Immune Checkpoint Inhibitors and Cancer Vaccines Flashcards
What is meant by immune surveillance in relation to cancer?
Immune system has evolved to constantly survery tissues for malignant transformation and target these cells
What is the relationship between immune regulation and cancer?
Immunocompromised have higher rates of cancer - unable to surveil for changes
Over active - inc inflammation inc risk of cancer
What immune system part is considered to be cancer killing?
NK cells
CD8+ cells.
What is the key response shown by the immune system against cancer shown by lymphocytes?
Antibodies against tumour antigens
T cells with TCR against tumour specific peptides
Lymphocytes infiltrate into solic tumours
What is the role of NK cells against cancerous cells?
Regulated by inhibitory and activatory receptor on surface that respond to antigen on cell surface
When activated -> cytotoxicity and cytokine production causes target cell death.
Innate immune system response
What changes in cancer cells make them more vulnerable to death by NK cells?
Loss of HLA class 1 -> norm acts as inhibitor ligand = loss of inhibitory signalling through NKG2A-CD94
Upregulation of stress ligands (MICA) = activatory signalling through NKG2D
What are the three signals required to activate naive immune cells?
- Antigen receptor signal - TCR on T cell to MHC bound peptide on APC
- Co-stimulation - CD28 on T cell with B7 (CD80 and CD86) on APC
- Polarising cytokine signals - released by APC to determinete type of effector response
What is the role of the different type of T cells in launching a response against cancer?
CD4+ - help prime CD8 T cell response and formation for CD8 memory
CD8+ - killing cancer cells, granzyme, perofin and death ligands.
Define tumour associated antigens?
Antigens unusually highly expressed on cancer cells compared to normal cells
Define tumour specific antigens
Only found on cancer cells (neoantigens) result of somatic mutations
What antigens are commonly associated with cancer?
Cancer testis antigens - previously found in testes, immune system previously ignorant
Viral antigens - HPV early proteins, virus was oncogenic trigger
Why is the tumour peptidome important to cancer immunosurveillance?
Is what proteins the tumour produces
Changes across time within an individual and can be different between individuals with same cancer
How to cancer cell evade detection from the immune system?
Develop due to selective pressure:
1. Not present immunogenic self-altered peptide
2. Downregulate HLA-1 to avoid CD8+ activation
3. Express surface and secreted molecules to inhibitor effector cells of immune system
4. Create a microenvironment that favours immunological tolerance
What is the tumour microenvironment?
Highly heterogeneity
‘Ecosystem’ of tumour and surrounding immune cells, stroma and blood vessels.
What immune components are typically found in the tumour microenvironment?
Cytotoxic T cells
Helper T cells
Regulatory T cells
Macrophages
Myeloid derived suppressor cells
Cytokine milieu -> what and proportion of cytokines present
What affects how immunogenic a tumour is?
Low or high number of mutations
Number of tumour infiltrating lymphocytes
Proportion of immune subsets (Th1 v reg, M1 v M2, NK etc)
What is the basic principle of the aim of immunotherapy against cancer?
Primar the activation of naive T cells against tumour specific antigens
Damplen the immunoregulatory mechanism of cancer cells
Shift the balance towards immune activation and tumour cancer killing
What is the general concern with immunotherapy?
Turn of immunoregulatory mechanism
Leads to increased response to self antigens, high levels of inflammation and damage to host tossues.
What is the role of Rituximab against cancer? (basic)
Targets CD20
Treatment for non-Hodgkin lymphoma
What is the role of rituximab against cancer?
Targets CD20 on B cells
Treatment for non-Hodgkins lymphoma
Triggers antibody dependent cell mediated cytotoxicity by NK and macro
Classical complement pathway activation
Formation of membrane attack complex.
What is the role of Trastuzumab (herceptin) in the treatment of cancer?
Targets HER2
Treatment of HER2-positive breast cancer
Blocks dimerisation and signalling - inhibits receptor signalling hence cell proliferation
What are immune checkpoint inhibitor drugs?
Monoclonal antibodies given IV - typically in combination with others.
Block antibodies that bind receptor or block receptor itself in immune checkpoint pathway -> inhibits inhibition of immune system.
Remove brakes on immune system.
What is important in practice for the use of Immune checkpoint inhibitor drugs against cancer?
Expensive
Typically used in combination with other drugs
Given IV
Used in advanced cancer - consider refractory or relapsed
Cause immune-related adverse events at high frequency (includes vitiligo, GI bleeding, pneumonitits)
What is the purpose of ipilimumab in cancer treatment?
Block CTLA-4
Used in comb with PD-1 inhibitor for advanced melanoma
CTLA-4 is found on surface of T cells, is bound to be signals on T reg and APC to turn off immune cell function
What is the purpose of nivolumab and pembrolizumab in cancer treatment?
Block PD-1 (receptor)
NSCLC with PD-L1 >50% tumour proportion
PD-1 found on surface of immune cells, ligand turn off immune cells
What is the purpose of atezolizumab, avelumab, duravalumab?
Block PD-L1
Atezolizumab is used to treat advanced urethelial carcinoma
PD-1 found on surface of immune cells, ligand (can be found on surface of cancer cells) turn off the cancer cells
What is the role of CTLa-4 in the immune system?
Found in secondary lymphoid organs on Tregs and activated T cells
Imhibits priming of immune cells (CD4>CD8)
Is a competitieve inhibitor of CD28 co-stimulation -> binds to B7 with high affinity
Norm = prevents autoimmune response to self-antigen, trig function Treg, prevents uncontrolled expansion of activated T cells or activation of naive T cells
How can resistance to immune checkpoint inhibitor therapy arise?
Inc immune response against tumour
Acts as a selective pressure
Results in cancer mutation for immune evasion leading to loss of response
Risk can be reduced by using combination treatments
What is a key side effect os a strong response to ipilimumab?
Vertiligo
What is the role of PD-1 in the immune system?
Expressed by activated T cells in peripheral tissues
Targets effector phase of immune response (CD8>CD4)
Ligand L1 and L2 express by host tissue
Chronic exposure to any antigen leads to inc expression of PD-1 by T cells (exhausted)
Signalling of Pd-1 decreases T cell proliferation, cytokine secretion and cytotoxic activity = anergic
What is important to know about checkpoint inhibitor therapy side effects?
Immune related adverse events - due to loss of normal tolerance mechanisms
More common with CTLA-4 than PD1
More common with combination therapy than signular
Can persist after treatment ends
Common = dermatitis and colitis
What are some common viruses associated with their respective cancers?
EBV, HBV, HCV HIV and HPV
Kaposi sarcoma in AIDs
Hodkgins and EBV
Liver and HBV > HCV
How does HPV lead to cervical cancer?
HOV 16 and 18 = main cancer causing
Viral protein E6 -> promotes degradation of p53
E7 binds and inactivates Rb
Suppress apoprotosis, allow DNA damage and progression through cell cycle
What HPV vaccination programme exists?
2008 - 12/13yrs females UK
2019 - 12/13yrs males UK
2012 changed from cervarix to gardasil vaccine
What is the Imlygic (T-VEC) vaccination for cancer?
Genetically modified oncolytic virus derviedfrom HSV-1
Targets metastatic melanoma (Not visceral organs)
Injected into lesion every 2-3 weeks
Infects tumour cells - secretes GM-CSF to recruit and activate APC
Also cause direct lysis of tumour cells
What can be done to improve the efficacy/safety of immune checkpoint inhibitor therapy in cancer?
New targets - TIM2, LAG3 and TIGIT
Not use in children - concern over organ damage and long term comp
Combine with personalised tumour antigen specific vaccine
Pre radio/chemo to inc chance of response (only 25% currently respond)
