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Module 3 > Immunotherapy in Haematological cancers > Flashcards

Immunotherapy in Haematological cancers Flashcards

1
Q

What is the indirect evidence that there is cancer immunosurveillance?

A

primary immunodeficiency results in high risk of cancer; acquired immunodeficieny-organ transplants and HIV increases risk; tumour infiltration by immune cells correlates with outcome; antibodies and T cells have been foudn specific for cancer somatic mutations; cancers accumulate mutations to evade immune response and secrete immunosuppressor cytokines

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2
Q

Which primary immunodeficiencies are linked to high risk of cancer?S

A

CVID; SCID-mice

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3
Q

Give examples of increased cancer risk in organ transplants?

A

10-30x risk of non-melanoma skin cancer; x12 lymphoma

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4
Q

Give examples of HIV-1 influencing cancer risk?

A

oncogenic viruses- Kaposi’s sarcoma; lung cancer incidence doubles with low CD4 coutn

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5
Q

Give an example of the adaptive system being specific for cancer neo-antigens?

A

autologous IgG have been foudn for >2000 neoantigens; CD8 cells against BCR-ABL1 protein in CML

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6
Q

What mutations do cancer cells accumulate to evade the immune response?

A

downregulation or mutation of MHC-I; mutations in beta-2 macroglobulin; downregulation of CD1d

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7
Q

What is the function of CD1d?

A

presentation of lipid antigens to NKTs

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8
Q

What immunosuppressive cytokines do cancers secrete?

A

IL-10 and TGFb

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9
Q

What receptor do NK and T cells express to eliminate premalignant cells?

A

NKG2D

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10
Q

When is NKG2D upregulated?

A

UV and oncogene, polymorphism in it relates to high cancer rates

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11
Q

What are the steps of cancer immunoediting?

A

Elimination; equilibrium and escape

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12
Q

How does allogenic stem cell transplantation work in cancer therapy?

A

give chemotherapy to reduce tumour and immune cells than give donor cells which recognise malignancy as target

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13
Q

What immune effect does alloSCT harness?

A

graft vs leukaemia effect

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14
Q

What is the evidence that there is graft vs leukaemia effect?

A

T cell depletion increases relapses rates; donor lymphocyte infusion can eliminate minimal residual disease or treat relapse- as can reducing immunsuppression

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15
Q

What are the different types of immunotherapy for haematological cancers?

A

vaccines; monoclonal antibodies; CAR T cells; checkpoint inhibition; alloSCT

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16
Q

What determines that clinical efficacy of monoclonal antibodies?

A

target specificity and humanised Mabs

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17
Q

What cells express CD52?

A

all lymphocytes

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18
Q

What are the mechanisms of action of anti-CD20 mAbs?

A

ADCC; complement dependent cytotoxicity; direct cytotoxicity; adaptive cellular immunity

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19
Q

How does anti-CD20 cause direct cytotoxicity?

A

induction of programmed cell death via a lysosomal pathway after homotypic adhesion

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20
Q

How does anti-CD20 cause adaptive cellular immunity?

A

debris from increased dead cancer cells is taken up by APCs and presented to effectors- ?vaccination effect

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21
Q

What cells express FcR and are involved in ADCC?

A

macrophages and NK cells

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22
Q

What is the effect of rituximab in B cell lymphomas?

A

adding rituximab to CHOP therapy increases overall suvival by 13% at 5 years

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23
Q

Aside from use as chemoimmunotherapy , how else is rituximab used in haem cancers?

A

maintenance therapy- longer remission and deeper repsonses over time

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24
Q

What is rituximab used for in haematology generally?

A

ITP and AHA

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25
Q

What AI diseases is rituximab used for?

A

RA; vasculitis; renal disease; EBV infection and post transplant lymphoproliferative disease

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26
Q

What is the fully humanised version of anti-CD20?

A

ofatumumab and obinutuzumab

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27
Q

What is the anti-CD52 agent?

A

alemtuzumab

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28
Q

When is alemtuzumab efficacious and what paradigm does this present?

A

effective in chemotherapy CLL with certain mutations adn demonstrates the use of immunotherapy in chemo-resistant disease; graft T cell depletion in SCT

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29
Q

What are the benefits and disadvantages of using alemtuzumab in conditioning for SCT?

A

minimises risk of GvHD but increases infections and risk of relapse

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30
Q

What marker is strongly expressed in plasma cells?

A

CD38

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31
Q

What mAb is used for multiple myeloma?

A

daratumumab

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32
Q

What is the efficacy of daratumumab in multiple myeloma?

A

36% patients with refractory disease respond; in combination with chemo improves progression free survival at 1 year from 60 to 83%

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33
Q

How is elotuzumab thought to work?

A

ant-SLAM7 which may prime NK cells to attack myeloma ; ADCC

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34
Q

Give an example of a toxin conjugate mAb?

A

brentuximab vedotin

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35
Q

What does brentuximab target?

A

anti-CD30 with a microtubule disrupting agent attached

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36
Q

What is brentuximab used for?

A

relapsed lymphoma- CD30+ T cell lymphoma and relapsed HL

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37
Q

What are bispecific T cell engager antibodies?

A

have 2 specificities e.g anti-CD3 and anti-CD19- one part will stick to tumour cell and then also bind to T cells and activate them

38
Q

What is the name for anti-CD3-anti-CD19 bispecific antibody?

A

bilatumomab

39
Q

What is bilatumomab used for?

A

acute lymphoblastic leuakaemia

40
Q

What is the benefit of CAR-T cells?

A

they aren’t dependent on MHC

41
Q

What is a disadvantage of CAR T cells?

A

only target cell surface antigens ; requires patient to have enough lymphocytes; cytokine storm; neurotoxicity; myelosuppression

42
Q

What is found in the endodomain of CARs?

A

activator molecules from the TCR e.g the xeta chain as well as co-stimualtory molecules

43
Q

What is found on the extracellular domain of CARs?

A

Fab portion of hte antibody

44
Q

What is usually the vector for creating CAR T cells?

A

lentiviruses

45
Q

Why does there need to be host conditioning before CAR-T cell therapy?

A

to reduce the immunoreaction against the CAR T cells as they cause strong immune reaction

46
Q

When have CAR T cells been shown to be effective?

A

anti-CD19 CAR-T cells have induced complete remission in 70-85% of patients with relapsed/refractory B cell acute lymphoblastic leukaemia; durable response in refractorydiffuse large B cell lymphoma in 40%

47
Q

What antigen have CAR T cells been targeted against for multiple myeloma?

A

B cell maturing antigen - specific for plasma cells

48
Q

Give an example of a malignancy where there are CTLA-4 polymorphisms?

A

myeloma

49
Q

What malignancies over express PD-L1?

A

solid tumours; myeloma; HL

50
Q

Give an example of an anti-PD1 mAb?

A

nivolumab

51
Q

What cancers is nivolumab used in ?

A

melanoma; squamous non-small cell lung cancer ; renal cell carcinoma; HL

52
Q

Is there not a problem with rituximab reducing B cell function?

A

doesn’t appear to cause clinically significant normal B cell and antibody depletion (CD20 not expressed on plasma cells)- only if repeated courses is there a risk of recurrent infection

53
Q

Why are yd T cells effective in anti-tumour effects?

A

potently cytotoxic and produce IFNy

54
Q

What do the non-redundant role of yd T cells in host protective responses result from?

A

combination of unique antigen specifities; high clonal frequencies and a pre-activated differentiation status that allows for very rapid repsonses

55
Q

What are the 2 subsets of yd T cells made in the mouse thymus?

A

IFNy producing and IL-17 producing

56
Q

What have recent reports suggested about the role of IL-17 producing yd T cells in cancer?

A

tumour-promoting in both mouse and humans

57
Q

What are hte main determinants of yd T cell tumour recognition?

A

yd TCR; NK cell receptor- NKG2D

58
Q

How does IFNy production enhance tumour cell clearance?

A

induces upregualtion of MHC-I and enhances CD8 reposnes; inhibits angiogenesis

59
Q

What is the function of IL17 in tumour promotion?

A

recruits immunsuppressive cells e.g MDSCs or small macropahges which can rpomote angiogenesis, tumour cell grwoth and iTreg differentation

60
Q

How are yd T cells generally split?

A

according to the Vy chain they use

61
Q

How was the role of yd T cells during tumour development inferred?

A

comparing tumour progression in yd T cell-deficient mice and wild type mice

62
Q

From mouse KO studies of yd T cells, what was foudn about their role in tumour development?

A

yd T cell prevented the chmical induced development of papillomas and their progression into squamous cell carinomas; protective against spon B cell lymphoma nad prostate whilst ab T cells promoted tumour progression

63
Q

What does the antitumour cytoxocity of skin resident yd T cells rely on?

A

both TCR and NKG2D expression

64
Q

What demonstrates the importance of NKG2D in tumours?

A

high cancer susceptbility in NKG2D deficient mice

65
Q

What is the function of NKg2d?

A

senses molecular stress signatures that are upegulated on transformed cells

66
Q

How do yd T cells carry out effector functions ?

A

release perforin and granzymes; express CD95L and TRAIL that engage death receptors; secrete IFNy

67
Q

What surface marker correlates with either IFNy or IL17 production in yd T cells?

A

CD27+ secrete IFNy whilst CD27- secrete IL17

68
Q

Although some studies have suggested a dentrimental effect to IL-17 producing yd T cells, when have they been shown anti-tumour?

A

cooperate with BCG vaccination to mediate bladder cancer regression (recruited antitumour neutrophils to the bladder)- which didn’t happen in yd defieint and IL-17 deficient mice

69
Q

What cancers have been domsonatrated to show reduced grwoth in yd T cell deficient mice and IL-17 deficient mice?

A

breast cacner mets and pancreatic intraepithelial neoplasia - correlates with increased angiogenesis due to increased VEGF

70
Q

Give examples of how MDSCs act in a protumour way?

A

inhibit IFNy and CD8 T cell cytotoxicity

71
Q

Where are yd T cells found in humans?

A

intestine and dermis

72
Q

What do IL-17 producing yd T cells secrete that recruit MDSCs ?

A

IL-8; TNF and GM-CSF

73
Q

How is IL-17 yd t cells related to human colorectal cancer?

A

major sourceo f IL-17 invovledi n chronic inflammation; IL-17 producing yd T cell infiltration positively correlated with clinical stage

74
Q

What causes human yd T cells to produce IL-17?

A

reqruire a highly inflammatory milieu

75
Q

Why is the concept of boosting type 1 cytotoxic yd T cells in patietns with cancer appealing?

A

indendent of MHC (tackles a common immune evasion mechanism) and of mutated epitopes (ideal effectors against tumours with low mutation loads)

76
Q

Why are bisphosphonates given before yd T cell therapy?

A

interfere with phosphoantigen processing enzymes so increase the intracellular levels of them

77
Q

What may limit the clinical performance of yd T cells in cancer therapeutics?

A

susceptibility to T cell exhaustion and activation induced cell death

78
Q

What may the cause of increased IL-17 yd T cell in human colon cancer?

A

tumour-induced disruption of the piethlail barrier may induce release of commensal bacterial products leading to activation of DCs, production of IL-23 and differenation into IL_17 yd T cells

79
Q

What is the name for the CTLA-4 mAb ?

A

ipilumumab (licensed for melanoma)

80
Q

What was the problem with the early vaccine formulation using short peptides?

A

minimal clinical effectivenness- poor pharmacokinetics leading to rpaid lcearance before DCloading; didn’t have an effective DC activating adjuvant- just as likely to induce tolerance as immunity

81
Q

What are the ideal tumour antigens for vaccination?

A

expressed in the target tumour population in a high number of patients with a cancer; expressed at low levels in normal tissues and should be essential for cancer survival to mimised immune escpe

82
Q

How does onclytic virus therapy work?

A

employs native or engineered viruses that selectively replicate in and kills cancer cells

83
Q

What are the mechanisms by whch oncolytic viruses function?

A

acute tumour debulking due to tumour cell infection and lysis, induction/initiation of systemic anti-tumour immunity- can be modified to express specific cytokines that favour immune cell recruitment or produce T cell costimuatlry moelcules on infected tumour cells

84
Q

How can the oncolytic viruses avoid immune killing before they can replicate and infect tumour cells?

A

PEGylation of the viral coat and polymer coating-preventing antibody binding and neutralisation

85
Q

What oncolytic virus has been approved by the FDC?

A

T-VEC- modified HSV-1 for advanced melonoma

86
Q

What are the downsides with oncolytic therapy?

A

immunocompromised patients may not be good candidates as OV-mediated antitumour immunity could be compromised; efficacy in advnaced

87
Q

What is the theory behind adoptive cell therapy?

A

circumvent the duty of breaking tolerance to tumour antigens and produce a large amount of high avidity effector T cells

88
Q

When ahve autologous TIL infeusions been successful?

A

melanoma

89
Q

Why is host lymphodepletion thought to improve ACT with TILs?

A

elimiates immunosuppressive cells- Tregs; MDSCs in tumour microenvironemnt and increasing IL-7 and IL-15

90
Q

Why is there a high immunogenicity of melanoma compared with otehr malignancies?

A

high frequency of mutational events in the cancer

91
Q

What are hte problems with TIL ACT?

A

cost; time; lymphodepletion can be life-threatening; only been efficacious in melanoma

Module 3 (33 decks)

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