Biologic Basis of Immunotherapy in Lung Cancer

Transcription

1 Biologic Basis of Immunotherapy in Lung Cancer Andrew R. Haas, MD, PhD Director, Interventional Pulmonary and Thoracic Oncology Perelman School of Medicine of the University of Pennsylvania Philadelphia, PA

2 Disclosures None

3 Objectives 1) To understand why immunosurveillance is important 2) To understand the complex nature of the tumor:immune system interaction 3) To understand how prognosis can be impacted by immun contexture of a tumor 4) To understand the various approaches to immune therapy in NSCLC

4 How do we know immunosurveillance is important? HIV positive patients higher risk of virally-mediated cancers Immune system can recognize tumor associated antigens Organ transplant recipients have higher risk of developing lung cancer Paraneoplastic immune syndromes most frequently seen in lung cancer Anti-Hu syndrome Anti-SOX antibodies al JAMA 306: ; Ichiki et al. J Immunol 172: ; Richardson and Johnson Curr Opin Oncol 4

5 at does the tumor croenvironment look like? t al. AJRCCM 191:

6 munohistochemical ining of the TSLs t al. AJRCCM 189:

7 Priming & ac(va(on CD28/B7.1 CD137/CD137L OX40/OX40L CD27/CD70 HVEM GITR IL-2 IL-12 CTLA-4/B7.1 PD-L1/PD-1 PD-L1/B7.1 prostaglandins 3 Lymph node 4 Blood vessel Trafficking of T cells to tumors CX3CL1 CXCL9 CXCL10 CCL5 5 Infiltra(on of T cells into tumors LFA1/1CAM1 Selec(ns VEGF Endothelin B receptor Cancer an(gen presenta(on TNF-a IL-1 IFN-a CD40L/CD40 CDN ATP HMGB1 TLR 2 tumor 6 Recogni(on of cancer cells by T cells T cell receptor Reduced pmhc on cancer cells IL-10 IL-4 IL-13 n S(mulatory factors n Inhibitors ellman I. Immunity. 2013;39: Release of cancer cell an(gens Immunogenic cell death Tolergenic cell death 7 Killing of cancer cells IFN-γ T cell granule content PD-L1/PD-1 PD-L1/B7.1 IDO TGF-β BTLA VISTA LAG3 Arginase MICA/MICB B7-H4 TIM3/ phospholipids

8 What characteristics of the immune microenvironment have shown benefit in lung cancer? resence of TILs demonstrated mproved survival ot limited to just TILs l Ann Thorac Surg 87:

9 ritic cells r in addition to + T-cells cer Res 2014;74:

10 Where the macrophages and T cells reside may matter Kawai, et al Cancer 113:13

11 ells may matter as well t al. AJRCCM 189:

12 CD8 T cells all that matter? egulatory T cells (Tregs) have important suppressive effects CTLA-4 TGF-beta IL-10 l. Lung Cancer 75:95-101

13 Incredibly complex tumor:immune microenvironment How can we exploit some of these pathways to therapeutic advantage?

14 Immune checkpoint pathways Programmed cell death protein-1 PD-1 Cytotoxic T-lymphocyte associated protein-4 (CTLA-4) T-cell immunoglobulin and mucin domain-3 (TIM-3) Bind to their cognate receptors on APCs and tumor cells to modify T cell function

15 resentative pathways for ivation and inhibition he APC/tumor:T cell rface at Rev Cancer 12:

16 PD-1 and lung cancer 20-60% of tumor cells express PDL-1 High expression of PDL1/2 worse prognosis Not consistently demonstrated High expression of PD1 on CD8+ TILs impaired T cell func]on exhaus]on May be associations between driver muta]ons and PDL1 expression Konishi et al. Clin Ca Res 10: ; Mu et al. Med Oncol 28 D Inecco et al British Journal of Cancer 112:95-102

17 CTLA-4 and PD-1 cognate receptors at different locations Pardoll N Cancer 1

18 For checkpoint blockade to work op(mally, mul(ple factors need to true: - T cells must express the IR - Tumor/tumor microenvironmen express the IR ligand - T cells must otherwise hone an] reac]vity - An]-tumor reac]vity will m if trafficking, infiltra]on, persistence intact Cri(cal assump(on in majority of efforts administering checkpoint inhibitors is that the TILs are an(-tumor reac(ve

19 w best do PD1 ibitors work? t Rev Cancer 12:

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21 Types of cancer immunotherapy 1) Immune checkpoint inhibitors: at level of antigenpresentation or intratumoral T cell activity 2)Adoptive cellular immunotherapy: Ex vivo anti-tumor cel generation 3) Monoclonal antibodies: efficacy in breast cancer 4) Cancer vaccines enhance or generate anti-tumor responses by stimulating CD8+/CD4+ T-cells 5) Non-specific immunotherapies: e.g. Interleukin-2 in renal cell cancer

22 Why have prior immunotherapy trials failed to show a benefit? START trial MUC1 vaccine - no benefit MAGRIT trial MAGE-A3 vaccine no benefit

23 Priming & ac(va(on CD28/B7.1 CD137/CD137L OX40/OX40L CD27/CD70 HVEM GITR IL-2 IL-12 CTLA-4/B7.1 PD-L1/PD-1 PD-L1/B7.1 prostaglandins 3 Lymph node 4 Blood vessel Trafficking of T cells to tumors CX3CL1 CXCL9 CXCL10 CCL5 5 Infiltra(on of T cells into tumors LFA1/1CAM1 Selec(ns VEGF Endothelin B receptor Cancer an(gen presenta(on TNF-a IL-1 IFN-a CD40L/CD40 CDN ATP HMGB1 TLR 2 tumor 6 Recogni(on of cancer cells by T cells T cell receptor Reduced pmhc on cancer cells IL-10 IL-4 IL-13 n S(mulatory factors n Inhibitors ellman I. Immunity. 2013;39: Release of cancer cell an(gens Immunogenic cell death Tolergenic cell death 7 Killing of cancer cells IFN-γ T cell granule content PD-L1/PD-1 PD-L1/B7.1 IDO TGF-β BTLA VISTA LAG3 Arginase MICA/MICB B7-H4 TIM3/ phospholipids

24 ow can we make immunotherapy even more successful? Nascent understanding of the malignant immune environment Is the immune environment unique to each patient Does primary tumor differ from nodal disease differ from metastases Does the immune environment change with stage of disease Does the immune environment change with our conventional therapies radiation and chemotherapy How do we define the immune environment and create precision immunotherapy for each patient?

25 This is where we all want to be! How do we get there on more consistent basis?

26 Thank you

27 Within that environment complex interactions among components. Vanneman & Dranoff Nature Reviews Cancer

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