Grundlagen der ImmunOnkologie Dr Henrik Flach Medical Affairs

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Grundlagen der Immun-Onkologie Dr. Henrik Flach Medical Affairs Celgene Deutschland Gmb. H CONFIDENTIAL

Grundlagen der Immun-Onkologie Dr. Henrik Flach Medical Affairs Celgene Deutschland Gmb. H CONFIDENTIAL

Immuno Oncology: A Graphical Abstract Dendritic Cell (APC) T T Tumor Cell T

Immuno Oncology: A Graphical Abstract Dendritic Cell (APC) T T Tumor Cell T

The Immune System vs. Cologne Underground

The Immune System vs. Cologne Underground

The Immune System Innate immunity Adaptive immunity B cell Dendritic cell APCs Macrophage NK

The Immune System Innate immunity Adaptive immunity B cell Dendritic cell APCs Macrophage NK cell Complement protein T cell NK T cell Granulocytes Antibodies CD 4+ T cell fast response and low specificity • • • CD 8+ T cell Antibodies Cytokines Ag receptors (109 / individual) Þ specificity, diversity, and memory Dranoff, 2004

The Founders of Modern Immunology and Immuno-Therapy William Coley Paul Ehrlich Emil v. Behring

The Founders of Modern Immunology and Immuno-Therapy William Coley Paul Ehrlich Emil v. Behring Robert Koch Louis Pasteur Rudolf Virchow Ilja Iljitsch Metschnikow

Immuno. Therapy: Does it Work in Solid Tumors? Paul Ehrlich’s Immunosurveillance Concept: 100+ years

Immuno. Therapy: Does it Work in Solid Tumors? Paul Ehrlich’s Immunosurveillance Concept: 100+ years of progress • Magic Bullet (Paul Ehrlich) • Immunosurveillance (P Ehrlich (1909) • Intratumoral application (Coley 1906) • Cancer Vaccines ? ? Paul Ehrlich – BCG bladder • Immunostimulants ? ? – Big business • Molecular understanding of the immune system!!!!! William Coley

Percent survival Anticancer Therapies and their Targets ? Time Chemotherapy Targeted therapy clinical responses

Percent survival Anticancer Therapies and their Targets ? Time Chemotherapy Targeted therapy clinical responses in majority of patients limited duration of responses Immune therapy long lasting responses? adapted from Allison et al. , 2015

Immuno. Therapy: Does it Work in Solid Tumors? Paul Ehrlich's magic bullet concept: 100+

Immuno. Therapy: Does it Work in Solid Tumors? Paul Ehrlich's magic bullet concept: 100+ years of progress • Magic Bullet (Paul Ehrlich) • Immunosurveillance (P Ehrlich (1909) • Intratumoral application (Coley 1906) • Cancer Vaccines ? ? – BCG bladder • Immunostimulants ? ? – Big business • Molecular understanding of the immune system!!!!!

The Cancer-Immunity Cycle - Immunoediting: 1. ) Elimination 4 Priming and activation (APCs and

The Cancer-Immunity Cycle - Immunoediting: 1. ) Elimination 4 Priming and activation (APCs and T cells) 3 Trafficking of T cells to tumors (CTLs) Infiltration of T cells 5 into tumors (CTLs and endothelial cells) Cancer antigen 2 presentation (DCs / APCs) Recognition of cancer 6 cells by T cells (CTLs and cancer cells) Release of cancer cell antigens 1 (cancer cell death) 7 Killing of cancer cells Chen and Mellman Immunity, 2013, 39: 1 -10

The Cancer-Immunity Cycle - Immunoediting: 2. ) Equilibrium anti-CTLA-4 Treg anti-PD-1 / anti-PD-L 1

The Cancer-Immunity Cycle - Immunoediting: 2. ) Equilibrium anti-CTLA-4 Treg anti-PD-1 / anti-PD-L 1 CTL Tumour equilibrium TAM Phan et al. , 2015

The Cancer-Immunity Cycle - Immunoediting: 3. ) Escape anti-CTLA-4 Treg anti-PD-1 / anti-PD-L 1

The Cancer-Immunity Cycle - Immunoediting: 3. ) Escape anti-CTLA-4 Treg anti-PD-1 / anti-PD-L 1 CTL TAM Phan et al. , 2015

Immune Checkpoint Inhibitors anti-CTLA-4 Treg anti-PD-1 / anti-PD-L 1 CTL TAM Phan et al.

Immune Checkpoint Inhibitors anti-CTLA-4 Treg anti-PD-1 / anti-PD-L 1 CTL TAM Phan et al. , 2015

Checkpoint Pathway in Cancer Immunology CTLA-4, cytotoxic T-lymphocyte-associated protein 4; MHC, major histocompatibility complex;

Checkpoint Pathway in Cancer Immunology CTLA-4, cytotoxic T-lymphocyte-associated protein 4; MHC, major histocompatibility complex; PD-1, programmed cell death 1; PD-L 1, programmed cell death ligand 1; TCR, T cell receptor. Ribas A. N Engl J Med. 2012; 366: 2517 -2519.

Immune Checkpoint Inhibitors 4 Priming and activation Anti-CTLA 4 Anti-CD 137 (agonist) 3 Anti-OX

Immune Checkpoint Inhibitors 4 Priming and activation Anti-CTLA 4 Anti-CD 137 (agonist) 3 Anti-OX 40 (agonist) Anti-CD 27 (agonist) Trafficking of T cells to tumors 5 Infiltration of T cells into tumors Anti-VEGF Cancer antigen presentation Vaccines 2 IFN-α GM-CSF Anti-CD 40 (agonist) TLR agonist 6 Recognition of cancer cells by T cells 1 Release of cancer cell antigens 7 Killing of cancer cells Chemotherapy Radiation therapy Targeted therapy Chen and Mellman Immunity, 2013, 39: 1 -10 Anti-PD-L 1 Anti-PD-1 IDO inhibitors

Immune Checkpoint Inhibitors: Breakthrough Therapy in NSCLC CHECKMATE 017 & 057: Nivolumab KEYNOTE 001:

Immune Checkpoint Inhibitors: Breakthrough Therapy in NSCLC CHECKMATE 017 & 057: Nivolumab KEYNOTE 001: Pembrolizumab 2 nd L POPLAR: Atezolizumab KEYNOTE 024: Pembrolizumab 1 st L

Immune Checkpoint Inhibitors: Breakthrough Therapy in Melanoma Pooled analysis of 12 studies (N=1. 861)

Immune Checkpoint Inhibitors: Breakthrough Therapy in Melanoma Pooled analysis of 12 studies (N=1. 861) Plateau at 21% Schadendorf D, et al. J Clin Oncol 33: 1889 -94, 2015

ORR (%) 10. 0% CRC MSI 20. 0% Melanoma Gastric Esophageal Bladder Moderate responders

ORR (%) 10. 0% CRC MSI 20. 0% Melanoma Gastric Esophageal Bladder Moderate responders Renal H&N NSCLC Breast HCC SCLC Ovarian Non-responders Mesothelioma Endometrial Cervical CRC MSS Pancreatic Prostrate Glioblastoma PD 1 -PDL 1 Monotherapy ORR Three Categories of Response to Anti-PD-1/PD-L 1 Higher responders 100. 0% 90. 0% 80. 0% 70. 0% 60. 0% 50. 0% 40. 0% 30. 0% ORR 0. 0%

SABCS 2016 - Immuno-Onkologie - > 80% kein Ansprechen

SABCS 2016 - Immuno-Onkologie - > 80% kein Ansprechen

Immunogenic vs. Non-immunogenic Tumors

Immunogenic vs. Non-immunogenic Tumors

Immunogenic vs. Non-immunogenic Tumors

Immunogenic vs. Non-immunogenic Tumors

Biomarker Analysis: Tumor-Infiltrating Lymphocytes Response based on TIL Levels 50% 40% 30% 20% 10%

Biomarker Analysis: Tumor-Infiltrating Lymphocytes Response based on TIL Levels 50% 40% 30% 20% 10% 0% 19% 7% 13% 7% 21% TIL Levelsa ■ > 10% (n = 53) ■ ≤ 10% (n = 55) 13% 19% 9% ■ ■ SD ■ ■ CR/PR RECIST v 1. 1 Schmid P, et al. AACR 2017 Phase Ia Atezolizumab in TNBC

Biomarker Analysis: Tumor-Infiltrating Lymphocytes Overall Survival OS OS Based on on TIL Levelsa ■

Biomarker Analysis: Tumor-Infiltrating Lymphocytes Overall Survival OS OS Based on on TIL Levelsa ■ > 10% (n = 53) ■ ≤ 10% (n = 56) P = 0. 0028 Time (months) m. OS (95% CI) ≤ 10% TILs > 10% TILs (n = 53) (n = 56) 6. 6 mo 12. 6 mo (4. 9, 10. 2) (10. 5, NA) • Higher ORR and longer OS were seen with higher baseline TIL (CD 8) infiltration Schmid P, et al. AACR 2017 Phase Ia Atezolizumab in TNBC

Immunogenic vs. Non-immunogenic Tumors

Immunogenic vs. Non-immunogenic Tumors

Immunogenic vs. Non-immunogenic Tumors Alexandrov et al. , 2013

Immunogenic vs. Non-immunogenic Tumors Alexandrov et al. , 2013

Immunogenic vs. Non-immunogenic Tumors

Immunogenic vs. Non-immunogenic Tumors

The next steps…Biomarkers, Biomarkers…The “Cancer Immunogram” Blank et al. , 2016

The next steps…Biomarkers, Biomarkers…The “Cancer Immunogram” Blank et al. , 2016

Percent survival Future Directions in Immuno-Oncology ? Time Chemotherapy Targeted therapy Immune checkpoint therapy

Percent survival Future Directions in Immuno-Oncology ? Time Chemotherapy Targeted therapy Immune checkpoint therapy long lasting responses applicable in various cancer types Combination therapy increase in response rate? increase in efficiency?

Future Directions in Immuno-Oncology 4. Trafficking of T cells to tumors 3. Priming and

Future Directions in Immuno-Oncology 4. Trafficking of T cells to tumors 3. Priming and activation 16 14 7 1 5. Effector T cell Infiltration into tumors 11 2. Cancer antigen presentation 2 12 6. T cell recognition of cancer cells 23 29 4 1. Release/Exposure of cancer antigens 7. T cell killing of cancer cells Chemotherapy The bubble contains # of trials in Phase III 26 Note - Trials may test more than 1 agent Chen and Mellman Immunity, 2013, 39: 1 -10 12

Future Directions in Immuno-Oncology 4. Trafficking of T cells to tumors 3. Priming and

Future Directions in Immuno-Oncology 4. Trafficking of T cells to tumors 3. Priming and activation 16 14 7 1 5. Effector T cell Infiltration into tumors 11 2. Cancer antigen presentation 2 12 6. T cell recognition of cancer cells 23 29 4 1. Release/Exposure of cancer antigens 7. T cell killing of cancer cells Chemotherapy The bubble contains # of trials in Phase III 26 Note - Trials may test more than 1 agent Chen and Mellman Immunity, 2013, 39: 1 -10 12

Immune response and chemotherapy Drug Effect on immune system Taxanes • • • Enhances

Immune response and chemotherapy Drug Effect on immune system Taxanes • • • Enhances T cell and NK cell function Increases recruitment of TIL Increase efficacy of immuno-stimulatory agents Doxorubicin • • Induces immunogenic cell death Increases proliferation of CD 8 T cells Stimulates antigen presentation by DCs Stimulates MCP 1 and M 6 PR • • Induces immunogenic cell death Suppresses Treg inhibitory functions and restores the proliferative capacity of effector T cells and NK cell cytotoxicity Gemcitabine • • Reduces the number of myeloid suppressor cells Increases the antitumor activity of CD 8(+) T cells and activated NK cells Oxaliplatin • • • Induces immunogenic cell death Increases MHC I complex Inhibits PD-L 2 Cyclophosphamide Kono et al. Cell Death and Disease 2013

Chemotherapy: Pleiotropic stimulatory effects on the immune system Increase in antigen presentation/ crosspresentation via

Chemotherapy: Pleiotropic stimulatory effects on the immune system Increase in antigen presentation/ crosspresentation via dendritic cells; MHC I upregulation; epitope spreading T cell function & Th 1 polarization Th 1 CTL Chemotherapy Proinflammatory cytokines IL-2 IFN- Treg & MSDC depletion tumor-antigen release/ presentation; danger signal release; immunogenic cell death

Chemotherapy: Pleiotropic stimulatory effects on the immune system Increase in antigen presentation/ crosspresentation via

Chemotherapy: Pleiotropic stimulatory effects on the immune system Increase in antigen presentation/ crosspresentation via dendritic cells; MHC I upregulation; epitope spreading T cell function & Th 1 polarization Th 1 CTL Chemotherapy Proinflammatory cytokines IL-2 IFN- Treg & MSDC depletion tumor-antigen release/ presentation; danger signal release; immunogenic cell death

Chemotherapy: Pleiotropic stimulatory effects on the immune system Increase in antigen presentation/ crosspresentation via

Chemotherapy: Pleiotropic stimulatory effects on the immune system Increase in antigen presentation/ crosspresentation via dendritic cells; MHC I upregulation; epitope spreading T cell function & Th 1 polarization Th 1 CTL Chemotherapy Proinflammatory cytokines IL-2 IFN- Treg & MSDC depletion tumor-antigen release/ presentation; danger signal release; immunogenic cell death

Chemotherapy: Pleiotropic stimulatory effects on the immune system Increase in antigen presentation/ crosspresentation via

Chemotherapy: Pleiotropic stimulatory effects on the immune system Increase in antigen presentation/ crosspresentation via dendritic cells; MHC I upregulation; epitope spreading T cell function & Th 1 polarization Th 1 CTL Chemotherapy Proinflammatory cytokines IL-2 IFN- Treg & MSDC depletion tumor-antigen release/ presentation; danger signal release; immunogenic cell death

Gepar. Nuevo - Studydesign

Gepar. Nuevo - Studydesign

Anti-PD-(L)1 plus Chemo in 1 st line NSCLC Trial Compounds Population ORR KEYNOTE-21 G

Anti-PD-(L)1 plus Chemo in 1 st line NSCLC Trial Compounds Population ORR KEYNOTE-21 G Pembro + Pt/Pem Non-sqm adv. NSCLC 56. 7% IMpower 150 Non-sqm adv. NSCLC …. Atezolizumab + Bev + Carbo/Pac Ph 1 Nivo + Nab Nivolumab + Carbo/Nab-P Sqm + non-sqm adv -P NSCLC 50. 0% Ph 1 Atezo + Nab-P 56. 3% Atezolizumab + Carbo/Nab Sqm + non-sqm adv -P NSCLC • ICI-Pt-doublet-Combos in PD-(L)1 unselected pts showed increased efficacy compared to either approach alone • Further results expected from Phase III Key. Note-189, CM 568, IMpower-130/131 • Cave: Toxicity Borghaei et al. IASCL 2017; Goldman et al. IASCL 2017; Camidge et al. IASLC 2015

Percent survival Summary and Future Directions Time Chemotherapy Targeted therapy Immune checkpoint therapy long

Percent survival Summary and Future Directions Time Chemotherapy Targeted therapy Immune checkpoint therapy long lasting responses applicable in various cancer types Combination therapy increase in response rate increase in efficiency

“Immune Checkpoint-Blockade In Cancer” Beginning of a New Era! Thank you for your attention

“Immune Checkpoint-Blockade In Cancer” Beginning of a New Era! Thank you for your attention