Progress of cancer immunotherapy
and its future perspectives
Yutaka Kawakami
Division of Cellular Signaling
Institute for Advanced Medical Research
Keio University School of Medicine

Cancer immunotherapy

topicsCurrent Today’s
status and futureperspectives•Cancer immunotherapy is now a promising therapy !
– Durable responses for advanced cancer patients with multiple cancer types– Immune-checkpoint blockade (PD-1/PD-L1, CTLA4)– T-cell based adoptive cell therapy (TIL, TCR/CAR-T cells)•The clinical issues to be solved;– Identification of biomarkers for personalized therapy• Selection of appropriate patients / Selection of appropriate immunotherapy– Development of combination immunotherapy
particularly for non-responsive patients to the current immunotherapy•Further understanding of immunopathology of cancer
particularly in tumor microenvironment and it’s modulation !
– Individual difference of immune status in cancer patients– It’s correlation with response to various cancer therapies– Multiple mechanisms of immune-evasion; Appropriate interventions !
– Personalized immunotherapy based on the immune-evaluation!
– Combination immunotherapy targeting multiple key regulation points!

Cancer immunotherapy
Active immunization(Cancer vaccines)

・Prophylactic vaccines for microbes
・Adjuvant vaccines to prevent relapse

Non-specificimmunomodulators

・Immunotherapy to reduce tumors(BCG, OK432, PSK, etc)

Passive immunotherapy
Adoptive immunotherapy

Anti-tumor mAb

Tumor Ags
（peptides, proteins, DNA etc)

Tumor Ag reactive T-cells
T cells

Tumor extracted Ags

CancerDendritic cells
pulsed with tumor Ags

Modified cancer cells

PBMC＋Tumor Ags＋Cytokines＋TCR/CAR transduction
TIL＋Cytokines
Allogeneic lymphocytes（Allo-BMT、DLI）

Reversal of immunosuppression(PD-1/PD-L1, etc)

Important issues for development of immunotherapy
Further understanding ofhuman cancer immunology !
Biomarkers for personalized therapy
・Selection of appropriate patients・Selection of appropriate immunotherapy

Survival

Improvement of immunotherapy
by combination immunotherapy？
Non-responders convert to responders？

MonthsStandard therapy

Current immunotherapy(e.g. Chemotherapy / molecular target therapy)(e.g. anti-CTLA-4 / PD-1 Ab)

Immunomonitoring methods ?

Clinical evaluation ?
irRC, irRECIST, delayed clinical effects

Positive and negative immune responses to cancer
・Oncogene triggered immunosuppression
・Anti-tumor T-cell triggered immunosuppression
Immunosuppressive cells
Oncogene triggered
immunosuppression

Cancer cell
Passengermutations

X

Drivermutations

X

Myeloid derived
suppressor cells(MDSC)

Regulatory
T-cells(Treg)

Dendritic cell

Cytotoxic T-cells

Tumor Ags

Tumor Ags

Chemokine, CXCL13, CCL4
Cytokine IL15

HLAT-cellreceptor

PD-1

IFN-γ

Gene alteration
Immunosuppressive molecules

IDOLocal negativeimmune-feedback
Adaptive resistance

PD-L1(e.g. TGF-β, VEGF, PGE2)

Cancer cells
Environmental factors•smoking, diet/obesity•microbiota, infection history

Immunotherapy using Ab specific for targets on T-cells
Anti-CTLA4 Ab

Anti-PD-1Ab（Nivolumab）（ Ipilimumab ）Response rate
MelanomaRCC
Lung cancer

26/94 (28%)
9/33 (27%)
14/76 (18%)

Durable responses (over 1 year ormore) in 20 of 31 (65%) responders

Effector T cells

PD-1(-)

PD-L1

CTLA4
CD80/86

・Median Survival:
10mo vs 6.4mo (n=676)

Cancer cellsHodi FS, et al, NEJM 2010

Topalian SL, et al, NEJM 2012

Anti-PD-L1Ab

CTLA4

Response rateMelanoma
RCC
Lung cancer

3/16 (19%)
2/17 (12%)
4/15 (16%)

T regLess immune-adverse effects
than anti-CTLA4 Ab
Brahmer JR et al, NEJM 2012

CTLA-4/Treg is involved in peripheral tolerance ー> More autoimmune AE

Human tumor antigens recognized by tumor infiltrating T-cells• Mutated antigens derived from DNA alterations in cancer cells(β-catenin, etc) SYLDSGIHS(F) －＞acquire HLA-binding
Neo-antigens• Viral related antigensT cell

(HPV-E6/E7)• Cancer-testis antigens(MAGEs, NY-ESO-1)• Tissue specific antigens(MART-1/Melan-A, gp100)
ペプチドスプライシング• Over-expressed antigens• Allo-antigens• Others

Mechanisms for
T-cell epitope generation

Cancer cell

Novel personalized immunotherapy targeting individual mutations
Identification of mutations by exomicsequencing of autologous cancer cells

Prediction of HLA binding peptides
by computer argorithsms

Confirmation of T cell epitopes by・ in vitro peptide induction of T cells
・ immunization of HLA transgenic mice・using HLA tetramers

・Active immunization with peptides / mRNA
・ACT with TIL / TCR-transduced T cellsIssues to be solved in the immuno-checkpoint blockade• When used ? Advanced cancer, frontline treatment, adjuvant setting• When stopped ? How long should be used? (high cost, economical issues)• Personalized immunotherapy– Unresponsive cancer： pancreas ca., MSS-CRC, myeloma, prostate ca,– Non-responders convert to responders*Biomarkers (PD-L1 exp, CD8+T cell infiltration, DNA mutations, MDSC, Treg, etc)
through systematic analysis of clinical trials (Omics, microbiota, immuno-analysis)*Pretreatment, early on-treatment*Biomarkers can be new treatment targets• Combination immunotherapy with personalized interventions– Immunogenic cancer cell death, adjuvant, vaccine, immune-regulators– Enhanced anti-tumor effects w/o increase of adverse effects ?
– Which combination ? Concurrent vs sequential ?

– Combination of chemotherapy / molecular target therapy
w/ checkpoint blockade： high immunogenic mutation (melanoma, NSCLC)
w/ ACT: less immunogenic leukemia, NSCLC, etc,

Combined immunotherapy targeting multiple key regulation points
in anti-tumor T cell response
Tumor antigen vaccine
Mutated Ags
Cancer stem cell Ags

T-cell activation / expantion

Augmentation of dendritic cell function

Cytokines (IL2,IL7,IL15,IL21)
Agonist Ab (4-1BB, OX40)など

Adjuvant (TLR3, STING), Ab (CD40 agonist)

Dendritic cell

CancerAnti-tumor T cells

CancerCox2

NKT/NK/γδT

Tumor Ag
HLA(-)

IDO/TDO

PD-1 PD-L1
Immunosuppressive molecules /cells
TGF-β, VEGF, IL10, IL6, PG-E2, T-reg, MDSCなど
in site tumor destruction<Immunogenic cell death>
Chemotherapy・Ab・physical・Virus, etc

Reversal of immunosuppression
Signal inhibitors, Chemotherapy, IDO inhibitor,
Ab （CTLA4, PD-1, LAG3, CCR4, TIM3, TIGIT）, RNAi, etc

Adoptive cellular immunotherapy
using tumor antigen specific ex vivo cultured T-cells

Blood T-cells

Tumor infiltrating T-cells
cytokine

Tumor Ag
stimulation

Gene transfer of tumor Ag receptor
TCR: T-cell receptor CAR: chimeric Agreceptor

CD3CD8Melanoma
Cervical caTCR
constantregion
Abvariableregion

TCR

HLA

Tumor Ag

Tumor Ag

Recognition w/o HLAImportant issues to be solved for developing effective immunotherapy

Survival

Identification ofBiomarkers ?

Further understanding of
human cancer immunology
in tumor microenvironments!
Combination
immunotherapy ?

MonthsStandard therapy

Current immunotherapy
Anti-PD-1/PD-L1 Ab +Personalized immunotherapy
based on the immune evaluation

・Anti-CTLA4 Ab （Other costimulatory mole.)
・IDO/TDO inhibitor
・Molecular target / chemotherapy
・Radiation
・Cancer vaccine
・T cell ACT・Novel therapies日本における個別化・複合がん免疫療法開発の課題＊日本での複合免疫療法の臨床試験実施と病態解析研究を！
・複合免疫療法臨床試験のための企業間連携はすでに進んでいる！
・新たな産学官連携の構築が必要（win-win situation, high cost, 得意分野）！

-アカデミアシーズ・ノウハウの効率的な企業への受け渡し
・日本医療研究開発機構(AMED)（Japan Cancer Research Project）でのシーズ開発
・複合免疫療法の医師主導臨床試験の実施を！ （AMEDにも期待 ?）・企業にとって 真に有用なシーズ、適切な組み合わせ、評価法と対策の提言！

-企業治験におけるアカデミアによる病態解析（治療効果・副作用機序）
・治験段階での免疫学的解析ー＞次のステップのためのシーズ（診断・治療標的）！
・治験の空洞化問題 （臨床研究中核病院）
・企業にとって 真に有用な評価法、臨床データとその解釈、さらにその検証！

・全国レベルでのがん患者ネットワークの構築、臨床検体収集システム、各種システム生物学的解析拠点体制の構築 ＜AMEDへの期待！＞
・米国NCIの全国ネットワーク （e.g. 肺癌変異シークエンスシステム）
・米国GoogleのCancer Immunotherapy開発への参画？

・日本における産官学コンソーシアムの確立 （議論の場の提供）＜米国SITC / CRI, EU-CIMT＞

新しい医療の健全な均てん化・教育• 異なる治療効果判定基準• RECISTだけでは不十分(irRCやirRECISTの併用)• 化学療法や分子標的治療薬とは異なる副作用と対策• 免疫性副作用（皮膚炎、甲状腺炎、腸炎、肝炎など）• 間質性肺炎や下垂体炎、筋無力症などの重篤、致死的な副作用• 適正使用ガイドが作成されており、医療従事者は十分に熟知する必要• 多職種医療チームへの教育• ガイドライン• 医師はもちろんのこと、がんチーム医療において、薬剤師、看護師など広く各職種への教育体制も重要