Checkpoint-Inhibitoren beim MM: Status Quo und Ausblick. Prof. Dr. Alexander Enk Ärztlicher Direktor Uni-Hautklinik Heidelberg

Transkript

1 Checkpoint-Inhibitoren beim MM: Status Quo und Ausblick Prof. Dr. Alexander Enk Ärztlicher Direktor Uni-Hautklinik Heidelberg

2 Die Geschichte der Immunonkologie beim MM Discovery of the dendritic cell Tumour specific mabs BCG approved for bladder cancer Adoptive T cell immunotherapy IFN-α as adjuvant therapy for melanoma Discovery of checkpoint inhibitor First immunotherapy approved for prostate cancer (sipuleucel-t) Anti-PD1/anti PDL1, other pipeline I-O agents 1970s 1980s 1990s 2000s 2010s Immune component to spontaneous regressions in melanoma First tumourassociated antigen cloned (MAGE-1) IL-2 approved for RCC and melanoma (US) First checkpoint inhibitor (ipilimumab) approved for advanced melanoma

3 Wo stehen wir jetzt? Bislang die Geschichte eines Moleküls

4 Rationale Grundlage für die Entwicklung eines anti-ctla-4 AK zur Tumortherapie Walunas TL, et al. Immunity 1994;1:405 13

5 A new era for melanoma treatment! Die erste Studie überhaupt, die eine Verbesserung des OS bei Stad. IV MM zeigte Hodi FS, et al. N Engl J Med. 2010;363:711 23

6 Blockade von CTLA-4 verstärkt die T-Zellaktivierung T-cell T-cell T-cell activation suppression activation TCR MHC CD28 B7 TCR MHC CTLA-4 B7 activation CTLA-4 Anti-CTLA-4 blocks CTLA-4 APC APC APC Signal-1 / Signal-2 activates T cells Hoos A, et al. Semin Oncol. 2010;37: Activated T-cells express the inhibitory molecule CTLA-4 Antibodies vs CTLA-4 block inhibitory signals

7 Anti-CTLA4 induziert die Depletion intratumoraler T-reg durch Makrophagen Injection of anti-ctla4 antibodies Y Y Treg CTLA4 ++ αctla4 Teff Antibodydependent cellmediated cytotoxicity FcγRIV CTLA4 + Mφ T eff predominance Treg Functional inhibition of Treg? Teff Lymph node Tumour Simpson TR, et al. J Exp Med. 2013;210:

8 Proportion alive Gepoolte OS-Daten von 1861 Ipi-Patienten aus klinischen Studien Median OS, months (95% CI): 11.4 ( ) 3-year OS rate, % (95% CI): 22 (20 24) Ipilimumab CENSORED Patients at risk Ipilimumab Months A plateau in the survival curve begins at approximately 3 years, with some patients followed for up to 10 years Consistency of long-term survival data for ipilimumab in metastatic melanoma, regardless of doses, regimens and treatment line Schadendorf D, et al. Presented at ECC 2013: oral presentation 24LBA

9 and much more to come

10 Tumoren supprimieren T-Zellaktivierung durch T-cell PD-L1 Expression Tumour Activation PD-1 PD-L1 ITIM Suppression APC T cell priming in LN No T-cell effector function

11 Die Blockade von PD-1 inhibiert die T-Zellsuppression T-cells Anti-PD-1 antibody PD-L1 Tumour Activation PD-1 APC T-cell priming in LN Effector function

12 Overall Survival (%) Langzeitüberleben bei Stad. IV MM-Patienten nach anti-pd-1 Ak 107 patients with advanced melanoma received nivolumab ( mg/kg) every 2 weeks for up to 96 weeks in a phase 1 dose escalation/dose expansion study All patients initiated treatment at least 14 months before this analysis Median OS 1-year OS 2-year OS 16.8 months 62% 43% Months Number at risk Among 33 patients (31%) with an objective response, median response duration was 2 years Topalian SL, et al. J Clin Oncol 2014, Epub ahead of print

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14 Context: Nivolumab compared to Pembrolizumab? Presented By Jeffrey Weber at 2014 ASCO Annual Meeting

15 CTLA-4 und PD-1 unterschiedliche Immunmechanismen Periphery Tumour microenvironment Activation (cytokines, lysis, proliferation, migration to tumour) Dendritic cell MHC B7 TCR CD B7 CTLA Anti-CTLA-4 T cell T cell TCR MHC PD-1 PD-L1 Anti-PD-1/PD-L1 PD-1 PD-L2 Anti-PD-1 Tumour cell CTLA-4 pathway PD-1 pathway Wolchok J, et al. J Clin Oncol 2013;31(15 suppl):abstract 9012^

16 Tumor Immuntherapie verstärkt Immunantworten gegen Tumor-spezifische mutierte Antigene anti-tumor Aktivität Tumor specific mutant antigen Antigen (TSMA) PD-1 TIM-3 LAG-3 CD8 Granzyme B IFN TNF PD-1 CTLA-4 CTLA-4 Treg CTLA-4 EFFECTIVE Normale Tumor Zelle

17 Proportion of patients alive (%) Klinische Aktivität der Kombinationsschemas Phase 1 trial in patients with advanced melanoma year survival 82% 95% CI ( ) Censored 1 mg/kg nivolumab + 3 mg/kg ipilimumab n=17 Died/treated Months 2/17 All concurrent regimen 9/53 53% of patients had grade 3/4 AEs on the concurrent regimen; most were manageable using standard protocols 1 With ~13 months of follow-up, 90% of patients continue to respond 1 Historical 1-year survival rates with ipilimumab or nivolumab monotherapy in patients with advanced melanoma are 45.6% (phase 3) 2 and 62% (phase 1), respectively 3 n=53 1. Adapted from Wolchok J, et al. J Clin Oncol 2013;31(15 suppl):abstract 9012^; 2. Hodi FS, et al. N Engl J Med 2010;363:711 23; 3. Sznol M, et al. Presented at ASCO 2013: oral presentation CRA9006

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19 Characteristics of Response LBA # Presented By Mario Sznol at 2014 ASCO Annual Meeting

20 Safety Overview LBA # Presented By Mario Sznol at 2014 ASCO Annual Meeting

21 Weitere Immuntherapien in Entwicklung Phase 1 Phase 1/2 Phase 2 Phase 3 Anti-PD-L1 MPDL3280A MEDI-4736 BMS Anti-PD-L2 rhigm12b7 Anti-GITR TRX518 LAG-3 protein IMP321 Vaccine NY-ESO-1 Prame Anti-PD1 Pidilizumab Anti-CD137 BMS Anti-CTLA-4 Ipilimumab Tremelimumab Anti-PD1 Nivolumab MK-3475 Vaccine CD40 agonist CP-870,893 T-VEC MAGE-A3 Vitespen GITR, glucocorticoid-induced TNFR family related gene

22 TIGIT: T cell ImmunoGlobulin and Immunoreceptor Tyrosine-based inhibitory domain TIGIT wird auf tumor-infiltrierenden CD4 + und CD8 + T-Zellen exprimiert PBMC CD4 + TIL CD8 + TIL Starke Korrelation mit dem inhibitorischen Molekül PD-1 10% 51% 39% Human: Lungentumore, Darmkrebs Mausmodelle: CT26; EMT6 Johnston R.J. et al Cancer Cell 26:923

23 Der PVR bindet an TIGIT und induziert Suppression Tumor Zelle (Polio Virus Rezeptor) PVR CD226 TIGIT ITIM T-Zell Erschöpfung Keine Dimerisierung Aktivierung wird verhindert Direkte Suppression?! T-Zelle Keine Effektorfunktionen

24 TIGIT und PD-1 sind ko-exprimiert und induzieren 2 unabhängige suppressive Signale Tumor Zelle PD-L1 (Polio Virus Receptor) PVR CD226 TIGIT ITIM PD-1 T-Zell Erschöpfung Keine Dimerisierung Aktivierung unterbleibt Signal 2 Suppressives Signal 1 T-Zelle Keine Effektorfunktionen

25 Y PD-L1 and TIGIT Antikörper stellen T-Zellfunktionen wieder her (Polio Virus Receptor) PVR Tumor Zelle PD-L1 Keine Interaktion PDL-1 TIGIT Stimulation CD226 TIGIT TCR ITIM PD-1 Effektorfunktionen IFN TNF Aktivierung Keine Dimerisierung Aktivierung unterbleibt Signal 2 Suppressives Signal 1 T-Zelle Keine Effektorfunktionen

26 Mögliche Synergismen unterschiedlicher Wirkprinzipien Radiation Adhesion molecules (CAM-1) and death receptors (FAS) Peptide pools CD8 T cell Upregulation of MHCI Uploading of antigen processing machinery Chemotherapy Effector immune infiltrate Release of tumour antigens (cascade) Targeted therapies Vascular normalisation T cell initiation Cytokine release Translocation of calreticulin CD8 T cells TAA crosspresentation MDSC Tregs M2 macrophages Dendritic cell TAA Upregulates MHCI Adhesion molecules/ death receptors APM CD8 T cells (homeostatic peripheral expansion) MDSC Tregs Activation of apoptosis Blockage of cell cycle CD8 T cells T cell function 1. Adapted from Hodge JW. Semin Oncol 2012;39:323 39; 2. Drake CG. Ann Oncol 2012;23(suppl 8):viii41 6; 3. Ménard C, et al. Cancer Immunol Immunother 2008;57: ; 4. Hannani D, et al. Cancer J 2011;17:351 8; 5. Ribas A at al. Curr Opin Immunol 2013:25:291 6

27 T cell Rekrutierung nach Niedrigdosisbestrahlung wird durch inos+m1 Makrophagen vermittelt inos induced nomalization of tumour vasculature mediates enhanced T cell recruitment Optimal inos Induction by low dose irradiation (0.5-2Gy) inos LDI NO-dependent vascular activation CCR5+Teff inos Klug F, et al. Cancer Cell 2013; 24:

28 Immunomonitoring 15 patients/group Total: 105 patients ELEKTRA-Study (Heidelberg) MM stage IV brain mets Number of brain mets Further comparison 15 pts without brain mets and ipi only 1-3 >4 45 Pat 45 Pat Depending on scheduling Depending on scheduling Stereotactic RT 1x Ipi Stereotactic RT GHRT + Boost 1x Ipi GHRT + Boost Stereotactic RT GHRT + Boost 4x Ipi No Ipi 4x Ipi No Ipi 3x Ipi 3x Ipi

29 Rationale für Kombination von PD-1/PD-L1 Ak mit Bestrahlung I Irradiation enables infiltration of the tumour by T cells But also induces suppressive PD-L1 ligands PD-L1 CD8 X X PD-1 CD8 CD8 X PD-L1 Tumour

30 Rationale für Kombination von PD-1/PD-L1 Ak mit Bestrahlung II Irradiation enables infiltration of the tumour by T cells and anti-pd-l1 blocks suppressive PD-L1 ligands PD-L1 Anti-PD-L1 CD8 Tumour destruction PD-1 CD8 CD8 PD-L1 TNFα Tumour

31 Zusammenfassung Die Immunonkologie eröffnet Patienten mit MM die Möglichkeit eines langfristigen Überlebens Die Kombination verschiedener Immuntherapeutika verspricht eine weitere Erhöhung der Ansprechraten o Ipilimumab und Nivolumab haben unterschiedliche immunologische Zielstrukturen Potentielle Synergismen existieren zwischen den unterschiedlichen Therapiemodalitäten

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