HelfieldBIOL462Week10b_Cancer_Immunotherapy.pdf

Immunology Week 10b: Cancer Immunotherapy Course: BIOL 462/633, Department of Biology, Concordia University Instructor: Brandon Helfield Office: SP367.23 Cancer: Mutations that Cause Uncontrolled Growth Tumor (neoplasm): Tissue in which cells are multiplying abnormally Oncology: branch of medicin...

Immunology Week 10b: Cancer Immunotherapy Course: BIOL 462/633, Department of Biology, Concordia University Instructor: Brandon Helfield Office: SP367.23 Cancer: Mutations that Cause Uncontrolled Growth Tumor (neoplasm): Tissue in which cells are multiplying abnormally Oncology: branch of medicine that addresses cancer patients and studies their tumors Benign Tumors: encapsulated, localized, limited in size Malignant Tumors: Continually increase size, break through basal laminae, can invade adjacent tissues Cancer: used for diseases caused by malignant tumors Cancer: Mutations that Cause Uncontrolled Growth Carcinomas: Cancers of epithelial cells • e.g. adenocarcinoma (breast) • Most cancers ~80-90% are carcinomas Sarcomas: Cancers derived from connective tissue (bone, fat, muscle) • e.g. Neuroblastoma (nerves); Fibrosarcoma (fibrous tissue); Osteosarcomas • ~1% of cancers Derived from Blood Cells: The remaining 9% • Leukemias: involve circulating cells • Lymphomas: Lymphoid tissues • Myelomas: involve plasma cells in bone marrow Cancer: Accumulation of Mutations • Two groups of genes in malignant transformation: • Proto-oncogene • normal gene involved in growth or proliferation (more than 100) • Growth factors, receptors, enzymes • Mutated form: oncogene • Tumor suppressor genes • Encode proteins that prevent proliferation of mutant cells • e.g. p53 made by cells with damaged DNA which induces apoptosis. • >50% of human cancers have mutant p53 • Accumulation of at least 5-6 independent mutations to become cancerous Exposure to chemicals, radiation, and viruses can facilitate cancer Mutagen: Chemical/Physical agents that damage DNA to cause increase rate of mutation Carcinogen: Mutagens that are known to increase risk of cancer Chemical: single nucleotide substitution Radiation: DNA breaks, abnormal recombination, etc… Oncogenic virus: associated with ~15% of cancers Hallmarks of Cancer Mutations: Tumor Antigens Tumor antigens: Unique or inappropriately expressed antigens Tumor Specific Antigens (TSAs) that can be detected by immune system 1. Encoded by genes exclusively expressed by tumors 2. Encoded by variant forms of normal genes 3. Antigens normally expressed only at certain stages of development Tumor Associated Antigens (TAAs) 4. Overexpressed antigens Immunosurveillance Three proposed mechanisms to control/inhibit cancer: 1.Destroy viruses that transforms cells. 2. Rapidly eliminating pathogens 3. Identifying and eliminating transformed cells (immunosurveillance) Normal state: • Tissue is constantly exposed to damage. Unhealthy cells are removed and new cells take their place. Once this tipped in favor of more cellular expansion than loss, tumors can arise. Phase 1: Immunosurveillance • In the process, some cells acquire mutations that allow them to resist Cancer Immunoediting Phase 2: Equilibrium • Balance between moderate destruction with survival of small number of cancer cells Phase 3: Escape • Further mutation in the surviving tumor cells leads to rapid growth Over time, inhibitory immune responses begin to dominate and immune activity shifts to pro-tumor • Shapes the properties of the tumor cells that survive Cancer Immunoediting Cells Involved in Cancer Eradication NK cells: • One of the first type recognized to kill tumor cells • Killing mechanism is similar to CTLs (granzymes, FasL-Fas interaction) • Do not possess TCRs • Balance between activating and inhibitory signalling (binds to MHC I) • Activating receptor: NKG2A-D • Inhibitory receptor: KIRs Cells Involved in Cancer Eradication NK cells Interaction with macrophages Interactions with dendritic cells Cells Involved in Cancer Eradication NKT cells: Unconventional 𝛼𝛼𝛼𝛼 T cells express TCRs that recognize lipid antigens presented by CD1d and NK receptors (e.g. NKG2D) • NKTs activated through TCR and IL-12 signals • NKTs can express either CD4 or CD8 • Interaction with pathogenloaded DCs results in mutual activation Cells Involved in Cancer Eradication Macrophages • Pro-inflammatory macrophages (M1) possess Fc receptors to recognize antibodies bound to tumor antigens to mediate ADCC (antibody-dependent cell-mediated cytotoxicity) • Secrete TNF (has potent anti-tumor activity) Tumor infiltrating lymphocytes (TILs): • Combination of T cells, NK cells and NKT cells • Presence correlates with a clinical prognosis of cancer regression • Specifically, high ratios of CD8+ T cell to Tregs is associated with enhanced survival. • B cells: antibodies mediate ADCC but can also hinder CTL access to tumor-specific antigens – unclear if this helps Cytokines: • Type I and II IFNs, TNF-𝛼𝛼, IL-12  strong CTL and Th1 response Cells Involved in Cancer Eradication Tumor Microenvironment (TME) Cancer Immunotherapy 1. Monoclonal Antibodies 1. Monoclonal Antibodies 1. Monoclonal Antibodies Opdivo (nivolumab): anti-PD-1 Keytruda (pembrolizumab): anti-PD-1 Yervoy (Ipilimumab): anti-CTLA4 Tecentriq (Atezolizumab) : anti-PD-L1 1. Monoclonal Antibodies • Antibodies against CTLA-4 or PD-1, both inhibitory receptors on T cells, as well as PD-L1 (frequently on cancer cells) • Lymphoid tissues (to enhance immune stimulatory signals) • Tumor site (block inhibitory pathways) 2. Antigen-loaded DCs Prophylactic vaccine: • Designed to elicit immune response before onset of infection Therapeutic vaccine: • Enhance or redirect existing immune response after exposure Provenge: • First ever approved therapeutic cancer vaccine (prostate in 2010) • Median of 4 month increase in life expectancy 3. Adoptive Cell Transfer (ACT) • Tumor specific TCRs have weaker affinity for antigen than TCRs that protect against viruses • Surgically remove tumor tissue, along with resident CTLs and culture in-vitro (e.g. IL-2) 4. CAR cells • Chimeric Antigen Receptor (CAR) is an engineered receptor designed to tightly bind to a defined ligand • Nonphysiological and very high affinity • Single polypeptide that comes antigen recognition and signalling • Synthesized from the heavy chain and light chain variable regions of an antibody (Fv fragments) • Cytoplasmic tail derived from the 𝜁𝜁 chain of the TCR complex, the CD28 costimulatory receptor and CD137 (TNF-𝛼𝛼 receptor family) • Much stronger affinity than TCR, and is protected from becoming anergic 4. CAR Cell Challenges 4. Emerging CAR cell Techniques Focused Ultrasound Immunotherapy Focused Ultrasound Treatment Region (Diseased Tissue) Focused Ultrasound Energy Helfield et al. UMB 2016 Intervening Region (Healthy Tissue) Brain Heart Helfield et al. PNAS 2016 Focused Ultrasound Immunotherapy Curley et al. 2017 Immunology Week 10b: Cancer Immunotherapy Course: BIOL 462/633, Department of Biology, Concordia University Instructor: Brandon Helfield Office: SP367.23