Tumour Immunology, Immunotherapy and Cancer Treatment

• Immune system


  Distinguishes self from non-self, eliminates harmful non-self molecules and cells from the body
• Antigen


  Any molecule recognized by the immune system, key to distinguishing self from non-self
• Physical barriers


  • The skin, cornea and mucosa of the respiratory, GI, and GU tracts form a physical barrier that is the body's first line of defense
• Innate immunity


  Does not require prior exposure to an antigen to be effective, responds immediately to an invader
• Adaptive immunity


  Requires prior exposure to an antigen to be effective, takes time to develop
• Immune response after injury

  1. Bacteria crosses barrier

  2. Dendritic cells are phagocytic

  3. T cells are activated by APC displaying a portion of an antigen

  4. CD4 T cells activate macrophages to be more toxic

  5. CD8 T cells kill
• Cytotoxic T cells (CTLs)


  • Have surface antibody-like molecules – T-cell receptors (TCRs) - helps to recognize and kill other cells
• Antigen presentation: MHC I

  1. Synthesized proteins are processed into oligopeptide fragments

  2. Oligopeptides enter ER and bind to MHC class I molecules

  3. MHC class I complexes are dispatched to the cell surface

  4. MHC class I presentation is performed by almost all cell types in the body
• Antigen presentation: MHC II

  1. Protein peptides engulfed by an antigen-presenting (APC) cell are presented on the surface

  2. TH cells bind to MHC II presented antigens

  3. Activated CD4+ T cells (helper T cells activate CD8+ T cells
• Mechanisms of killing by CTLs

  • CTLs contain lytic granules in its cytoplasm
  • Granules release perforin which forms holes in the plasma membrane of the target
  • CTLs express Fas ligand which binds Fas receptor and triggers receptor trimerization
• Natural Killer (NK) Cells

  • Recognize cells with reduced MHC expression or tumor cell surface antigens
  • Activated by cytokines, release perforins, granzymes, and chemokines
  • Have killer activating and killer inhibitory receptors, balance of signals determines fate of infected cell
• Immunosurveillance: The immune system surveys the body and eliminates newly transformed cells before they are clinically apparent
• Tumour antigens


  MHC class I restricted and recognized by CTLs, seen as different from self
• Tumour antigens


  • Tumour specific antigens (TSAs)
  • Mutated antigens
  • Over-expressed antigens
  • Oncogenic viral products
  • Proteins normally only expressed in embryos
• Tumour associated antigens (TAAs)


  Associated with tumour cells but also present in normal tissues
• Evidence for tumour immunosurveillance: Immune system recognizes tumour cells and eliminates them, deficiency in lymphocytes is associated with increased incidence of neoplasms
• Immunoediting


  Weeding out some tumors and tolerance for others, strongly immunogenic tumors are effectively eliminated, weakly immunogenic tumors survive
• Tumour Escape Mechanisms


  1. Reducing immunogenicity

  2. Resisting immune-mediated killing

  3. Subverting the immune response
• Mechanisms of tumour escape

  • Suppressing TAA and TSA expression
  • Suppressing MHC class I expression
  • Modulating the MHC antigen presentation
  • Suppressing apoptosis
  • Impairing binding of perforin
  • Expressing "don't eat me" signals
  • Immune checkpoint inhibition
  • Producing TGFβ
• Immune Checkpoint Inhibition


  T cell response regulated by balance of co-stimulatory and inhibitory signals, tumors hijack these mechanisms to escape immune surveillance
• 1. cell stimulation and inhibition


  1. T cell activation requires both TCR/MHC and B7/CD28 signals

  2. CTLA4 competes with CD28 for B7 ligands, dampening the signal

  3. PD-1 limits the activity of activated T cells
• Immunotherapy approaches


  • Infusion of activated tumor-infiltrating lymphocytes (TILs)
  • Infusion of dendritic cells with pre-loaded tumor antigens
  • Adding B7 costimulatory molecules
  • Blocking CTLA-4, PD-1 etc.
• Ipilimumab (anti-CTLA4)


  First FDA approved checkpoint inhibitor for melanoma, counteracts stimulatory role of CD28
• Chimeric Adoptive Receptor Transfer (CAR-T)

  Engineered T cells enhanced to have cancer-killing ability, combines specificity of antibodies with killing power of T-cells
• Checkpoint inhibitors


  Block CTLA-4 (receptor for B7 ligand), PD-1 (receptor for PD ligand)
• By removing something


  You can activate something
• Ipilimumab


  Anti-CTLA4, the Godfather of Checkpoints
• Ipilimumab


  • First FDA approved checkpoint inhibitor - Melanoma – 2011
  • Ongoing clinical trials for multiple cancers
  • CTLA4 counteracts stimulatory role of CD28 – share similar ligands
• Ipilimumab drives antitumor cell response
• Chimeric Adoptive Receptor Transfer (CAR-T)

  Chimeric Antigen Receptor (CAR) enhanced T-cells are lymphocytes enhanced to have cancer-killing ability
• CAR-T


  1. Engineer them to showcase antigen

  2. Put back into patients, it expands

  3. Taken from patient and engineered to bind to a universally expressed protein on the tumor cell (cd19, cd20, and cd22)

  4. Persists and expands in body, act like "living drug"

  5. Amplifies the drug effect because it expands
• CAR-T


  • Combines specificity of antibodies with killing power of T-cells
  • Engineered against tumour antigens combined with T cell killer
• CAR-T process


  1. Leukapheresis

  2. Reprogrammed cells

  3. Expansion

  4. Quality check

  5. Lymphodepleting chemotherapy

  6. Cell infusion
• CAR-T is a very expensive process, has to be effective for it to be worth the money
• The Rational Treatment of Cancer
• Cancer Treatments


  • Surgery
  • Radiation
  • Chemotherapy
  • Molecularly Targeted Therapies
  • Emerging treatments (Angiogenesis, Immunotherapy, Epigenetic targeting)
• Surgery


  • The oldest approach of treating cancer
  • If it was primary tumor it is worth it
• Types of surgery for cancer treatment

  • Scalpel surgery
  • Laser surgery (cervix, larynx, liver, skin, rectum)
  • Electrosurgery (skin and mouth)
  • Cryosurgery (prostate cancers, dysplastic cervix)
• Radiation Therapy


  • Surgery is not always sufficient or practical
  • Radiation therapy and adjuvant - additional (post-surgery) radiation therapy
  • Radiation kill cancer cells in two ways: p53 activation and activation of cell death by apoptosis, Chromosomal damage severe enough to prevent cells from progressing through mitosis and the cells die while trying to divide
• Goals of Cancer Chemotherapy

  • Cure- if possible
  • Prolong survival
  • Palliation- just making their life better, quality of life improves