon et al, Science 2006
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Type, Density, and Location of Immune Cells
J Galon et al, Science 2006
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Association of Immune Cell Infiltration and Prognosis
Fridman WH et al, Nat Rev Cancer 2012
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다음 중 직접 암세포 살상 기능이 알려진 면역세포는?
1) Naïve T cell
2) Dendritic cells
3) Foxp3+ CD4 T cells
4) CD8+ T cells
5) CD19+ B cells
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Cancer Immunity Cycle
Immunity 39, July 25, 2013
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Stimulatory vs Inhibitory Factors in Cancer Immunity Cycle
Immunity 39, July 25, 2013
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How to harness immune system to treat cancer?
- Make TME ‘Inflamed’
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Therapeutic Strategies to Harness Immune System
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Effect of Anti-cancer Treatment on Immune Cells
Trends in Immunology April 2015, Vol. 36, No. 4, 2015
Indirect Effects Direct Effects
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Malignant Melanoma
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Role of RT in Induction of the Antitumor Immune Response
2013, JCI
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Abscopal Effect by Radiotherapy
N Engl J Med 2012;366:925-31
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M/62, mRCC
• Rt RCC – Radical nephrectomy, clear cell type
• 5년 후 Recur: 1L Bevacizumab/IFNg 임상참여
• 2L Sunitinib: PD
• General condition and organ function - fair
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What’s your next treatment in Korea?
1) Everolimus
2) Pazopanib
3) Axitinib
4) High dose IL-2
5) Nivolumab
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Cytokine therapy: HD IL-2
Clin Cancer Res; 21(3) February 1, 2015
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Durable response & Life Prolongation
Clin Cancer Res; 21(3) February 1, 2015
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Cancer Vaccines
Educating APCs properly
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GVAX Probably Improves PDA Patients
• GVAX: a human whole cell granulocyte macrophage colony-stimulating factor (GM-CSF) secreting pancreatic cancer vaccine
• Phase II Study in patients received CCRT after R0/R1 resection for PDA
Ann Surg Oncol. 2013 Dec; 20(0 3): S725–S730.
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Combination Strategy: GVAX + PD-1/PD-L1 Ab
J Immunother. 2015 Jan;38(1):1-11
Patients
Mouse CD8+IFNɣ+ (Spleen, TIL) IFNɣ+ (Spleen, TIL)
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Personalized Immunotherapy based on Tumor Neoantigen
Schreiber et al, JCI Aug 2015
Neoantigen-specific and self-antigen–specific T cells? Proteosomal processing? Correct identification of CD4 epitopes? In vitro detection of Ag processing and presentation?
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Dendritic Cell in Cancer Immunotherapy
Nature Medicine 6, 966 - 968 (2000)
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DC Therapy for CRPC Study 1 Study 2
Provenge (n=341) Control (n=171) Provenge (n=82) Control (n=45)
mOS (m) 25.8 21.7 25.9 21.4
HR (95%CI) 0.775 (0.614, 0.979) 0.586 (0.388, 0.884)
p-value 0.032 0.010
www.dendreon.com
US FDA Approval! April 2010
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Intervention Based on Tumor Burden
1:10,000 T cells >1:10,000 T cells >1:100 T cells?
Vaccine Prevention
Therapeutic Vaccines
Alternative Strategies
Dis
eas
e B
urd
en
Vaccines Adoptive Cell Therapy
No Disease Microscopic Disease Established Disease
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52세 여자가 우측 발뒤꿈치에 생긴 점을 주소로 내원하여 악성 흑색종 광
범위 절제 및 서혜부 감시 림프절 생검술 및 절제 후 3기암 (BRAF mutant)
으로 진단되었다.
향후 환자의 경과를 호전시키기 위해 적용할 수 있는 가장 적절한 면역학
적 치료법은?
1) Nivolumab
2) CAR-T cell therapy
3) Vemurafenib
4) High dose IL-2
5) Cancer vaccine
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Immune checkpoint Inhibitors – a new Breakthrough
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Priming phase Effector phase
CTLA-4
PD-L1
NEJM 366;26 2518 June 28, 2012
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History of anti-CTLA Antibody
AACR Cancer Progress Report 2014
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Phase III Trial: Ipilimumab/gp100 vs Ipilimumab vs gp100
OS Ipilimumab/gp100 (n=403)
Ipilimumab (n=137)
Gp100 (n=136)
mOS (mon) 10.0 10.1 6.4
vs gp100 HR 0.68 (0.55–0.85) 0.66 (0.51–0.87)
P <0.001 0.003
vs Ipilim HR 1.04 (0.83–1.30)
P 0.76
ORR 5.7 % 11.0 %
N Engl J Med 363;8 august 19, 2010
US FDA Approval in March 2011 KFDA Approval in Dec 2014
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Mechanisms of PD-1 Expression
Nature Immunology 14, 1212–1218 (2013)
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CD8+T cell Dynamics in Infection
Trends in Immunology April 2015, Vol. 36, No. 4
Acute Ag/functional memory Chronic Ag/ Exhaustion
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PD-1/PD-L1: Exhaustion of T cells
1) Antagonizing TCR signaling
2) Decreased survival, proliferation, altered metabolism
3) Reduced proliferation via RAS path
4) Altered transcription
5) Altered T cell motility
Trends in Immunology April 2015, Vol. 36, No. 4
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PD-1 and T cell Dysfunction
Jan, 2015, Nature Rev Immunology
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Expression of PD-L 1 in Tumors
Cancer types % PD L-1(+) Cancer types % PD L-1(+)
Melanoma 40-100 Ovarian cancer 33-80
NSCLC 35-95 Gastric carcinoma 42
Nasopharyngeal ca 68-100 Esophageal ca 42
Glioblastoma/ mixed glioma
100 Pancreatic cancer 39
Colon 53 RCC 15-24
HCC 45-93 Breast cancer 31-34
Urothelial cancer 28-100 Lymphomas 17-94*
Multiple myeloma 93 Leukemias 11-42
Chen DS, Clin Cancer Res October 19, 2012.
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Phase I Study of Single-Agent Anti–PD-1 in Refractory Solid Tumors
• MDX-1106 (BMS-936558/ONO-4538)
: fully human IgG4 mAb specific for humanPD-1
• Patients (n=39): CRC(14), Melanoma(10), NSCLC(8), Prostate(6), RCC(1)
Dose (mg/kg) No. of patients
Total No. of Doses Best Response (Duration in month) 1 2 3 5 11
0.3 6 6 0 0 0 0 N/A
1 6 3 1 1 1 0 1 MXR (1)
3 6 3 0 2 1 0 1 CR (21+)
10 21 15 1 4 0 1 2 PR(3+, 16+), 1MXR (1)
Total 39 27 2 7 2 1 1 CR, 2 PR, 2 MXR
Brahmer JR, J Clin Oncol 28:3167-3175. 2010
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Expanded Phase I Study
Dose of anti-PD-1 Ab
Objective response
ORR Duration of
response Stable disease ≥
24wk PFS rate at
24 wk
Melanoma
NEJM June 28, 2012
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Dose of anti-PD-1 Ab
Objective response
ORR Duration of
response (M) Stable disease ≥
24wk PFS rate at
24 wk
NSCLC
NEJM June 28, 2012
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NK Cells: Selected clinical trials with expanded allogeneic NK cells
Front. Immunol., 03 June 2015
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Phase I : Random Healthy Donor–Derived Allo-NK Cell Therapy in Patients with Malignant Lymphoma or Advanced Solid Tumors
• Maximum dose (3 × 107 cells/kg, triple infusion): tolerable without significant AE
• Of 17 evaluable patients, 8 patients (47.1%) SD, 9 (52.9%) PD.
Cancer Immunol Res March 2016 4; 215
Treg TGFβ1
MDSC
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Adoptive T cell Therapy • Genetically engineered TCR expressing T cells
2006 Science
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Genetically engineered T-cell receptor recognizing NY-ESO-1 in Synovial Sarcoma
• T cells transduced with a retrovirus encoding a TCR against an HLA-A*0201 restricted NY-ESO-1 epitope
Clinical Cancer Research, 21 (2015)
Synovial sarcoma (n=18) Melanoma (n=20)
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CAR T-Cell Therapy
: Chimeric Antigen-Receptor based Therapy
52 Clin Cancer Res; 18(10) May 15, 2012
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CAR T-Cell Therapy
: Engineering Patients’ Immune Cells to Treat Their Cancers
53
Clin Cancer Res; 18(10) May 15, 2012
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CAR-T cell Therapy in ALL
N Engl J Med 2014; 371:1507-1517
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CAR-T cells Immunotherapy in Solid Cancers
• Target antigen?
• T cell expansion protocol
• Appropriate cell dose
• Patient conditioning
• Monitoring
• Elimination of CART
2016 AAAS, Riddell et al
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Metastatic Cancer Remission
• Patient selection ?
• Anti-tumor immune response? • How long treat? • Combination approach?
• Still immune response? • Retreat?
Clinical Questions that you might have….
PD-1 blockade
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Usual Pattern of Clinical Response
Progressive Disease - 왜 반응이 없는가? - 항종양 면역 반응의 부재
Stable Disease - 더 효과를 높일 방법은 없는가? - Immune signal 증폭 방법은?
Durable responses - 완전 관해를 이루는 방법은? - 면역 반응유지를 모니터 할 방법은?
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Rational Application of Immunotherapeutics
• Biomarkers
- PD-1/PD-L1 expression
- Mutational load
• Combination strategy
• Immune monitoring
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MPDL3280A (anti-PD-L1) in Urothelial Cell Cancer
Nature, 2014 Nov
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PD-L1 Expression on TILs
Nature, 2014 Nov
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• PD-L1 expression status by IHC: anti–PD-L1 antibody clone 22C3 (Merck)
• Cells counted: neoplastic and intercalated mononuclear inflammatory cells
KEYNOTE-001: Phase Ib study of Pembrolizumab for the Treatment of NSCLC
N Engl J Med 2015;372:2018-28.
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PFS OS All patients
Prev Tx
No Prev Tx
All patients
Prev Tx
No Prev Tx
N Engl J Med 2015;372:2018-28.
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Randomised, phase 3 study of Nivolumab vs Docetaxel in advanced Squamous NSCLC
after one prior Platinum-containing regimen
Stage IIIB or IV squamous-cell NSCLC who had disease recurrence after one prior platinum-containing regimen
Nivolumab 3 mg/kg q 2 wks
Docetaxel 75mg/㎡ q 3wks
R 1:1
Stratification: Prior use of paclitaxel therapy (yes vs. no)
Geographic region
(United States or Canada vs.Europe vs. rest of the world
[Argentina, Australia, Chile, Mexico, and Peru]). Primary endpoint: Overall survival
N=272
N Engl J Med 2015;373:123-35.
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N Engl J Med 2015;373:123-35.
9.2 mon vs 6.0 mon
3.5 mon vs 2.8 mon
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N Engl J Med 2015;373:123-35.
• Percent membranous staining in ≥100 tumor cells. • Archival or recent biopsy • (Dako North America) used a rabbit monoclonal antihuman
PD-L1 antibody (clone 28–8, Epitomics).
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Randomised, phase 3 study of Nivolumab vs Docetaxel in advanced non-Squamous NSCLC
after one prior Platinum-containing regimen
Stage IIIB or IV nonsquamous-cell NSCLC who had progressed during or after platinum-based chemotherapy
Nivolumab 3 mg/kg q 2 wks
Docetaxel 75mg/㎡ q 3wks
R 1:1
• Stratification: Prior maintenance treatment (yes vs. no)
Line of therapy (second line vs. third line).
• Primary endpoint: Overall survival
N=582
N Engl J Med SEP2015; DOI: 10.1056/NEJMoa1507643
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N Engl J Med SEP2015; DOI: 10.1056/NEJMoa1507643
12.2 mon vs 9.4 mon
2.3 mon vs 4.2 mon
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PD-L1 expression predicts Survival
N Engl J Med SEP2015; DOI: 10.1056/NEJMoa1507643
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PD-L1 as a Biomarker?: Issues
• Tumor heterogeneity
• Interval between biopsy and treatment
• Primary vs metastatic disease
• Ab and staining conditions
• Defining a positive result (cut-offs)
- Immune cells vs tumor cells
- Location of expression: intracellular vs surface vs stroma
- Intensity, percent of positive cells
- Distribution
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Estimate of the Neoantigen Repertoire in Human Cancer.
Science 3 April 2015
Somatic mutation frequencies (mutation burden) observed in “exomes” from 3,083 tumor–normal pairs.
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PD-1 Blockade in mCRC
N Eng J Med, Jun 2015
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Prognosis
N Eng J Med, Jun 2015
Progression Free Survival for CRC Overall Survival for CRC
How about the efficacy of PD-1 blockade in other cancers with MRD?
Uterus, stomach, biliary tract, pancreas, ovary, prostate, and small intestine
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Mutational Landscape of Melanoma according to the CTLA-4 blockade Response
Snyder A et al. N Engl J Med 2014;371:2189-2199.
Mutational Load
Survival in Discovery set
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Nonsynonymous mutation burden associated with clinical benefit of anti–PD-1 therapy: NSCLC
Science 3 April 2015
Mutational burden vs Response
Mutational burden vs Prognosis
Smoking vs Prognosis
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Mutation burden, clinical response, and factors contributing to mutation burden: NSCLC
Science 3 April 2015
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Neoantigen burden & Intratumoral Heterogeneity (ITH)
Science MAR 2016
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다음 중 항 PD-1/PD-L1 저해제 치료로 가장 큰 임상적
이득이 가장 적을 것으로 예상되는 환자는?
1) Luminal A type 골전이만 있는 32세 유방암 환자
2) Lynch syndrome으로 진단받은 43세 전이성 대장암 환자
3) 흡연력이 있는 56세 4기 폐편평상피세포암 환자
4) BRCA1 돌연변이가 있는 36세 전이성 삼중음성 유방암 환자
5) 50갑년의 흡연력이 있는 72세 전이성 방광암 환자
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Nanda et al, 2014 SABCS
Monotherapy might not be enough!
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Rational Application of Immunotherapeutics
• Biomarkers
- PD-1/PD-L1 expression
- Mutational load
• Combination strategy
• Immune monitoring
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Therapeutic Strategies to Harness Immune System
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Combination of anti-CTLA4/anti-PD-1 in Untreated Melanoma
Postow MA et al. N Engl J Med 2015;372:2006-2017.
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Rational Application of Immunotherapeutics
• Biomarkers
- PD-1/PD-L1 expression
- Mutational load
• Combination strategy
• Immune monitoring
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Strategies for Immune Monitoring
Annu. Rev. Med. 2014.65:185-202
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CD8+ T cells with Pembrolizumab
Nature 515, 568–571 (27 November 2014)
Response (n=22)
Progression (n=24)
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Proliferating CD8+ T cells in Regressing Tumors
Nature 515, 568–571 (27 November 2014)
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Anything in blood? - Immune cell profiles - Cytokines - PBMC Immunomics
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Baseline serum Cytokine score impacts OS in NSCLC
• Explorative analysis of CM-063 and 017
• SQ-Cytoscore: IL-6, FRTN, CRP, MIP-16, Ip-10, IL-16, MICA, IL-1RA, MMP3, MIG, ICAM1, VDBP, vWF
2016 ASCO
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Personalized Immunotherapy Strategy
Briefings in Bioinformatics, 2015, 1–15
Optimized Immunotherapy Protocol Computational
Immunotherapy : Vaccine etc
Immune Monitoring
Patient Profiling
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Future Oncology Treatment Paradigm…
89
Biomarkers supported by - Genomics - Seromics - Immunomics
Personalized, Combined, Immunotherapy
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Summary & Future…
• Immunotherapy changed the paradigm of cancer therapy.
• CTLA-4 opened the door to age of immunotherapeutics for cancer.
• PD-1/PD-L1 antibodies harnessed new cancers to immunogenic ones.
• Identification of combinatorial strategy is a future direction.
• Development of predictive biomarkers is ongoing.
• More Understanding about tumor biology.
• Characterizing tumor immune microenvironment according to types and stages of tumors.
• Rational application of ‘omics’ for personalized approach.
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Research Cures Cancer!