emerging targets in immunotherapy · so jin shin, m.d. department of obstetrics and gynecology,...
TRANSCRIPT
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So Jin Shin, M.D. Department of Obstetrics
and Gynecology, Keimyung University, School of
Medicine, Daegu, Korea
Emerging Targets in Immunotherapy
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nno-0ncology
Cancer Immunotherapy?
and immunotherapy in cancer
nno-0ncology Todays is …..
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Cancer Immunotherapy overview
War for Cancer
Chemotherapy : lack of selectivity, long-term resistance
Target therapy : acquired resistance
Immunotherapy : from promising to disappointing ?
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New active substance Launches 2011-2015
Cancer Immunotherapy overview
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Rapid uptake of new immune- oncology drug: PD-1 inhibitor uptake in the U.S.
Cancer Immunotherapy overview
135 clinical trial ---- additional indication for 30 tumor type
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Pipeline of oncology drug in clinical development
• Small molecule protein kinase inhibitor
• biologic monoclonal antiboides
Cancer Immunotherapy overview
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Cancer Immunotherapy
• Immuno-oncology focuses on harnessing the tremendous power of the human immune system to detect and destroy cancer
Cancer Immunotherapy overview
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Cancer Immunity Cycle Cancer Immunotherapy overview
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Cancer Immunotherapy
To specifically target cancer cells
To recruit efficient immune cells that can generate a robust and long lasting response
Most importantly prevent relapse
➔ To educated and boost tumor-specific immune cells
Cancer Immunotherapy overview
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Type of Cancer Immunotherapy
Active : Induced Directly in the Tumor-Bearing Animal or in the Patient : Can be Specific or Non Specific
Passive or Adoptive : Immunologically Active Material Transferred into Mouse or Patient as a Passive Recipient : Can be Specific (Antibodies, T-Cells, Antigen presenting cells – Dendritic Cell Vaccines) Or Non-Specific (Non-specifically-activated T-Cells; Cytokines)
Cancer Immunotherapy overview
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nno-0ncology
Cancer Immunotherapy?
and immunotherapy in cancer
Cancer Immunotherapy?
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What is Next for Cancer Immunotherapy?
Immunotherapy 2.0 : ASCO 2017
To understand
• Who will benefit,
The growing wave of progress using cancer immunotherapy
• Whether combining immunotherapy treatment is effective
-→ Expanding use and refining Patient selection
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Drug Registered name Mechanism of
action FDA approval
date Indication
(advanced Dz)
EMA approval
date Indication
Sipuleucel-T Provenge Dentritic cell vaccine
2010 Prosatate cancer -- --
Ipilimumab Yervoy Anti –CTLA-4 2011
Melanoma 2011 Melanoma
Nivolumab Opdivo Anti-PD1 2014 2015 2016
Melanoma NSCLC, RCC Hodgkin lymphoma
2015 Melanoma NSCLC RCC
Pembrolizumab Keytruda Anti-PD1 2014 2015 2016
Melanoma NSCLC SCCHN
2015 Melanoma
Atezolizumab Tcentriq Anti-PDL1 2015
Urothelial carcinoma
-- --
Durvalumab -- Anti-PDL1 2016 Urothelial carcinoma
-- --
Ipilimumab+ Nivolumab
Yervoy + Opdivo Anti-CTLA4+ Anti PD1
2015 Melanoma 2016 Melanoma
Blinatumumab Blincyto Anti-CD3/CD19 BiTE
2014 B cell ALL 2015 B cell ALL
Talimogene latherparepvec (T VEC)
Imlygic Onolytic virus 2015 Melanoma 2015 Melanoma
-- -- TCR therapy targeting NY-ESO
2016 Synovial sarcoma -- --
FDA and EMA approved immunotherapy drug since 2010
New approved
New uses
What is Next for Cancer Immunotherapy?
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Cancer immunotherapy must be personalized
• To identify the rate-limiting steps in patients
• To combine strategies to overcome these hurdles
• To trigger the Cancer –immunity cycle to proceed
What is Next for Cancer Immunotherapy?
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Cancer Immunoediting
- paradigm shift toward overcoming immunosuppression
- SCINECE VOL331 p1565 (2011) -
What is Next for Cancer Immunotherapy?
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Outline of tumor antigen-specific Immunotherapy
Tissue-specific (e.g. MART-1, gp100)
Denderitic Cells
Cancer Cells
Ag-specific CD8+ T Cells
CAR T Cells
• CAR: (chimeric
antigen receptor)
PD-1/PD-L1 Antibody
PD-L1 (PD-1 ligand)
PD-1 (Programmed
cell death)
apoptosis
Tumor-associated Ag (e.g. MAGE-A1, NY-ESO-
1)
What is Next for Cancer Immunotherapy?
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Immune based therapy
• Cytokines
• Immune checkpoint
inhibitor
• Engineered cell therapy
• Oncolytic viruse
--→ durable clinical response in diverse solid tumor and hematological malig
What is Next for Cancer Immunotherapy?
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Clinical development of cancer antigen-based vaccine and engineered T cell Immunotherapy
Cancer Vaccine development MAGE-A3 peptide /protein : Phase II/III , NSCLC : failed in phase III
NY-ESO-1 recombinant protein : Melanoma , Ovarian cancer : Antigen specific immune response : failed
NY-ESO-1 recombinant + MHC class I and II : Prostate cancer, Phase I : prolonged median PSA doubling time & decreased PSA level
What is Next for Cancer Immunotherapy?
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Clinical development of cancer antigen-based vaccine and engineered T cell Immunotherapy
CAR-engineered T cell immunotherapy CD19-CAR T cell therapy
: refractory B cell malignancy , ALL, CLL : cytokine release syndrome : on-off system using small molecule
CART technology based on NOTCH receptor : T cell activation through recognition of combinational antigen ➢Recurrence (40-50%)
within 1yr ➢Not work in solid tumor
What is Next for Cancer Immunotherapy?
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Clinical development of cancer antigen-based vaccine and engineered T cell Immunotherapy
TCR engineered T cell immunotherapy
Patient derived MART-1 or MAGE-A3 TCR engineered T : safety
HLA –A2 restricted NY-ESO-1 TCR transduced T cell : Response rate 55-60% : Metastatic synovial sarcoma , melanoma, myeloma, triple (-) breast ca, : Toxicity (-) : best target
➢NY-ESO-1 TCR-engineered T-cell immunotherapy
➢Solid tumor
What is Next for Cancer Immunotherapy?
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The second wave of tumor antigen discovery
Mutation derived neoantigens
Mutated protein expressed in cancer cell and recognized by immune system : Not affected by central T cell tolerance : TCGA data - numbers of predicted MHC class I associated neoepitope and increased patient survival : T cell activity against neoantigen be enhanced by anti CTLA-4 : clinical correlate with mutational load
What is Next for Cancer Immunotherapy?
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Breast cacner (2017) 24:16-24
The second wave of tumor antigen discovery : neoantigen based immunotherapy
What is Next for Cancer Immunotherapy?
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“ Final common pathway of human cancer immunotherapy
: Targeting random somatic mutation”
Breast cacner (2017) 24:16-24
What is Next for Cancer Immunotherapy?
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“Limitation of neoantigen based immunotherpay”
Miss many immunogenic antigens
Necessary to identify neoantigens individually
➢Whole genome sequencing + RNA sequencing
➢Accurate prediction program
➢ Target multiple neoantigens with specific vaccine using RNA, DNA or peptide or TCR based immnunotherapy
Expensive and require new regulatory guideline
What is Next for Cancer Immunotherapy?
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➔Consider both cancer specific shared antigens and patient-specific unique neoantigens.
➔ Establishment of neoantigen-specific TCR bank
What is Next for Cancer Immunotherapy?
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nno-0ncology
Cancer Immunotherapy?
and immunotherapy in cancer Combining targeted and
immunotherapy in cancer
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Combining of Targeted and conventional cancer therapy with Immunotherapy
Metastatic Melanoma : BRAF antagonist (Vemurafenib, debrafenib) MEK antagonist ( trametinib, combimetinib) : CD8+ T세포의 종양 침투 증가 -> immune checkpoint inhibitor 병용
Combined targeted and immunotherapy in cancer
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Combined targeted and immunotherapy in cancer
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Challenges for combination therapies
Requirement for deeper understanding : targeted, conventional and immune based therapy
Optimization of efficacy, toxicity, and tolerability through appropriate dosing and sequencing
Robust approach to prioritizing and resourcing the myriad possibilities for combination therapy
➢기존의 치료제를 통해 치료받는 환자의 종양 샘플과 혈액의 면역 시스템을 정학하게 분석
➢임상, 면역세포 분석과 유전자 연구가 통합적으로 운영되어야 함
➢소규모의 잘 디자인된 임상연구를 통해 toxicity, tolerability 및 efficacy data를 얻어내고 이를 바탕으로
적절한 병용치료를 위한 임상시도
➢병용 치료를 선택함에 있어서 우선순위는 standard of care를 대처할 수 있을 정도의 의료적 혜택을 줄 수 있는지에
초점. ➢학계, 산업계, 정부와 비영리 연구소간의 협력과 정보 공유
Combined targeted and immunotherapy in cancer
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감사합니다