Immune Checkpoint Inhibitors and Cancer Vaccines

Question 1

What is meant by immune surveillance in relation to cancer?

Answer 1

Immune system has evolved to constantly survery tissues for malignant transformation and target these cells

Question 2

What is the relationship between immune regulation and cancer?

Answer 2

Immunocompromised have higher rates of cancer - unable to surveil for changes
Over active - inc inflammation inc risk of cancer

Question 3

What immune system part is considered to be cancer killing?

Answer 3

NK cells
CD8+ cells.

Question 4

What is the key response shown by the immune system against cancer shown by lymphocytes?

Answer 4

Antibodies against tumour antigens
T cells with TCR against tumour specific peptides
Lymphocytes infiltrate into solic tumours

Question 5

What is the role of NK cells against cancerous cells?

Answer 5

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

Question 6

What changes in cancer cells make them more vulnerable to death by NK cells?

Answer 6

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

Question 7

What are the three signals required to activate naive immune cells?

Answer 7

1. Antigen receptor signal - TCR on T cell to MHC bound peptide on APC
2. Co-stimulation - CD28 on T cell with B7 (CD80 and CD86) on APC
3. Polarising cytokine signals - released by APC to determinete type of effector response

Question 8

What is the role of the different type of T cells in launching a response against cancer?

Answer 8

CD4+ - help prime CD8 T cell response and formation for CD8 memory

CD8+ - killing cancer cells, granzyme, perofin and death ligands.

Question 9

Define tumour associated antigens?

Answer 9

Antigens unusually highly expressed on cancer cells compared to normal cells

Question 10

Define tumour specific antigens

Answer 10

Only found on cancer cells (neoantigens) result of somatic mutations

Question 11

What antigens are commonly associated with cancer?

Answer 11

Cancer testis antigens - previously found in testes, immune system previously ignorant
Viral antigens - HPV early proteins, virus was oncogenic trigger

Question 12

Why is the tumour peptidome important to cancer immunosurveillance?

Answer 12

Is what proteins the tumour produces
Changes across time within an individual and can be different between individuals with same cancer

Question 13

How to cancer cell evade detection from the immune system?

Answer 13

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

Question 14

What is the tumour microenvironment?

Answer 14

Highly heterogeneity
‘Ecosystem’ of tumour and surrounding immune cells, stroma and blood vessels.

Question 15

What immune components are typically found in the tumour microenvironment?

Answer 15

Cytotoxic T cells
Helper T cells
Regulatory T cells
Macrophages
Myeloid derived suppressor cells
Cytokine milieu -> what and proportion of cytokines present

Question 16

What affects how immunogenic a tumour is?

Answer 16

Low or high number of mutations
Number of tumour infiltrating lymphocytes
Proportion of immune subsets (Th1 v reg, M1 v M2, NK etc)

Question 17

What is the basic principle of the aim of immunotherapy against cancer?

Answer 17

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

Question 18

What is the general concern with immunotherapy?

Answer 18

Turn of immunoregulatory mechanism
Leads to increased response to self antigens, high levels of inflammation and damage to host tossues.

Question 19

What is the role of Rituximab against cancer? (basic)

Answer 19

Targets CD20
Treatment for non-Hodgkin lymphoma

Question 20

What is the role of rituximab against cancer?

Answer 20

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.

Question 21

What is the role of Trastuzumab (herceptin) in the treatment of cancer?

Answer 21

Targets HER2
Treatment of HER2-positive breast cancer
Blocks dimerisation and signalling - inhibits receptor signalling hence cell proliferation

Question 22

What are immune checkpoint inhibitor drugs?

Answer 22

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.

Question 23

What is important in practice for the use of Immune checkpoint inhibitor drugs against cancer?

Answer 23

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)

Question 24

What is the purpose of ipilimumab in cancer treatment?

Answer 24

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

Question 25

What is the purpose of nivolumab and pembrolizumab in cancer treatment?

Answer 25

Block PD-1 (receptor) NSCLC with PD-L1 >50% tumour proportion PD-1 found on surface of immune cells, ligand turn off immune cells

Question 26

What is the purpose of atezolizumab, avelumab, duravalumab?

Answer 26

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

Question 27

What is the role of CTLa-4 in the immune system?

Answer 27

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

Question 28

How can resistance to immune checkpoint inhibitor therapy arise?

Answer 28

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

Question 29

What is a key side effect os a strong response to ipilimumab?

Answer 29

Vertiligo

Question 30

What is the role of PD-1 in the immune system?

Answer 30

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

Question 31

What is important to know about checkpoint inhibitor therapy side effects?

Answer 31

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

Question 32

What are some common viruses associated with their respective cancers?

Answer 32

EBV, HBV, HCV HIV and HPV Kaposi sarcoma in AIDs Hodkgins and EBV Liver and HBV > HCV

Question 33

How does HPV lead to cervical cancer?

Answer 33

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

Question 34

What HPV vaccination programme exists?

Answer 34

2008 - 12/13yrs females UK 2019 - 12/13yrs males UK 2012 changed from cervarix to gardasil vaccine

Question 35

What is the Imlygic (T-VEC) vaccination for cancer?

Answer 35

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

Question 36

What can be done to improve the efficacy/safety of immune checkpoint inhibitor therapy in cancer?

Answer 36

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)