O slideshow foi denunciado.
Utilizamos seu perfil e dados de atividades no LinkedIn para personalizar e exibir anúncios mais relevantes. Altere suas preferências de anúncios quando desejar.
Immunotherapy for Colorectal
Cancer
Michael Overman, MD
MD Anderson Cancer Center
Gastrointestinal Medical Oncology
Immune Infiltrate and Prognosis in Primary CRC:
Immunoscore
JCO 2006 Pages et al., NEJM 2005 Pages et al.
411 stage I and ...
Deficient mismatch repair (dMMR) or microsatellite instability-
high (MSI-H)
Tejpar BJC 2009; Koopman BJC 2009
• Mutations...
Universal Testing for HNPCC
1158 (31.5)
992(27)
2125 (57.8)
2394(65.2)
3671(100)
No Tested (%)
Moreira et al. JAMA 2012
Re...
dMMR or MSI-H Have Better Outcomes (Prognostic Effect)
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5
Years
%DiseaseFree
HR:...
Metastatic MSI-high CRC
Retrospective reivew of 55
metastatic MSI-H pts from
MDACC + Royal Melbourne
Hospital, Australia
–...
Somatic mutation frequencies CRC
Nature
2012
Colon
TCGA
CRC TCGA
Nature 2012
Colon TCGA
Mutational Rates Across Tumors
Lawrence Nature 2013
Schreiber et al. Science 2011
Tumor Antigens:
Differentiation (melanocyte differentiation antigens…)
Overexpressed (HER-2…...
Matsushita A et al. Nature (2012); 482 (7385); 400-4
Immunogenic
methylcholantherene-
induced sarcoma cell
lines from Rag2...
Corbiere et al. Can Res 2012; Robbins J Exp Med 1996; Gaudin et al. J Immun 1999
Peptide In silico HLA nM
affinity
A0201
S...
BMS-936550
RR: 0/18 CRC
Tremelimumab
RR: 1/45 CRC
(response duration 15m)
Nivolumab
RR: 0/19 CRC
Nivolumab
RR: 1/14 CRC
(r...
CMS 400 MSI-high CRC patient
Immune Escape Mechanisms in MSI-high CRC
Llosa et al. Cancer Discovery 2014
Invasive FrontStroma
TIL
Le DT, et al. NEJM. 2015: 372: 2509-20.
Pembrolizumab 10 mg/kg every 14 days
Pembrolizumab: Response Rate
Pembrolizumab: Additional
Efficacy Endpoints
CEA response Progression-free survival
Immune Infiltrate
PDL1 expression
CD8 density
CD8 density and response
Ongoing Anti-PD1 or Anti-PDL1 Clinical Trials
with MSI-high CRC Subsets
• NCT01876511: Phase 2 study of MK-3475 in patient...
Immune checkpoint in melanoma
Ipilimumab in advanced melanoma
Wolchok et al. Lancet Oncol 2010
Nivolumab/Ipilimumab: Chort...
CheckMate 142 Study Design
Responses seen
Limited activity
Nivolumab single agent
MSI-High CRC
Pre-rectal Xrt Pre-tx Restaging at 4months
Cap/xrt to
rectum Nivolumab
Pre-tx Restagin...
Nivolumab single agent
MSI-High Gastric Cancer
Pre-tx
11/13/2013
Restaging
6/10/2015
Conclusion
• Test for MSI-high
– As universal testing approach for HNPCC
– For prognostic relevance in stage II
– For clin...
Próximos SlideShares
Carregando em…5
×

Immunotherapy for Colorectal Cancer

3.826 visualizações

Publicada em

Immunotherapy for Colorectal Cancer. Dr. Mike Overman

Publicada em: Educação
  • DOWNLOAD FULL BOOKS, INTO AVAILABLE FORMAT ......................................................................................................................... ......................................................................................................................... ,DOWNLOAD FULL. PDF EBOOK here { https://tinyurl.com/yyxo9sk7 } ......................................................................................................................... ,DOWNLOAD FULL. EPUB Ebook here { https://tinyurl.com/yyxo9sk7 } ......................................................................................................................... ,DOWNLOAD FULL. doc Ebook here { https://tinyurl.com/yyxo9sk7 } ......................................................................................................................... ,DOWNLOAD FULL. PDF EBOOK here { https://tinyurl.com/yyxo9sk7 } ......................................................................................................................... ,DOWNLOAD FULL. EPUB Ebook here { https://tinyurl.com/yyxo9sk7 } ......................................................................................................................... ,DOWNLOAD FULL. doc Ebook here { https://tinyurl.com/yyxo9sk7 } ......................................................................................................................... ......................................................................................................................... ......................................................................................................................... .............. Browse by Genre Available eBooks ......................................................................................................................... Art, Biography, Business, Chick Lit, Children's, Christian, Classics, Comics, Contemporary, Cookbooks, Crime, Ebooks, Fantasy, Fiction, Graphic Novels, Historical Fiction, History, Horror, Humor And Comedy, Manga, Memoir, Music, Mystery, Non Fiction, Paranormal, Philosophy, Poetry, Psychology, Religion, Romance, Science, Science Fiction, Self Help, Suspense, Spirituality, Sports, Thriller, Travel, Young Adult,
       Responder 
    Tem certeza que deseja  Sim  Não
    Insira sua mensagem aqui

Immunotherapy for Colorectal Cancer

  1. 1. Immunotherapy for Colorectal Cancer Michael Overman, MD MD Anderson Cancer Center Gastrointestinal Medical Oncology
  2. 2. Immune Infiltrate and Prognosis in Primary CRC: Immunoscore JCO 2006 Pages et al., NEJM 2005 Pages et al. 411 stage I and II CRC
  3. 3. Deficient mismatch repair (dMMR) or microsatellite instability- high (MSI-H) Tejpar BJC 2009; Koopman BJC 2009 • Mutations in MMR (inherited) or loss of MMR by methylation (acquired) results in microsatellite instability (MSI) – Increased duplication of tandem dinucleotide repeats (microsatellites) – Resulting increased mutations rate and higher risk of colon cancer – Unique clinicopathological features (lymphocytic infiltrate, Crohn’s-like reaction, varigated histology, poor differentiation, right sided) Anti-CD3 MSI-high CRC ≈3% HNPCC ≈12% sporadic
  4. 4. Universal Testing for HNPCC 1158 (31.5) 992(27) 2125 (57.8) 2394(65.2) 3671(100) No Tested (%) Moreira et al. JAMA 2012 Revised Bethesda criteria: 1. CRC <50y/o 2. Synchronous, metachronous CRC or other HNPCC cancer 3. CRC with MSI-high histology in <60y/o 4. CRC in ≥1 1st-degree relative with hnpcc cancer with 1 cancer diagnosed <50yrs 5. CRC in ≥2 1st or 2nd-degree relatives with hnpcc cancer regardless of age Jerusalem criteria: all CRC <70 years old
  5. 5. dMMR or MSI-H Have Better Outcomes (Prognostic Effect) 0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 Years %DiseaseFree HR: 0.51 (0.29-0.89) p=0.009 Untreated (N=515) MSI-H 80% MSS 56% 5 yr DFS Sargent, et al. ASCO 2008 and ASCO 2014; Tejpar BJC 2009; Koopman BJC 2009 Stage MSI-H II 22% III 12% IV 3.5% 5-year OS HR 95% OS P-value dMMR pMMR Stage II Surgery alone (n=307) 90% 78% 0.27 0.10 - 0.74 0.011 Stage III Surgery alone (n=264) 59% 54% 0.69 0.35 – 1.36 0.283 ACCENT database 14 phase III adjuvant studies
  6. 6. Metastatic MSI-high CRC Retrospective reivew of 55 metastatic MSI-H pts from MDACC + Royal Melbourne Hospital, Australia – 14 BRAF V600E (25%) Goldstein + Overman AoO 2014 BRAF V600E
  7. 7. Somatic mutation frequencies CRC Nature 2012 Colon TCGA
  8. 8. CRC TCGA Nature 2012 Colon TCGA
  9. 9. Mutational Rates Across Tumors Lawrence Nature 2013
  10. 10. Schreiber et al. Science 2011 Tumor Antigens: Differentiation (melanocyte differentiation antigens…) Overexpressed (HER-2…) Viral (HPV proteins…) Cancer/testis (MAGE, NY-ESO-1…) Mutational (p53…) Immunity and Cancer
  11. 11. Matsushita A et al. Nature (2012); 482 (7385); 400-4 Immunogenic methylcholantherene- induced sarcoma cell lines from Rag2-/- mice demonstrate ≈20% tumor rate in naïve wildtype mice Spectirn β-2 R913L mutation predicted and cloned from TIL MHC class I
  12. 12. Corbiere et al. Can Res 2012; Robbins J Exp Med 1996; Gaudin et al. J Immun 1999 Peptide In silico HLA nM affinity A0201 SLFEGIDFYT 11 SLFEGIDIYT 18 A2403 SYLDSGIHS 5646 SYLDSGIHF 6 A0201 ILDKVLVHP 16730 ILDKVLVHL 42
  13. 13. BMS-936550 RR: 0/18 CRC Tremelimumab RR: 1/45 CRC (response duration 15m) Nivolumab RR: 0/19 CRC Nivolumab RR: 1/14 CRC (response duration >21m, MSI-H pt) Immune Checkpoint Agents in CRC
  14. 14. CMS 400 MSI-high CRC patient
  15. 15. Immune Escape Mechanisms in MSI-high CRC Llosa et al. Cancer Discovery 2014 Invasive FrontStroma TIL
  16. 16. Le DT, et al. NEJM. 2015: 372: 2509-20. Pembrolizumab 10 mg/kg every 14 days
  17. 17. Pembrolizumab: Response Rate
  18. 18. Pembrolizumab: Additional Efficacy Endpoints CEA response Progression-free survival
  19. 19. Immune Infiltrate PDL1 expression CD8 density CD8 density and response
  20. 20. Ongoing Anti-PD1 or Anti-PDL1 Clinical Trials with MSI-high CRC Subsets • NCT01876511: Phase 2 study of MK-3475 in patients with microsatellite unstable (MSI) tumors – MSI-high CRC, MSS CRC, MSI-high non-CRC • NCT02060188: A study of nivolumab and nivolumab plus ipilimumab in recurrent and metastatic colon cancer (CheckMate 142) – MSI-high CRC, MSS CRC • NCT02227667: Evaluate the Efficacy of MEDI4736 in Immunological Subsets of Advanced Colorectal Cancer – MSI-high CRC, TIL high CRC • NCT02404411: phase I/II study of PDR001 in patients with advanced malignancies – MSI-high CRC, other tumors • NCT01633970: A phase 1b study of MPDL3280A (an engineered anti-PDL1 antibody) in combination with bevacizumab and/or chemotherapy in patients with advanced or metastatic solid tumors – MSI-high CRC, other tumors • A phase 1, open-label study of GSK3174998 administered alone and in combination with anticancer agents including Pembrolizumab in subjects with selected advanced solid tumors – MSI-high CRC, other tumors
  21. 21. Immune checkpoint in melanoma Ipilimumab in advanced melanoma Wolchok et al. Lancet Oncol 2010 Nivolumab/Ipilimumab: Chort 2a (n=16): Nivolumab 3mg/kg + ipilimumab 1mg/kg Clinical benefit of 73% G3/4 immmune Aes: 11 Wolchok et al. NEJM 2013 What about combo data in MSI-high CRC? Nivolumab in frontline melanoma Robert et al. NEJM 2014
  22. 22. CheckMate 142 Study Design Responses seen Limited activity
  23. 23. Nivolumab single agent MSI-High CRC Pre-rectal Xrt Pre-tx Restaging at 4months Cap/xrt to rectum Nivolumab Pre-tx Restaging at 4months Nivolumab Patient #1 Patient #2
  24. 24. Nivolumab single agent MSI-High Gastric Cancer Pre-tx 11/13/2013 Restaging 6/10/2015
  25. 25. Conclusion • Test for MSI-high – As universal testing approach for HNPCC – For prognostic relevance in stage II – For clinical trial options in metastatic patients • Clinical trials of immune-checkpoints in MMR deficient (MSI-high) CRC should be engaged upon • Targeting PD1/L1 and/or CTLA-4 have demonstrated limited to no activity in MMR proficient CRC

×