Emerging Targets in Immunotherapy

Transcription

1 Emerging Targets in Immunotherapy So Jin Shin, M.D. Department of Obstetrics and Gynecology, Keimyung University, School of Medicine, Daegu, Korea

2 no-0ncology Todays is.. ancer Immunotherapy? nd immunotherapy in cancer

3 Cancer Immunotherapy overview War for Cancer Chemotherapy : lack of selectivity, long-term resistance Target therapy : acquired resistance Immunotherapy : from promising to disappointing?

4 Cancer Immunotherapy overview New active substance Launches

5 Cancer Immunotherapy overview Rapid uptake of new immune- oncology drug: PD-1 inhibitor uptake in the U.S. 135 clinical trial ---- additional indication for 30 tumor type

6 Cancer Immunotherapy overview Pipeline of oncology drug in clinical development Small molecule protein kinase inhibitor biologic monoclonal antiboides

7 Cancer Immunotherapy Cancer Immunotherapy overview Immuno-oncology focuses on harnessing the tremendous power of the human immune system to detect and destroy cancer

8 Cancer Immunotherapy overview Cancer Immunity Cycle

9 Cancer Immunotherapy Cancer Immunotherapy overview 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

10 Type of Cancer Immunotherapy 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) Active : Induced Directly in the Tumor-Bearing Animal or in the Patient : Can be Specific or Non Specific Cancer Immunotherapy overview

11 no-0ncology ancer Immunotherapy? nd immunotherapy in cancer

12 What is Next for Cancer Immunotherapy? Immunotherapy 2.0 : ASCO 2017 The growing wave of progress using cancer immunotherapy To understand Who will benefit, Whether combining immunotherapy treatment is effective - Expanding use and refining Patient selection

13 What is Next for Cancer Immunotherapy? FDA and EMA approved immunotherapy drug since 2010 Drug New approved 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 Melanoma 2011 Melanoma Nivolumab Opdivo Anti-PD Pembrolizumab Keytruda Anti-PD New uses Melanoma NSCLC, RCC Hodgkin lymphoma Melanoma NSCLC SCCHN 2015 Melanoma NSCLC RCC 2015 Melanoma Atezolizumab Tcentriq Anti-PDL Urothelial carcinoma Durvalumab -- Anti-PDL Urothelial carcinoma Ipilimumab+ Nivolumab Yervoy + Opdivo Anti-CTLA4+ Anti PD 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 -- --

14 What is Next for Cancer Immunotherapy? Cancer immunotherapy must be personalized To identify the ratelimiting steps in patients To combine strategies to overcome these hurdles To trigger the Cancer immunity cycle to proceed

15 Cancer Immunoediting What is Next for Cancer Immunotherapy? - paradigm shift toward overcoming immunosuppression - SCINECE VOL331 p1565 (2011) -

16 What is Next for Cancer Immunotherapy? Outline of tumor antigen-specific Immunotherapy CAR: (chimeric antigen receptor) Tumor-associated Ag (e.g. MAGE-A1, NY-ESO- 1) CAR T Cells apoptosis Cancer Cells Tissue-specific (e.g. MART-1, gp100) Denderitic Cells Ag-specific CD8 + T Cells PD-1/PD-L1 Antibody PD-1 (Programmed cell death) PD-L1 (PD-1 ligand)

17 What is Next for Cancer Immunotherapy? Immune based therapy Cytokines Immune checkpoint inhibitor Engineered cell therapy Oncolytic viruse -- durable clinical response in diverse solid tumor and hematological malig

18 What is Next for Cancer Immunotherapy? 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

19 Clinical development of cancer antigen-based vaccine and engineered T cell Immunotherapy CAR-engineered T cell immunotherapy What is Next for Cancer 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

20 Clinical development of cancer antigen-based vaccine and engineered T cell Immunotherapy TCR engineered T cell immunotherapy What is Next for Cancer Immunotherapy? 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 Patient derived MART-1 or MAGE-A3 TCR engineered T : safety NY-ESO-1 TCR-engineered T-cell immunotherapy Solid tumor

21 What is Next for Cancer Immunotherapy? 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

22 What is Next for Cancer Immunotherapy? The second wave of tumor antigen discovery : neoantigen based immunotherapy Breast cacner (2017) 24:16-24

23 What is Next for Cancer Immunotherapy? Final common pathway of human cancer immunotherapy : Targeting random somatic mutation reast cacner (2017) 24:16-24

24 What is Next for Cancer Immunotherapy? Limitation of neoantigen based immunotherpay Miss many immunogenic antigens Whole genome sequencing + RNA sequencing Necessary to identify neoantigens individually Accurate prediction program Expensive and require new regulatory guideline Target multiple neoantigens with specific vaccine using RNA, DNA or peptide or TCR based immnunotherapy

25 What is Next for Cancer Immunotherapy? Consider both cancer specific shared antigens and patient-specific unique neoantigens. Establishment of neoantigen-specific TCR bank

26 no-0ncology ancer Immunotherapy? nd immunotherapy in cancer Combining targeted and immunotherapy in cancer

27 Combined targeted and immunotherapy in cancer Combining of Targeted and conventional cancer therapy with Immunotherapy Metastatic Melanoma : BRAF antagonist (Vemurafenib, debrafenib) MEK antagonist ( trametinib, combimetinib) : CD8+ T 세포의종양침투증가 -> immune checkpoint inhibitor 병용

28 Combined targeted and immunotherapy in cancer

29 Combined targeted and immunotherapy in cancer Challenges for combination therapies 기존의 Requirement 치료제를 for 통해 deeper 치료받는 understanding 환자의종양샘플과혈액의면역 : 시스템을 targeted, 정학하게 conventional 분석 and immune based therapy 임상, 면역세포분석과유전자연구가통합적으로운영되어야함 소규모의 Optimization 잘디자인된 of efficacy, 임상연구를 toxicity, 통해 and toxicity, tolerability tolerability 및 through efficacy appropriate data를얻어내고 dosing 이를 and 바탕으로 sequencing 적절한병용치료를위한임상시도 병용 Robust 치료를 approach 선택함에 to 있어서 prioritizing 우선순위는 and resourcing standard of care 를 the 대처할 myriad 수있을 possibilities 정도의의료적 for combination 혜택을줄수 therapy 있는지에초점. 학계, 산업계, 정부와비영리연구소간의협력과정보공유

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