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Module 3 > Cancer Immunotherapy > Flashcards

Cancer Immunotherapy Flashcards

1
Q

What are teh 4 major methods of immunotherapy?

A

stimulate/block components of hte immune system; inject tumour specific immune cells; genetically engineer immmune cells to recognise tumour; deplete immune subsets- Tregs ; MDSC

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2
Q

What are the only 2 cytokine therapies approved?

A

IFNa and IL-2

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3
Q

What cancers is IL-2 used against?

A

metastatic melanoma nad renal cell carcinoma

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4
Q

What is the function of IL-2?

A

activation and expansion of CD4 and CD8 T cells

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5
Q

When is IFNa used in treating cancers?

A

as an adjuvant therapy of stage III melanoma

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6
Q

What is the function of type I IFNs?

A

induce expression of MHC-I; mediates maturation of DCs; activates CTLs

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7
Q

What is the efficacy of cytokine therapy?

A

recent meta-analysis found significant increases in disease free survival and overall survival

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8
Q

Why would IFNa therapy be thought to be particularly good?

A

many cancers switch off this expression in order to evade the immune repsonse

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9
Q

What makes developing a therapeutic cancer vaccination difficult?

A

need to find a protein/peptide that specifically expressed in cancers and not normal cells, however most tumour associated antigens are self-antigens and therefore there is tolerance to them; even if generate good responses, cancers create immunosuppressive microenvironment which is notovercome by the vaccine

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10
Q

What makes peptide vaccination difficult?

A

class I MHC restriction limits relevance of individual peptides to certain HLA types; short peptides may bind directly to MHC on non-professional APCs inducing tolerance; rapidly degraded by proteases

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11
Q

What is the overall response rate for protein/peptide vaccination?

A

3-5%

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12
Q

How many the efficacy of protein/peptide vaccines be improved?

A

combinding with otehr treatments e.g checkpoints inhibitors or once finished cancer treatment

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13
Q

What are the most common carcinogenic HPV types?

A

types 16 and 18

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14
Q

What is the result of HPV infection?

A

causes cellular transformation and leads to changes to a less differentiated cell type

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15
Q

What proteins does HPV cause the production of ?

A

E6 and E7

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16
Q

What is the function of E6?

A

binds and inactivates host p53 which is essential in apoptosis in DNA damaged cells

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17
Q

What is the function of E7?

A

promotes host and viral DNA replication

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18
Q

What are the two forms of monoclonal antibody?

A

naked and conjugated

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19
Q

What are naked mAbs?

A

bind to antigens on tumour cell, other cells in tumour environment or free proteins

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20
Q

What are conjugated mAbs?

A

act as homing devices to deliver radioactive particle, toxin or chemo drug to tumours

21
Q

What is the double-edged sword of the specificity of monoclonals ?

A

reduction in SE profile but antigen identification is important and may differ between cancers

22
Q

What are the 4 methods by which mAbs work?

A

block receptor mediated signalling for tumour cell survival and/or growth; mark the tumour cell fro immune mediated destruction; delivering targeted drugs; blocking immunosuppression pathways

23
Q

What happens when a ligand binds to a growth factor receptor?

A

triggers a dimerisation event and activation of a signalling casacde leading to cellular proliferation and resistance to cytotoxic agents

24
Q

How does mAb block signalling?

A

can occur by blocking the dimerisation event or by interfering with ligand binding

25
Q

What is herceptin used for?

A

to treat HER2 positive tumours in breast and gastric cancers

26
Q

What are the mechanisms of action of herceptin?

A

triggers HER2 internalisation and degradation; marks cells for NK cell attack and inhibits MAPK and PI3K/Akt pathways

27
Q

What is a major problem with herceptin?

A

resistnace develops in virtually all patients

28
Q

What are the mechanisms of cancer resistance?

A

altered target expression ( as cancer progresses de-differentiates); altered target (mutation in receptr); overexpression of other receptors and signalling by alternative pathways- bypassing blockade

29
Q

What are hte 2 benefits of ADCC with mAbs?

A

causes direct killing or tumour cell whilst creating cell debris that can be presented to other immune cells to stimulate immune response against more tumour cells

30
Q

What is rituximab used to treat in cancer?

A

CLL and non-hodgkins

31
Q

What is the response rate to rituximab?

A

48%

32
Q

What are the methods of tumour killingwith rituximab?

A

complement mediated cytotoxicitiy; direct lysis; FcyR/CR-mediated opsonic phagocytosis or ADCC

33
Q

Give an example of an antibody-drug conjugate?

A

Brentuximab vedotin which targets CD30 antigen on lymphocytes attached to a chemotherapy drug

34
Q

How does antibody-directed enzyme prodrug therapy work?

A

mAb enzyme conjugate bind to tumour cell-surface antigen and prodrug adminstered binds to mAb-enzyme conjugate on the tumour cell surface releasing prodrug at highest concentrations in the tumour microenvironment

35
Q

What is the problem with autologous tumour cell vaccine?

A

low cell numbers and not very efficacious

36
Q

How does autologous tumour cell vacine work?

A

remove tumour cells at surgery, treat with radiation to increase immunogenicity and then give back to patietn

37
Q

How have tumour infiltrating lymphocytes been used in cancer immunotherapy?

A

select and expand TILs from biopsies which have not been very repsonsive and is very expensive and labour intensive

38
Q

What are the 2 methods of engineering T cells?

A

genetically insert a TCR specific for a tumour antigen or insert genes encoding a tumour specific chimeric antigen receptor

39
Q

What is the benefit of CAR T cells?

A

they tagret surface antigens in an MHC independent fashion

40
Q

What is the T body in CAR T cells?

A

essneitally an antibody with an intracellular signalling domain

41
Q

Where has there been evidence of CAR persistence?

A

in immunohistochemistry and PCR of bone marrow

42
Q

What is the problem with CAR T cells?

A

can cause cytokine storms and there is no knowledge of the long-term effects

43
Q

When have CAR T cells been used successfully?

A

in treating chronic lymphocytic leukaemia and ALL

44
Q

What solid tumour have CAR T cells been shown to be effective in mice?

A

ovarian tumours

45
Q

What type of antigen do yd T cells recognise?

A

phosphoantigen

46
Q

What are the benefits of using yd T cells?

A

very effective at killing tumour cells; don’t rely on MHC

47
Q

What is the most common subpopulation of yd T cells in humans?

A

Vy9Vd2 T cells

48
Q

Waht is hte function of combination therapies?

A

to increase immune recognition of cancer cells

Module 3 (33 decks)

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