Dr. Gülderen Yanıkkaya Demirel TUMOR IMMUNOLOGY Dr. Gülderen Yanıkkaya Demirel

WHAT YOU WILL LEARN Cancer stem cell Tumor Immunity Tumor Antigens Tumor Cell Escape Mechanisms Immunosurveillance/Immunoediting

CANCER STEM CELL Ikehara S, J of Hematotherapy & SC Research, 12:643-653, 2003

EVIDENCE for TUMOR IMMUNITY Spontaneous regression Regression of metastases after removal of primary tumor Infiltrations of tumors by lymphocytes and macrophages Lymphocyte proliferation in draining lymph nodes Increased cancer risk after immunosuppression and immunodeficiency

IMMUNODEFICIENCY and TUMOR

IMMUNOGENECITY of TUMORS

TUMOR IMMUNOLOGY

TUMOR ANTIGENS mutations abnormal expression oncogenic viruses oncofetal antigens altered surface modifications tissue specific differentiation antigens

BCR/ABL http://en.wikipedia.org/wiki/Philadelphia_chromosome

Origin of tumor antigens Figure 14-11 part 1 of 2

Figure 14-11 part 2 of 2

Figure 14-14 part 1 of 2

Figure 14-17

IMMUNE RESPONSES TO TUMORS Innate immune responses NK cells Macrophages Innate like cells Adaptive immune responses T cells Antibodies

IMMUNOSURVEILLANCE An hypothesis that states that a physiologic function of the immune system is to recognize and destroy malignantly transformed cells before they grow into tumors. Proposed by Paul Ehrlich, Macfarlane Burnet and Lewis Thomas Implies that cells of the immune system recognize something “foreign” on transformed/tumor cells.

IMMUNOSURVEILLANCE & IMMUNOEDITING No disease Preneoplasia Disease

IMMUNE MODIFIERS Cytokines requiring host participation: aldesleukin [interleukin (IL)-2] and IFN a 2; Antibodies requiring host participation—to the extent that they invoke antibody dependent cellular cytotoxicity for optimal efficacy: alemtuzumab, tositumomab, cetuximab, ibritumomab, rituximab, and trastuzumab; Immunostimulants known to require host participation: Bacillus Calmette-Guerin, levamisole, and imiquimod; Immunostimulants with unknown host participation: lenalidomide and thalidomide

RESIDUAL DISEASE Reya, T., et al. Nature, 2001

Cancer immunotherapy with mRNA transfected dendritic cells - A personalized form of cell therapy Antigen Loading (mRNA transfection) GM-CSF, IL-4 Immature DC Monocytes DC maturation IL-1b, IL-6, TNF-a, PGE2 Tumor antigens (mRNA) Antigen-Loaded Mature DC Cryopreserved DC Vaccine Tumor Biopsy Leukapheresis

POTENTIAL CYTOTOXIC MECHANISMS of ANTI TUMOR ANTIBODIES

INDUCTION of ANTI TUMOR RESPONSE

LAK (Lymphokine Activated Killer) CELLS

SUMMARY 1) Immunological recognition of tumor occurs. 2) Tumors emerge in individuals who have overcame the immunological surveillance. 3) Evasion mechanisms include reduced tumor antigen presentation and local immunoregulatory factors: inhibitory cytokines and cells. 4) Reversal of tolerogenic response is goal of immunotherapy Passive immunization (antitumor antibodies, adoptive T cell therapy). Active immunization (vaccine=antigen plus adjuvant). The goal is to induce antigen specific effector T cells while eliminating regulatory negative immunoregulatory pathways