T-cell recognition of cancer

Transcription

1 T-cell recognition of cancer Nana Haahr Overgaard Postdoc Technical University of Denmark Department of Micro- & Nanotechnology T-cells and Cancer

2 T cells are crucial mediators of anti-tumor immunity MHC I or HLA I 2 Technical University of Denmark Towsend & Allison, Science 1993

3 Major Histocompatibility Complex (MHC) molecules are essential for T-cell activation HLA: human MHC molecules 3 Technical University of Denmark Kobayashi & van den Elsen, Nat Rev Imm 2001

4 CD8 + T cells recognize intracellularly-derived peptides presented in the context of MHC class I molecules 4 Technical University of Denmark Kershaw et al, Nat Rev Cancer 2013 and Coulie et al, Nat Rev Cancer 2014

5 Cross-presentation by dendritic cells allows presentation of tumor antigens via the MHC class I pathway to CD8 + T cells Clonal expansion!! 5 Technical University of Denmark Heath & Carbone, Nat Rev Imm 2001

6 What kind of tumor antigens do the CD8 + T cells recognize? 6 Technical University of Denmark Coulie et al, Nat Rev Cancer 2014

7 State-of-the-art for detection of antigen-specific T cells: Combinatorial encoding of fluorescently-labeled MHC multimers 7 Technical UniversityRodenko of Denmark et al, Nat Protocols 2006 ; Hadrup et al, Nat Methods 2009 Presentation ; Andersen name et al, 17/04/2008 Nat Protocols 2012

8 Evolution of T-cell detection technologies 8 Technical University of Denmark Bentzen & Hadrup, CII, 2017

9 Next-generation detection of antigen-responsive T cells by use of peptide-mhc class I multimers labeled with DNA barcodes 9 Technical University of Denmark Bentzen et al. Nat. Biotechnology 2016

10 Correlation to state-of-the-art method Buffy coat samples Melanoma TILs 10 Technical University of Denmark Bentzen et al. Nat. Biotechnology 2016

11 T-cell recognition of shared tumor antigens in melanoma patients 11 Technical University of Denmark Bentzen et al. Nat. Biotechnology 2016

12 Central tolerance limits the T-cell repertoire recognizing self-proteins including shared tumor antigens 12 Technical University of Denmark Anderson & Maureen, Nat Rev Imm 2016 and Heemskerk et al, EMBO J 2013

13 The relevance of neoantigens as T-cell targets may differ amongst cancer types 13 Technical University of Denmark Schumacher & Schreiber, Science 2015

14 T-cell recognition of neoepitopes in NSCLC patients HLA A*1101 A*2402 B*3501 MTFR2 (FAFQEYDSF) n= Technical University Barcoding of (-Denmark Log 10 (p)) McGrananhan, Science 2016 and Bentzen et al. Nat. Biotechnology 2016

15 Does T-cell recognition of neoantigens correlate with clinical outcome in bladder cancer patients treated with anti-pd-l1? Mutational load Individualized neoepitope screening libraries Snyder et al, PLOS Med Technical University of Denmark Collaboration with Memorial Sloan Kettering Cancer Center ongoing work

16 Mind the gap in neoepitope in silico prediction First and last author Robbins et al. Rosenberg van Roij et al. Schumacher Wick et al. Nelson Rajasagi et al. Wu Journal Tumor type Patients Peptides tested T cell responses Test method Peptide lengths Nat Med SKCM ELISPOT 9 10 J Clin Oncol SKCM 1-1 FLT 9 Clin Cancer Res HGSC ELISPOT 8 11 Blood CLL ELISPOT 9 10 Lu et al. Robbins Clin Cancer Res SKCM ELISA 8 11 Snyder et al. Chan N Engl J Med SKCM 1-1 ICS 9 Rizvi et al. Chan Science NSCLC 1-1 FLT 9 Cohen et al. Robbins J Clin Invest SKCM FLT 9 10 ~3% of all predicted neoepitopes give rise to a T-cell response Kalaora et al. Samuels McGranahan et al. Swanton Oncotarget SKCM ICS 9, 11 Science NSCLC /8 FLT / BLM 9 11 Strønen et al. Schumacher Bassani- Sternberg et al. Krackhardt Bentzen et al. Hadrup Science SKCM FLT 9 11 Nature Commun SKCM MS-FLT 8 10,12 Nat Biotechnol NSCLC BLM 9 11 TOTAL Technical University of Denmark Bjerregaard AM, Front Imm 2017

17 Improved understanding of what determines neoepitope immunogenicity will improve neoepitope prediction and treatment strategies? 17 Technical University of Denmark Presentation name 17/04/2008

18 Neoepitopes are stronger HLA binders than neopeptides 18 Technical University of Denmark Bjerregaard AM et al. Front Imm. 2017

19 Loss of self-similarity contributes to immunogenicity specifically for conserved binders 19 Technical University of Denmark Bjerregaard AM et al. Front Imm and Coulie et al, Nat Rev Cancer 2014

20 T-cell recognition of clonal neoantigens correlates with durable clinical benefit in NSCLC patients Clonal neoantigens 20 Technical University of Denmark T-cell responses Increased sensitivity to checkpoint blockade Increased overall survival McGrananhan et al, Science, 2016

21 First-in-human RNA-based poly-neoepitope vaccine for melanoma patients Neoepitope-specific T-cell responses in all patients Specific killing of autologous tumor cells Reduced metastatic events 21 Technical University of Denmark Sahin et al. Nature 2017

22 Personalized cancer immunotherapy using adjuvanted neoepitope peptidebased vaccines 22 Technical University of Denmark Collaboration with Herlev Hospital, Statens Serum Institut, and Evaxion (Denmark) ongoing work

23 Understanding of T-cell recognition and potential correlations with clinical outcome may improve current therapies 23 Technical University of Denmark Presentation name 17/04/2008

24 Fantastic collaborators!! Morten Nielsen Aron Eklund Zoltan Szallasi Technical University of Denmark Bioinformatics Inge Marie Svane, Marco Donia Per thor Straten Özcan Met Center for Cancer Immune Therapy, Herlev Hospital, Copenhagen Paul Nghiem University of Washington, Seattle Jürgen Becker University Hospital Essen, Germany Carsten Linnemann & Ton Schumacher Netherlands Cancer Institute 24 Technical University of Denmark Samuel Funt Alexander Snyder Memorial Sloan Kettering Cancer Center Kirsten Grønbæk, Rigshospitalet, KU SU2C team, Peter jones & Stephen Baylin Christian Schmees NMI, Tubingen Germany Sergio Quezada Charlie Swanton UCL and CRICK, London Susanne Kruger Kjær Kræftens Bekæmpelse Claus Garbe Kilian Wistuba-Hamprecht Tubibingen Medical Center, Germany Dennis Christensen Peter Andersen SSI Finn Sellebjerg MS center, Rigshospitalet Birgitte Kornum KU Flemming Pociot Joachim Størling Steno Diabetes Center & Herlev Hospital Biotech/industri collaborations Immudex, Copenhagen MedImmune BioNTech ARMO Evaxion ImmuMap services Presentation name 17/04/2008

25 Funding 25 Technical University of Denmark Presentation name 17/04/2008

26 The research group T cells and Cancer 26 Technical University of Denmark Presentation name 17/04/2008