Raymond Steptoe Raymond Steptoe Senior Research Fellow Senior Research Fellow Diamantina Institute for Cancer, Immunology and Metabolic Medicine Diamantina Institute for Cancer, Immunology and Metabolic Medicine University of Queensland, Princess Alexandra Hospital University of Queensland, Princess Alexandra Hospital [email protected][email protected]Tumour Tumour immunotherapy immunotherapy
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Raymond Steptoe Senior Research Fellow Diamantina Institute for Cancer, Immunology and Metabolic Medicine University of Queensland, Princess Alexandra.
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Raymond SteptoeRaymond SteptoeSenior Research Fellow Senior Research Fellow
Diamantina Institute for Cancer, Immunology and Metabolic Diamantina Institute for Cancer, Immunology and Metabolic MedicineMedicine
University of Queensland, Princess Alexandra Hospital University of Queensland, Princess Alexandra Hospital
• evidence from mouse models -immune-compromised mice have increased incidence of cancers-immunisation induces tumour-specific immunity & reduces tumour mass/tumour growth
• clinical observations -spontaneous regressions-immunodeficiency increases some cancers-immune infiltrates –better prognosis-tumour specific T cells can be isolated
Use effectors of the immune system to kill tumours
Tumour antigens -immune targets Tumours are ‘altered self’
Tumour antigens are usually self-proteins selectively over expressed by a tumourcell type specific (e.g)
Modified from: Schuster et al., Biotechnology J. 2006. 1:138-
Macrophage
xx
xxx
Immune-escape of tumours - II
Antigenic loss variants
Loss/down regulation of antigen targets -Tumour Specific Antigens
-loss of CD4+ & CD8+ T-cell epitopes -CD20
-loss of antibody binding (Rituximab)
Loss of MHC class I / antigen processing -MHC class I expression -TAP etc. (for processing /loading)
- loss of CD8+ T cell recognition
Modified from: Schuster et al., Biotechnology J. 2006. 1:138-
Immunotherapy - purpose
• actively enhance immune response or passively deliver immune effectors
-boost impaired components
-replace missing elements
Passive (adoptive) immunotherapy
Transfer of efferent elements of the immune system
Effector T cells in-vitro activated T cells
Antibodies -surface antigens CD20 Non-Hodgkins lymphoma -growth factors / receptors HER2/neu breast cancer VEGF colorectal cancer
Macrophage
Effector T cellsAntibody
Passive (adoptive) immunotherapyAdoptive antibody therapy - targets surface molecules expressed or over-expressed by tumour cells
Antibody-dependent cytoxicity (ADCC), complement-dependent cytotoxicity (CDC) – cells are killed by these mechanismsCD20 Rituximab Non-Hodgkins lymphoma (NHL)CD33 Gemtuzumab Acute myelogenous leukemia (AML)CD52 Alemtuzumab Chronic lymphocytic leukemia (CLL)
Disruption of signalling through receptors or growth factors -prevents growth of cells
HER2/neu Herceptin Breast cancerVEGF Avastin Colorectal cancer (CRC)EGF-R Cetuximab Colorectal cancer (CRC)
-limitations-loss of antigen expression- large quantities required/expensive- surface molecules only – limits repertoire
Passive (adoptive) immunotherapyAdoptive cellular therapy (ACT) -provides an exogenous source of anti-tumour T cells
Patient’s own T cells are activated in vitro and retransferred -tumour specificity generated by:
-using defined tumour-specific antigen-tumour infiltrating lymphocytes
-most effective for highly immunogenic tumours-melanoma-EBV-induced post-transplant lymphoproliferative disorder-allogeneic HSCT for acute myelogenous leukemia
-may be boosted by concurrent immunisation etc.
-can target intracellular proteins, more diverse targets than antibody
-limitations-persistence of transferred cells
(overcome by lymphodepletion)-diverse specificities required-experimental procedure
Rosenberg et al. Nat Rev Cancer, 2008
Active immunotherapyAdjunctive therapy-promotes immune responsiveness
Immune-stimulatory cytokines-interleukin-2 (IL-2)
-boosts function of T cells, NK cells -interferon-2b (IFN-2b )
-mechanism unclear Limitations:
-side effects-limited effectiveness
Suppression of immune inhibitors-lymphodepletion (promotes expansion of antigen-specific T cells)-anti-CTLA4 (prevents inactivation of T cells)-anti-PD-L1 (prevents inactivation of T cells)
-limitations:
-experimental
Active immunotherapyVaccination (therapeutic) -boosts ‘ineffective’ T cell responses
Whole tumour vaccines
-tumour cells poorly immunogenic so immunogencity must be increased-addition of BCG-addition of adjuvants-use of allogeneic tumour cells -gene-engineering of tumour cells -cytokines-GM-CSF,
-costimulatory molecules B7
-evidence of T-cell priming often apparent in vitro, but with little clinical effect
-limitations-modest clinical effects-under development
Active immunotherapyVaccination (therapeutic) -boosts ‘ineffective’ T cell responses (and induces de-novo responses?)
Specific antigen vaccines -a range of tumour-specific antigens have now been defined (see Kim et al., - best prospects are those that are widely expressed in tumours
Development of active immunotherapy has been slow -still experimental
- large range of tumour-specific antigens defined for some tumours
-limited somewhat by stage of disease treated (ie late/advanced disease)
Immunotherapy (primarily) is considered an adjunct to ‘conventional’ therapies and particularly for clearing minimal residual disease of metastases
Noteable success have been very profound
Rituximab
Gardasil
Further reading
• Immunotherapy of melanoma:Fang et al., Journal of Investigative Dermatology, 128:2596- (2008).Kirkwood et al., Journal of Clinical Oncology, 26:3445- (2008).
• Adoptive T cell therapy:Rosenberg et al., Nature Reviews Cancer, 8:299-, (2008).
• DC therapy:Banchereau & Palucka, Nature Reviews Immunology, 5:296-, (2005).