Immunotherapy of HNC: immune mechanisms and therapeutic targets

Transcription

1 Immunotherapy of HNC: immune mechanisms and therapeutic targets Ourania Tsitsilonis, MD, PhD Department of Biology National & Kapodistrian University of Athens

2 What does the Immune System see in Cancer? T cell & Virus T cell & Tumor T cell & Self Protein DANGEROUS PAMPs & DAMPs Innate immunity activated TLRs triggered Inflammation Cytokines CD40 signals +++ WEAK No DAMPs No CD40 signals Pro-inflammatory cytokines TOLERANCE None of these signals Vinay et al, 2015

3 Sequence of events generating and regulating anti-tumor immunity 1. Immunization (DCs capture Ag & receive maturation signals) 2. Generation of desired T cell responses (CD8+ effectors, Abs NK/NKT effectors) Mellman et al., Overcome suppression PD-L1/2, IDO, MDSCs, hypoxia, adenosine,

4 Checks & Balances in the Immune System? IL-12, IL-2, IFN-γ, TNF-α IL-4, IL-5, IL-10, TGF-β DeNardo et al, 2010

5 Cancer immunotherapy strategies Active immunotherapy VACCINES Peptide vaccine DC vaccine (G-VAX) Genetic vaccine CYTOKINES IL-2 IL-12 IFN-α IL-15 IL-21 CHECKPOINT BLOCKERS CTLA-4 PD-1, PD-L1 CHECKPOINT ENHANCERS CD40, CD137, OX T CELL CLONES TIL (LAK, CIK) CAPRI Passive immunotherapy TUMOR-SPECIFIC Abs Naked Conjugated GENETIC ENGIN. T CELLS TCR-transduced CAR-modified + + +

6 Cell populations targeted by checkpoint mabs Moy et al, 2017

7 Pardoll D, 2012; Bakdash et al, 2013; Giuroiu & Weber, 2017 More checkpoint molecules to be targeted DC or tumor cell LAG3 The Co-Stim Family The Co-Stim Family The Co-Stim Family The Co-Stim Family mabs in pipeline T cell + BTLA; VISTA; A2A-R

8 Combination therapies Nivo + Ipi a-pd1 + a-ctla-4 Phase III Durvalumab + Tremelimumab a-pdl1 + a-ctla-4 Phase III 1 st line R/M HNSCC 1 st line; platinum-refractory R/M HNSCC (PDL1+/-) Nivo + BMS a-pd1 + a-lag3 Phase I Advanced HNSCC Nivo + Lirilumab a-pd1 + a-kir Phase I Progressed to at least 1 std regimen a-pd1 +TSR-022 a-pd1 +a-tim3 Phase I Advanced tumors Atezolizumab + MOXR0916 a-pdl1 +a-ox40 Phase I Advanced tumors Nivo + Urelumab a-pd1 +a-4-1bb Phase I Advanced tumors Pembro + Epacadostat a-pd1 + IDO inhib. Phase I/II Advanced HNSCC Pembro + TVEC a-pd1 + oncol. virus Phase Ib/III R/M HNSCC not amenable to surgery/radiation Pembro + p53mva a-pd1 + vac. vaccine Phase I Advanced HNSCC Economopoulou et al, 2017

9 Cancer immunotherapy strategies Active immunotherapy VACCINES Peptide vaccine DC vaccine (G-VAX) Genetic vaccine CYTOKINES IL-2 IL-12 IFN-α IL-15 IL-21 CHECKPOINT BLOCKERS CTLA-4 PD-1, PD-L1 CHECKPOINT ENHANCERS CD40, CD137, OX T CELL CLONES TIL (LAK, CIK) CAPRI Passive immunotherapy TUMOR-SPECIFIC Abs Naked Conjugated GENETIC ENGIN. T CELLS TCR-transduced CAR-modified + + +

10 [ Preventive HPV vaccines ]

11 Peptide vaccines Earlier generations latest generations Single peptide for single HLA Multi peptide for single HLA CTL epitope alone OR CTL and helper epitope peptides Long peptide Multi-peptide (non-cocktail) Peptide cocktail Hybrid peptide Personalized peptide(s) Peptide-pulsed DC CTL epitope Helper epitope

12 Peptide vaccine goals Induce strong and lasting effective T cell responses 1. T cells that recognize and kill tumor cells 2. T cells that infiltrate tumors and resist immunosuppression How to develop effective T cell vaccines 1. Select peptide epitopes (processed & presented by tumor cells; induce T cells recognizing tumor cells) 2. Optimize peptides (improve MHC binding; amphipathic constructs) 3. Select adjuvants (PRR ligands; constim agonists; cytokines) 4. Mode of administration (systemic/local; single/multiple; + PD-1 blockade) Test effectiveness & immunogenicity Kumai et al, 2017

13 Rational for personalized vaccine design Common vaccines CTL to A CTL to B No memory cells SLOW and WEAK immune response (primary type response) Peptide C A CTL response Peptide A + Peptide B TIME Antigen-specific memory cells QUICK and STRONG immune response (secondary type response) Personalized vaccines

14 Cancer immunotherapy strategies Active immunotherapy VACCINES Peptide vaccine DC vaccine (G-VAX) Genetic vaccine CYTOKINES IL-2 IL-12 IFN-α IL-15 IL-21 CHECKPOINT BLOCKERS CTLA-4 PD-1, PD-L1 CHECKPOINT ENHANCERS CD40, CD137, OX T CELL CLONES TIL (LAK, CIK) CAPRI Passive immunotherapy TUMOR-SPECIFIC Abs Naked Conjugated GENETIC ENGIN. T CELLS TCR-transduced CAR-modified + + +

15 CAR-modified T cells 1 st generation 2 nd generation 3 rd generation 4 th generation CAR/TRUCK Haji-Fatahaliha et al., 2015

16 Clinical & preclinical studies in HNC Research group CAR specificity Type of study Additional therapy Delivery method Van Schalkwyk (UK) T1E28z (ErbB) + cytokine receptor 4a/2-15β Phase I cyclophosphamide U/S guided intratumoral injection Van der Stegen (UK) T1E28z (ErbB) + cytokine receptor 4a/2-15β Preclinical - Intraperitoneal Davies (UK) T1E28z (ErbB) + cytokine receptor 4a/2-15β Preclinical - Intraperitoneal Sridhar & Petrocca, 2017

17 Cancer immunotherapy strategies Active immunotherapy VACCINES Peptide vaccine DC vaccine (G-VAX) Genetic vaccine CYTOKINES IL-2 IL-12 IFN-α IL-15 IL-21 CHECKPOINT BLOCKERS CTLA-4 PD-1, PD-L1 CHECKPOINT ENHANCERS CD40, CD137, OX T CELL CLONES TIL (LAK, CIK) CAPRI Passive immunotherapy TUMOR-SPECIFIC Abs Naked Conjugated GENETIC ENGIN. T CELLS TCR-transduced CAR-modified + + +

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19 Cancer immunotherapy strategies Active immunotherapy VACCINES Peptide vaccine DC vaccine (G-VAX) Genetic vaccine CYTOKINES IL-2 IL-12 IFN-α IL-15 IL-21 CHECKPOINT BLOCKERS CTLA-4 PD-1, PD-L1 CHECKPOINT ENHANCERS CD40, CD137, OX T CELL CLONES TIL (LAK, CIK) CAPRI Passive immunotherapy TUMOR-SPECIFIC Abs Naked Conjugated GENETIC ENGIN. T CELLS TCR-transduced CAR-modified + + +

20 T cell modulation in HNSCC Th > Th > Th2 CCR4+ CTLA-4+ PD-1+ CD39+ β-gbp+ Premalignant lesion > HNSCC > Metastatic HNSCC Maggioni et al, 2017

21 What next?

22 New targets in the HNSCC environment Schmitz & Machiels, 2017

23 Microbiota profiling in HNC Wang et al, 2017

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25 Normal level of epimutations H YPOMETH YLATION Genomic instability Activation of oncogenes Abnormal chromosome structures H YPERMETH YLATION Inactivation of Ag presentation Inactivation of TU suppressor genes (BRCA1) Inactivation of DNA repair genes (MGMT)

26 The crossroads between HNC treatment & tumor immunotherapy Schoenfeld JD, 2015

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