Emerging Targets in Immunotherapy · So Jin Shin, M.D. Department of Obstetrics and Gynecology,...

transcript

So Jin Shin, M.D. Department of Obstetrics

and Gynecology, Keimyung University, School of

Medicine, Daegu, Korea

Emerging Targets in Immunotherapy

nno-0ncology

Cancer Immunotherapy?

and immunotherapy in cancer

nno-0ncology Todays is …..

Cancer Immunotherapy overview

War for Cancer

Chemotherapy : lack of selectivity, long-term resistance

Target therapy : acquired resistance

Immunotherapy : from promising to disappointing ?

New active substance Launches 2011-2015

Rapid uptake of new immune- oncology drug: PD-1 inhibitor uptake in the U.S.

135 clinical trial ---- additional indication for 30 tumor type

Pipeline of oncology drug in clinical development

• Small molecule protein kinase inhibitor

• biologic monoclonal antiboides

Cancer Immunotherapy

• Immuno-oncology focuses on harnessing the tremendous power of the human immune system to detect and destroy cancer

Cancer Immunity Cycle Cancer Immunotherapy overview

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

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)

nno-0ncology

and immunotherapy in cancer

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

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

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

Cancer Immunoediting

- paradigm shift toward overcoming immunosuppression

- SCINECE VOL331 p1565 (2011) -

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-

Immune based therapy

• Cytokines

• Immune checkpoint

inhibitor

• Engineered cell therapy

• Oncolytic viruse

--→ durable clinical response in diverse solid tumor and hematological malig

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

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

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

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

Breast cacner (2017) 24:16-24

The second wave of tumor antigen discovery : neoantigen based immunotherapy

“ Final common pathway of human cancer immunotherapy

: Targeting random somatic mutation”

Breast cacner (2017) 24:16-24

“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

➔Consider both cancer specific shared antigens and patient-specific unique neoantigens.

➔ Establishment of neoantigen-specific TCR bank

nno-0ncology

and immunotherapy in cancer Combining 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+ T세포의 종양 침투 증가 -> immune checkpoint inhibitor 병용

Combined targeted and immunotherapy in cancer

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

감사합니다

Emerging Targets in Immunotherapy · So Jin Shin, M.D. Department of Obstetrics and Gynecology,...

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