Applied Immunology: Cancer Therapy

• What is immune surveillance?

  Immune system constantly surveys tissues for cells undergoing malignant transformation
• What are the important cells in immune surveillance & destruction of malignant cells?

  Innate & adaptive arms of immune system

  Macrophages

  NK cells

  B cells

  CD4 & CD8 T cells
• In cancer patients, there is an immune response present.

  Can see antibodies against tumour antigens
• What is the function of NK cells in immunosurveillance?

  NK cells have activatory & inhibitory receptors on the surface -> cytotoxicity & cytokine production

  In cancer...

  • loss of HLA class I on cancer cell -> loss of inhibitory signalling with NK cell -> lysis
  • upregulation of stress ligands (e.g. MICA) on cancer cell -> activatory signalling with NK cell -> lysis
• What are the 2 main types of tumour antigens?

  Tumour associated antigens -> antigens that are unusually highly expressed on cancer cells vs normal cells

  Tumour specific antigens -> antigens only found on cancer cells & result from mutations -> called neoantigens
• How do tumour cells escape from T cell immune surveillance?

  Downregulate HLA class I -> evade potential recognition by CD8+ cytotoxic T cells

  Express surface & secreted molecules that directly inhibit function of effector cells

  Create microenvironment that favours immunological tolerance over immune activation
• What is the goal of immunotherapy?

  Shift balance towards immune activation & tumour cell killing
• What are immune checkpoint inhibitor drugs?

  Monoclonal antibodies

  Block antibodies that bind a receptor or its ligand, prevents inhibitory signalling in immune cells -> 'take the brakes off' immunity & cause immune-related adverse effects (IrAEs)

  Most often used in advanced cancers
• What is rituximab?

  Monoclonal antibody

  Used to treat non-Hodgkin's lymphoma

  Targets CD20

  Triggers antibody dependent cell mediated cytotoxicity by NK cells & macrophages
• What is trastuzumab?

  Monoclonal antibody

  Used to treat HER2 positive breast cancer

  Targets HER2

  Blocks dimerisation & signaling of tyrosine kinase receptor -> inhibits growth
• Give examples of checkpoint inhibitor therapies in the UK.

  Ipilimumab

  Nivolumab

  Pembrolizumab

  Atezolizumab

  Avelumab

  Durvalumab
• What are the side effects of checkpoint inhibitor therapy?

  Dermatitis & colitis (common)

  Can be life-threatening

  
• What are the main cancer-causing types of HPV?

  16 & 18
• Cancer viruses/vaccines

  Viruses that can cause cancer -> EBV, Hep B, Hep C, HIV, HPV

  Kaposi's sarcoma in AIDS pts

  Hodgkin's lymphoma & EBV

  50% of liver cancers are due to Hep B (worldwide)
• What is Imlygic?

  Therapeutic vaccination

  Genetically modified oncolytic virus (derived from HSV-1)

  Intra-lesional injection given every 2-3 wks

  Infects tumour cells -> secretion of GM-CSF -> recruits & activates APC -> direct lysis of tumour cells (primes immunity against tumour antigens)
• What are the current CAR T cell therapies approved in the UK?

  Axicabtagene ciloleucel (Yescarta)

  • treatment of adult pts with relapsed/refractory diffuse large B cell lymphoma

  Tisagenlecleucel (Kymriah)

  • treatment of children & young adults with relapsed/refractory B cell ALL
• Effector cytotoxic T cells do not need co-stimulation to kill.
• What 3 signals are required to activate naive T cells?

  Antigen receptor signal

  Co-stimulation

  Polarising cytokine signal
• How do CAR T cells kill tumour cells?

  Perforin & granzyme

  FasL-Fas killing

  (secretion of IFN-y -> sensitises cancer cells to apoptosis)
• What are CAR T cells?

  Genetically modified T cells used to kill tumour cells
• How are CAR T cells made?

  Manufactured from the pts own leukocytes (autologous)

  Manufacturing time = few weeks

  Cells take from peripheral blood -> transduce cells -> T cell proliferation -> frozen transfer bags shipped back to hospital -> thawed & administered by infusion

  NOTE: Pt will already have advanced cancer at this time
• Process of CAR T therapy

  Test for appropriateness

  Leukapheresis (blood drawn)

  Bridging chemotherapy (prednisone, vincristine, doxorubicin)

  Lymphodepletion (fludarabine + cyclophosphamide)

  Infusion (paracetamol & anti-histamine before infusion)

  Management

  • Low B cells and antibody (intravenous immunoglobulin, IVIG)
  • Cytokine release syndrome & neurotoxicity (tocilizumab)
  • Tumour lysis syndrome (hydration + anti-hyperuricaemic agent)
• What is cytokine storm?

  Potential side effect of CAR T cell therapy

  CAR T cells produce lots of cytokines after recognition of tumour cells -> systemic inflammatory response (IL-6, can be treated with tocilizumab)

  Common (1 in 10), can vary in severity

  • fever -> life-threatening
• What is ICANS?

  Immune effector cell associated neurotoxicity

  Potential side effect of CAR T cell therapy
• What is tumour lysis syndrome?

  Complication of cancer treatment

  Seen most often after treatment of bulk, treatment-

  sensitive haematopoietic malignancy

  Dying cells empty contents into ECM -> hyperuricaemia, hyperkalaemia & hyperphosphataemia

  Can cause acute renal failure, cardiac arrhythmias, seizures
• CAR T cell therapy has poor efficacy against solid tumours.