Introduction to Tumour Immunology

Question 1

What is ipilimumab?

Answer 1

mAb against CTLA-4

Question 2

What was the efficacy of ipilimumab for metastatic melanoma with one round of treatment?

Answer 2

more than 20% of patients were alive 10 years later with no evidence of disease vs survival or <10%

Question 3

What is nivolumab?

Answer 3

mAb against PD-1 receptor

Question 4

What is the response rate of nivolumab in metastatic melanoma?

Answer 4

50%

Question 5

what has suggested that the immune system plays a major role in neoplastic development?

Answer 5

patients who are immunsuppressed have a higher risk of cancer and spontaneous regression is rare but well recognised phenomenon- esp. after infectious and/or high febrile episode

Question 6

What was the first use of modulating hte immune system to treat cancer?

Answer 6

notice of the regression of tumours in cancer patients after erysipelas then intentional infection of cancer patients

Question 7

How was the the bacterium BCG used in cancer treatment?

Answer 7

effective against superficial bladder cancer

Question 8

What are Coley’s toxins?

Answer 8

injection of heat-inactivated bacteria into patients with inoperable cancers

Question 9

What are the non-self antigens that that cells use to recognise cancer cells?

Answer 9

tumour-associated antignes

Question 10

Give examples of tumour-associated antigens?

Answer 10

products of mutated proto-oncogenes; tumour suppressor genes; overexpressed or aberrantly expressed proteins; tumour antigens produced by oncogenic viruses, altered glycolipids and glycorproteins

Question 11

What was the first experiment of evidence of immune response to cancer?

Answer 11

a mouse with chemically induced sarcoma had the tumoue resected then retransplanted which resulted in tumour rejection, but if given to naive genetically identical mouse, develops tumour, if give CTLs from original mouse, gets rid of tumour

Question 12

What demonstrated that immune responses in cancer associated with prognosis to cancer?

Answer 12

presence of tumour infiltrating lymphocytes resulted in better prognosis; with Tregs associated with worse prognosis

Question 13

What are the hallmarks of cancer?

Answer 13

sustained proliferative signalling; evading growth suppressors; activating invasion and mets; enabling replicative immortality; evasion of cell death and induction of angiogenesis; avoidance of immune destruction

Question 14

What are the enabling characteristics of cancer?

Answer 14

genome instability and mutation; tumour-promoting inflammation

Question 15

What are tumour associated antigens?

Answer 15

over-expressed normal genes; products of mutated genes; extopic expression of normal gene products; abnormally glycosylated proteins; viral gene products; novel products of chromosomal instability

Question 16

What are hte major mechanisms by which CTLs kill target cells?

Answer 16

perforin/granzyme and Fas/FasL

Question 17

What are the stages of the cancer-immunity cycle?

Answer 17

release of tumour-associated antigens; cancer antigen presenation; priming and activation of T cells; trafficking of T cells to tumours; infiltration of T cells into tumours; reconigiton and killin

Question 18

What reduces infiltration of t cells into tumours?

Answer 18

VEGF; enfothelin B receptor

Question 19

What prevents recognition of cancer cells by T cells?

Answer 19

reduced p/MHC on cancer cells

Question 20

How do traditional cancer drugs contribute to the cancer immunity drugs?

Answer 20

kill tumour cells releasing tumour-associated antigens

Question 21

What are the stages of cancer immunoediting?

Answer 21

elimination through the cancer-immunity cycle which then provides immune pressure for cells not expressing p/MHC in the equilibrium stage and then escape

Question 22

Waht si the goal of cancer immunotherapy?

Answer 22

initiate or reinitiate a self-sustaining cycle of cancer immunity enabling it to amplify and propagate but not so as to create n unrestrained autoimmune inflammatory response

Question 23

Waht can enhance priming and activation in the cancer immunity cycle?

Answer 23

anti-CTLA4

Question 24

What can enhance infiltration of T cells into tumours?

Answer 24

anti-VEGF

Question 25

What can enhance recognition of cancer cells by T cells?

Answer 25

CARs

Question 26

What can enhance immune killing of cancer cells?

Answer 26

anti-PD-1; anti-PD-L1 and IDO inhibitors

Question 27

What is the cancer immunosurveillance hypothesis?

Answer 27

the immune system is capable of detecting and killing nascent non-self malignant cells

Question 28

What is the equilibrium phase of cancer immunoediting?

Answer 28

when any tumour cells survive the initial elimination attempt but are not able to progress

Question 29

How does the immune system regulation contribute to cancer progression?

Answer 29

upregulation of immune checkpoint molecules on their surfaces due to cytokine produced by activated T cells- part of normal negative feedback to control excessive tissue damage from inflammation

Question 30

What provided the proof that the immune system was capable of seeking and destroying tumour cells and identified the first molecular target?

Answer 30

first human tumour antigen : melanoma antigen-encoding gene encoding an antigen recognised by CTLs

Question 31

What are the main ways of evasion of the immune destruction by cancer cells?

Answer 31

modulates its own cellular characteristics and creating its own tumour microenvironment by recruiting normal immune cells to shield it from attack

Question 32

What immune cells do cancers recruit to shield it from the immune repsonse?

Answer 32

macrophages; Tregs; immature myeloid cells (which become myeloid-derived suppressor cells); Th17; Bregs

Question 33

How do tumours create pre-metastatic niches?

Answer 33

influence the systemic environment through cytokines by altering haematopoiesis and tissue parenchyma of distant organs

Question 34

What is the cancer immune set point?

Answer 34

intrinsic immunological ability of an individual to comabt cancer

Question 35

What is the only therapeutic vaccine for cancer licensed?

Answer 35

DC vaccine for prostate carcinoma

Question 36

How is the prostate cancer vaccin created?

Answer 36

DCs from the patient are exposed to prostatic acid phosphatase and GM-CSF and re-infused into the patietn

Question 37

What is the goal of all tumour vaccines?

Answer 37

exposure of patients immune system to tumour antigens provoking an anti-tumour immune repsonse

Question 38

How does BCG vaccination treat bladder carcinoma?

Answer 38

indirectly increases the expression of tumour antigens after the tumour cells internalise the bacteria

Question 39

What is the function of oncolytic viruses?

Answer 39

genetically modified viruses to lack virulence against normal cells but are able to invade and lyse cancer cells (releasing tumour antigens )which have sacrifieced many anti-viral cellular defnses in order to increase growth potential

Question 40

What oncolytic virus has been approved?

Answer 40

HSV-1 virus against advanced melanoma

Question 41

What has allowed a much simpler and efficient method of gene editing for use in adoptive cell therapy?

Answer 41

CRISPR/Casp9 technique

Question 42

What is a problem with adoptive cell therapy?

Answer 42

deaths due to cytokine storm and cerebral oedema

Question 43

What is the first disease to receive approval for CAR T cell therapy?

Answer 43

relapsed and refractory B cell ALL

Question 44

When was T cell exhaustion first observed?

Answer 44

in mice infected with a chronically persistent strain of lymphocytic choriomeningitis virus

Question 45

Waht is the function of T cell exhaustion?

Answer 45

reversible physiologicaly protective mechanism against autoimmunity

Question 46

How does the immune checkpoint LAG-3 work ?

Answer 46

structurally homologos to CD4 but has a higher binding affinity to MHC-II than CD4

Question 47

How can checkpoint molecules be used as markers of T cell exhaustion?

Answer 47

upregulated in suppressed T cells

Question 48

Why is CTLA-4 considered the leader of the immune checkpoints ?

Answer 48

stops potentially autoreactive T cells at the priming stage of naive T cell activation occuring chiefly in the lymph nodes

Question 49

When is PD-L1 upregulated on many cell types ?

Answer 49

after exposure to IFNy

Question 50

Why are immune checkpoint inhibitors an exciting model?

Answer 50

less toxic than conventional therapies and much easier to prepare and administer than other cancer immunotherapeutics

Question 51

What was the result of a phase I trial of an antibody to the CD28 ligand?

Answer 51

massive cytokine storm associated with multiorgan failure

Question 52

What is important about the timing of administration of immune checkpoint inhibitors?

Answer 52

to coincide with a high inflammatory microenvironment in the tumoue to ensure presence of many potential tumour-fighting CD8 T cells--tumoue necrosis provoked by chemo; mutational burden of the tumour which has higher antigenicity

Question 53

Give an example of how increased mutational burden in the tumoue improves response to immune checkpoint inhibitors?

Answer 53

lung cancers in smoker have higher mutation burden and show higher reposnse

Question 54

How has the gut microbiota been shown to impact immune checkpoint inhibitors?

Answer 54

patients with metastatic renal cell carcinoma shoed faster tumour progression in patietns who had received broad spec antibiotics a month before treatment with ICIs; differences in gut microbiota in melanoma patients between responders and non-responders

Question 55

Why is cancer immunotherapy particularly active in melanoma?

Answer 55

appears atypically immunogenic

Question 56

Where do the immunogenic signals resulting in immune activation rather than tolerance to tumour-assocaited antigens?

Answer 56

proinflammatory cytokines and factors released by dying tumour cells or by the gut microbiota

Question 57

What created a significant problem in stimulating immune responses against cancers?

Answer 57

local immunsuppressive tumour microenvironment

Question 58

Why are multivalent vaccines more effective than a single antigenic target?

Answer 58

may not generate sufficiently robust T cell repsonses in all patients, if not derived from an inherent oncogenic driver, it will enable resistance by antigenic drift

Question 59

What are CARs?

Answer 59

a patients T cells are transfected with a construct encoding an antibody against a tumour surface antigen fused to T cell signalling domains

Question 60

What underlies the significant immune -related toxicities seen with CTLA-4 inhibitors?

Answer 60

lack of selectivity in T cell expansion and the fundamental importance of CTLA4 as a checkpoint

Question 61

What is the frequency of expression of PD- | L1 across all human cancer?

Answer 61

20-50%

Question 62

What does the efficicacy of the anti-PD-L1 antibodies suggest about the cancer immunity cycle?

Answer 62

it is intact up until the point of tumour cell killing by T cells which can be potently restrained by PD-L!

Question 63

What is the signalling pathway of PD-1?

Answer 63

recuits the phosphatase SHP-2 and inactivates PI 3-kinase

Question 64

Why is the safety profile of PD-L1 inhibitors better than CTLA-4?

Answer 64

many cancer types express PD-L! to inhibit anticancer immune repsonses; most patients do not have underyling autoimmunity inhibited by only DP-L1 expression

Question 65

Who first suggested that the immune system could repress a potentially overwhelming frequency of carcnomas?

Answer 65

Paul Ehrlich

Question 66

How does invasive growth cause pro-inflammatory cytokines to be released?

Answer 66

causes minor disruptions within the surrounding tissue

Question 67

What is the function of CXCL10 and CXCL9 induced by IFNy in the context of tumour growth?

Answer 67

potent angiostatic capacities blocking the formation of new blood vessels in the tumour nad more tumour death