Potentialet for forskning i immuno-onkologi

Omfanget af evidens for et immunrespons mod cancer

Både solide tumorer og hæmatologiske maligniteter er i stand til at inducere et immunrespons, som kan regulere deres initiale vækst. Denne evne er kendt som tumorimmunogenicitet.1,2

PRÆSENTATION

Traditionelt set defineres immunogene tumorer, herunder melanom og ikke-småcellet lungecancer (NSCLC), ud fra en høj forekomst af mutationer.3 Disse mutationer danner tumorantigener, som genkendes af immunsystemet, hvilket aktiverer et antitumorimmunrespons.4

 

Infiltration

Tumorinfiltrerende immunceller er til stede i tumors mikromiljø.5-17 Deres tilstedeværelse viser deres evne til at identificere og migrere til tumorceller.18

 

Elimination

Tidligt i deres udvikling kan nogle tumorer udvise tegn på spontan regression. Det tyder på, at immunsystemet er i stand til at genkende og dræbe nogle tumorceller.19

Det understøtter endvidere konceptet, at kroppens eget immunsystem har evnen til at inducere et antitumorrespons mod cancer.20 Der forskes i øjeblikket aktivt i at målrette immunsystemets signalveje til at hjælpe med at eliminere tumorceller.


Det store potentiale i immuno-onkologi

Immunsystemets evne til at opdage og dræbe tumorceller er grundlaget for forskningen i immuno-onkologi. Evidensen for tumorimmunogenicitet på tværs af mange forskellige solide tumorer og hæmatologiske maligniteter udgør rationalet for det vide spænd i forskningen inden for immuno-onkologi på tværs af tumortyper.21

Evidens for tumorimmunogenicitet
Tumortype PRÆSENTATION
Tilstedeværelse af
somatiske
mutationer
INFILTRATION
Evidens for
immuncelleinfiltration
ELIMINATION
Evidens for spontan regression
Blære3,15  
Mamma17,22  
Kolorektal16  
Gastrisk/øsofagus8,23  
Glioblastom4,6  
Hoved og hals9,24  
Hepatocellulær13  
Lunge3,8  
Melanom3,8,19
Ovarie12,25  
Pancreas16  
Prostata10,26 check check  
Renalcellekarcinom3,11
Non-Hodgkin lymfom5,27 check  
Hodgkin lymfom14,28  
Leukæmi29  
Multipelt myelom7,30  

Bristol-Myers Squibb forsker forsat i immun-onkologi, et forskningsområde i vækst. Vores forskning er motiveret af de mange patienter med fremskreden cancer, som venter på fornyet håb og muligheden for et længere liv.

Referencer

1. Bachireddy P, Burkhardt UE, Rajasagi M, Wu CJ. Hematological malignancies: at the forefront of immunotherapeutic innovation. Nat Rev Cancer. 2015;15(4):201-215. 2. Blankenstein T, Coulie Pg, Gilboa E, Jaffee EM. The determinants of tumour immunogenicity. Nat Rev Cancer. 2012;12(4):307-313. 3. Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214-218. 4. Schumacher T, Bunse L, Pusch S, et al. A vaccine targeting mutant IDH1 induced antitumor immunity. Nature. 2014;512(7514):324-327. 5. Ansell SM, Stenson M, Habermann TM, Jelinek DF, Witzig TE. CD41 T-Cell Immune Response to Large B-Cell Non-Hodgkin’s Lymphoma Predicts Patient Outcome. J Clin Oncol. 2001;19(3):720-726. 6. Berghoff AS, Kiesel B, Widhalm G, et al. Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro Oncol. 2015;17(8):1064-1075. 7. Dhodapkar MV, Krasovsky J, Olson K. T cells from the tumor microenvironment of patients with progressive myeloma can generate strong, tumor-specific cytolytic responses to autologous, tumor-loaded dendritic cells. Proc Natl Acad Sci USA. 2002;99(20):13009-13013. 8. Gentles AJ, Newman AM, Liu CL, et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med. 2015;21(8):938-945. 9. Heusinkveld M, Goedemans R, Briet RJP, et al. Systemic and local human papillomavirus 16-specific T-cell immunity in patients with head and neck cancer. Int J Cancer. 2012;131(2):E74-E85. 10. Hussein MR, AL-Assiori Mana, Musalan AO. Phenotypic characterization of the infiltrating immune cells in normal prostate, benign nodular prostatic hyperplasia and prostatic adenocarcinoma. Exp Mol Pathol. 2009;86(2):108-113. 11. Itsumi M, Tatsugami K. Immunotherapy for Renal Cell Carcinoma. Clin Dev Immunol. 2010; 2010;284581. doi:10.1155/2010/284581. 12. Kandalaft LE, Motz GT, Duraiswamy J, Coukos G. Tumor immune surveillance and ovarian cancer: lessons in immune mediated tumor rejection or tolerance. Cancer Metastasis Rev. 2011;30:141-151. 13. Liang J, Ding T, Guo Z-W, et al. Expression pattern of tumour-associated antigens in hepatocellular carcinoma: association with immune infiltration and disease progression. Br J Cancer. 2013;109(4):1031-1039. 14. Schreck S, Friebel D, Buettner M, et al. Prognostic impact of tumour-infiltrating Th2 and regulatory T cells in classical Hodgkin lymphoma. Hematol Oncol. 2009;27(1):31-39. 15. Sharma P, Shen Y, Wen S, et al. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc Natl Acad Sci USA. 2007;104(10):3967-3972. 16. Tran E, Ahmadzadeh M, Lu Y-C, et al. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science. 2015;350(6266):1387-1390. 17. Whitford P, Mallon EA, George WD, Campbell AM. Flow cytometric analysis of tumour infiltrating lymphocytes in breast cancer. Br J Cancer. 1990;62(6):971-975. 18. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14(10):1014-1022. 19. Kalialis LV, Drzewiecki KT, Klyvner H. Spontaneous regression of metastases from melanoma: review of the literature. Melanoma Res. 2009;19(5):275-282. 20. Maio M. Melanoma as a model tumour for Immuno-Oncology. Ann Oncol. 2012;23(suppl 8):viii10-viii14. 21. Antonia SJ, Larkin James, Ascierto PA. Immuno-Oncology Combinations: A Review of Clinical Experience and Future Prospects. Clin Cancer Res. 2014;20(24):6258-6268. 22. Wood LD, Parsons DW, Jones S, et al. The Genomic Landscapes of Human Breast and Colorectal Cancers. Science. 2007;318(5853):1101-1113. 23. Matsueda S, Graham DY. Immunotherapy in gastric cancer. World J Gastroenterol. 2014;20(7):1657-1666. 24. Kass ES, Greinber JW, Kantor JA, et al. Carcinoembryonic Antigen as a Target for Specific Antitumor Immunotherapy of Head and Neck Cancer. Cancer Res. 2002;62(17):5049-5057. 25. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian Carcinoma. Nature. 2011;474(7353):609-615. 26. Berger MF, Lawrence MS, Demichelis F, et al. The genomic complexity of primary human prostate cancer. Nature. 2011;470(7333):214-220. 27. Morin RD, Mendez-Lago M, Mungall AJ, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011;476(7360):298-303. 28. Gunawardana J, Chan FC, Telenius A, et al. Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma. Nat Genet. 2014;46(4):329-335. 29. Rajasagi M, Shukla SA, Fritsch EF, et al. Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood. 2014;124(3):453-462. 30. Walz S, Stickel JS, Kowalewski DJ, et al. The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell–based immunotherapy. Blood. 2015;126(10):1203-1213.