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Immunology > Immunotherapy > Flashcards

Immunotherapy Flashcards

1
Q

what is imunotherapy

A

the use of the patient’s own immune system to fight disease (cancers/chronic viral infections)

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2
Q

what therapies give a a significant advance in cancer treatment beyond traditional treatment (chemotherapy, radiotherapy and surgery)

A

Immuno-oncology therapies

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3
Q

why should patients be treated as early as possible with immunotherapy

A

as this will be before the immune system has selected for highly-resistant variants as over time, tumours become resistant to the immune system

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4
Q

what do immunotherapies recognise - unlike in autoimmune disease where IS can attack own cells

A

recognises an antigen that is dissimilar to the host

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5
Q

what response do Immunotherapies induce when engaging and recruiting the immune system to combat disease

A

an antibody generation response against a specific antigen (foreign entity) typically present on the cell surface of a virus or cancer cell.

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6
Q

what are immunotherapies directed at

A

A specific antigen/cluster of antigens that compose the unique signature of a virus or cancer cell that is dissimilar to its host thus recognizing self from non-self.

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7
Q

2 reasons immunotherapy success is dependent on tumour load first being reduced

A

Immune system cannot cope with large tumours

Lots of antigen shedding would stimulate the regulatory T-cells (stop immune response against tumour)

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8
Q

what is the most promising area of immunotherapy (targetting cell-surface component s of tumour cells)

A

Humanized monoclonal antibodies

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9
Q

how do antibodies reacting with antigens on the surface of tumour cells protect the host

A

by complement mediated opsonization and lysis and also through recruitment of macrophage and NK ADCC

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10
Q

what do The FcR cells act as and do

A

act as cytoxic effectors

cause crosslinking of antibody coated cells which leads to apoptosis or exit from the cell cycle, and makes the cells sensitized to irradiation and DNA damaging chemotherapy

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11
Q

3 things unmodified naked antibodies to

A

inhibit functions of signalling receptors so stop tumour growth (like neutralisation during infection)

Promote opsonisation of tumour cells and their phagocytosis (complement mediated lysis recruitment of macrophage)

Opsonisation of tumour cells also causes their destruction by NK ADCC, apoptosis and sensitization (chemo and radio)

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12
Q

what are modified antibodies called

A

immunoconjugates (a tumour targeting antibody linked with a toxic effector component) - such as radioisotope, toxin or small drug molecule

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13
Q

How many humanized or fully human monoclonal antibodies and immunotoxins were approved by the US Food and Drug Administration by the end of 2019 for use in cancer

e.g.

A

More than 20

e.g. MAb approved for HER2 in breast cancer, CD20 in lymphoma, EGF in colorectal cancer

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14
Q

what do Therapeutic antibodies do to tumour cells to activate the NK cell to kill tumour cell (antibody-mediated cell-mediated cytotoxicity)

A

coat a tumor cell with their Fc regions pointing away from the cell.

These engage the FcγRIII receptors on an NK cell.

Signals from the receptors activate the NK cell to kill the tumor cell

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15
Q

what were monoclonal antibodies originally produced using - makes them very useful for treating a broad range of clinical conditions.

A

mouse hybridomas-
Specificity of mouse monoclonal antibodies

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16
Q

problem when mouse monoclonal antibodies are introduced into humans

A

Recognised as foreign, and evoke an immune response known as the HAMA response. human anti-mouse antibody quickly clears the mouse monoclonal antibodies. This reduces efficiency of the treatment

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17
Q

2 other complications from introducing mouse monoclonal abs into humans

A

allergic reactions

the accumulation of mouse and human ab complexes in organs such as the kidneys which can cause life threatening problems.

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18
Q

2 main ways of making mouse monoclonal abs more like those from humans

A

Design and construct genes to clone the promoter, leader and variable region from a mouse ab gene, and constant region exons from a human ab gene (a mouse human chimera - chimeric ab) -
is partially humanised.

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19
Q

e.g of a chimeric ab that is used for treatment in non-Hodgkin’s lymphoma.

A

rituximab - targets CD20 of the B cells in non-Hodgkin’s lymphoma. A human anti-chimeric antibody response (HACA) is observed.

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20
Q

CDR grafting and what does it involve

A

now possible to engineer abs in which all of the sequence is human except the CDRs

involves the substitution of non-human cdr domains from a mouse ab into the most closely related human ab sequence available, so that only the cdr domains are non-human.-this is a fully humanized ab

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21
Q

2 advantages of humanized abs due to CDR grafting

A

retain the biological effector functions of human antibody and are more effective than mouse abs in triggering complement activation and fc receptor mediated processes such as phagocytosis in humans.

Less immunogenic in human than mouse-human chimeric abs

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22
Q

what is mouse abs half-life compared with the half lives of their human or humanized counterparts - this is another advantage to humanising abs

A

very short half-life of a few hours compared to 3 weeks of human/humanised counterparts

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23
Q

why have technological developments been undertaken so that fully human antibodies are produced by engineering the Ig loci, rather than components within the Ig molecule.

A

as chimerization and humanization of abs are labour intensive procedures, involving sequence analysis, engineering approaches, analysis and optimization of binding affinity, and evaluation of immunogenicity for each ab.

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24
Q

how are fully human Ig produced in mice by antibody engineering

A

Mice Ig H and L loci removed (Knockout mice)

Embryonic stem cells from KO - from blastocyst and
HAC (human artificial chromosome) containing human Ig H and L loci - transfected into ES cells.
Transgenic mice that produced human Ig

Can make hybridomas that produce human Ig from mice

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25
Q

after Human artificial chromosome gets transfected into ES cells what happens to the modified ES cells

A

they get put back into a blastocyst and transplanted into surrogate mothers. The B cells of the offspring produced human abs in response to antigen.

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26
Q

whats the transgenic mice response useful for

A

producing large quantities of human abs

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27
Q

2 drugs produced using human Ig in mice production

A

Panitumab - approved for tx of metastatic colorectal cancer

Zanolimumab (lymphoma) - in phase III trials for t-cell lymphoma

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28
Q

how many deathscausedbyskin cancer does melanoma account for

A

75%

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29
Q

what did James Allison study

A

a known protein that functions as a brake on the immune system. He realized the potential of releasing the brake, unleashing our immune cells to attack tumours. He then developed this concept into a brand new approach for treating patients

30
Q

what did James Allison study

A

a known protein (CTLA-4) that functions as a brake on the immune system. He realized the potential of releasing the brake, unleashing our immune cells to attack tumours. He then developed this concept into a brand new approach for treating patients

31
Q

what did Tasuku Honjo discover

A

a protein expressed in dying T cels (PD-1) which is also a brake, but with a different mechanism of action. Therapies based on his discovery proved to be strikingly effective in the fight against cancer.

32
Q

what did KEYTRUDA (PD-1 inhibitor) result in with melanoma

A

3 year survival of metastatic melanoma patients 40%, whereas previously survival was measured in months

33
Q

what was KEYTRUDA approved as first line treatment for (whose tumours express PD-L1 at >50%, and other cancers)

A

advanced non small cell lung cancer (NSCLC)

34
Q

when was KEYTRUDA FDA approved as the first cancer treatment for any solid tumour

A

May 2017

35
Q

5 cancers keytruda (pembrolizumab) is approved to treat

A

melanoma
non-small cell lung cancer
colon/rectal cancer
cervical cancer
renal cell carcinoma

36
Q

what do monoclonal antibodies as Immune Agonists drugs target

A

specific cell surface proteins on T cells, causing stimulation of T cell activity

37
Q

where is the target for therapeutic antibodies CD30 found

A

on the surface of anaplastic large cell lymphoma tumour cells (T cell lymphoma) or Hodgkins lymphoma

38
Q

What does the anti-CD30 antibody brentuximab coupled to the cytotoxic drug auristatin (brentuximab–vedotin) help prevent and do

A

Prevents mitosis and induces the tumour cell to die by apoptosis - after ab has attached the conjugate to the surface of the tumor cell, the conjugate is internalized into endosomes, where cathepsin cleaves the linker and releases the auristatin. This drug passes to the nucleus and binds to microtubules which prevents them from forming a mitotic spindle.

39
Q

One advantage ofimmunotoxinsoverconventional
chemotherapy

A

thetoxin’sdestructive
powerisspecifically
targetedatthetumourandawayfromhealthyproliferatingtissues.

40
Q

why must Auristatinonlybeadministeredwhenconjugatedtoanantibody

A

as its so toxic

41
Q

what are Bispecific T cell engager (BiTE®) Antibodies designed to do to cancer cells

A

bridge cancer cells to CTLs

42
Q

what does Adoptive T cell transfer involve doing outside of the body (ex vivo)

A

generating large numbers of T cells, outside the body

43
Q

What are the isolated T cells genetically engineered to do in adoptive t cell transfer

A

to produce cytokines such as IL-2, which will boost their activity.

44
Q

how are the t cells expanded in vitro in adoptive t cell transfer, before being put back into the patient

A

in vitro stimulation with antigen-presenting cells

45
Q

what are CAR—chimeric antigen receptors

A

genetically engineered protein constructs which can be incorporated into a patients own cytotoxic T cells to try to help them recognise and fight cancer cells

46
Q

how is CAR T cell therapy provided

A

by removing/harvesting T cells from a patient with cancer

Transfecting cells with CAR genes which are directed against patient’s tumour type to expand the modified T cell population

reinfusing cells back into patients

47
Q

what was one CAR T-cell therapy approved to treat in 2017

A

children with acute lymphoblastic leukemia (ALL)

48
Q

what type of cell are dendritic cells

A

type of antigen presenting cells

49
Q

how do dendritic cells induce an adaptive immune response

A

they take up antigen and present it on MHC class II to T cells

50
Q

dendritic cell vaccine process

A

Peripheral Blood mononuclear cells (Monocytes, NK cells and lymphocytes) are isolated from patient’s blood

Dendritic cell progenitors are negatively selected using magnetic beads (CD3, CD11b, CD16)

These cells are cultured in the presence of the growth factors GM-CSF and TNFa for 9 days.

Tumour cells from the patient or tumour specific antigens are added to the cells and they are re-infused back into patient (stimulates adaptive IR)

51
Q

E.g of a cancer subunit vaccine given in USA since 1982 to healthcare professionals

A

Hep B subunit vaccine - prevents liver cancer (hepatic carcinoma)

52
Q

how many deaths from cervical cancer does HPV cause worldwide per year prior to vaccination

A

250,000 deaths

53
Q

what 2 types of HPV are responsible for 70% cases

A

HPV-16, HPV-18

54
Q

whats the HPV vaccine called in the NHS programme

A

Gardasil

55
Q

4 types of HPV gardasil protects against

A

HPV6
HPV11
HPV16
HPV18

56
Q

What is research being undertaken to develop a vaccine for

A

exploit the ability of CTLs to target EBV-related antigens on the cells of all Burkitt lymphomas

57
Q

advantage of immunization with whole tumour cells

A

do not need to have identified the tumour antigen

58
Q

disadvantage of immunisation with whole tumour cells

A

most tumours are weakly immunogenic, and do not present antigen effectively and so cannot overcome the barrier to activation of resting T cells

59
Q

what does Antigen independent cytokine therapy use cytokines such as IL-2, interferon and TNF to do

A

boost the immune system non-specifically (ie not in an antigen dependent manner).

60
Q

what patients has interleukin treatment been used on (high doses of IL-2)

A

patients with metastatic melanoma or kidney cancer

61
Q

what was observed in 15-20% of patients who had interleukin treatment

A

at least partial tumour regression in 15-20%. Some patients displayed complete regression - maybe due to stimulation of pre-existing t cells/due to NK activation

62
Q

what is the only drug so far which has generated long-term responses in metastatic melanoma and metastatic renal cell carcinoma

A

Proleukin (high dose recombinant IL-2)

63
Q

What treatment has generated good clinical trial responses with a massive response rate of 80-90% in hairy cell leukemia

A

interferon alpha and beta treatment

64
Q

What do colony-stimulating factors do that has worked in mice e.g granulocyte-macrophage colony-stimulating factor (GM-CSF)

A

induce tumour cell differentiation and suppress tumour growth

65
Q

why may in vivo expansion and transfer of large numbers of activated NK cells be beneficial

A

as NK cells are important in tumour surveillance and killing

66
Q

what have trials shown, regarding NK cell numbers and drug administration

A

daily administration of low-dose IL-2 after high-dose chemotherapy expanded NK cell numbers

67
Q

why were NK cells from related haploidentical donors given to acute myeloid leukaemia patients in a trial

A

to achieve a partial mismatch between donor NKs and recipient that could provoke NK activation and more tumour kill (5/19 patients went into complete remission)

68
Q

targetting what should deprive the tumour of oxygen and nutrients, causing regression.

A

target the antigens expressed in the blood vessels

69
Q

what are leukaemias treated by which is classed as immunotherapy

A

bone marrow transplantation (bone marrow removal and replacement)

70
Q

5 e.gs of diseases BMTs can treat people with

A

acute leukaemia
aplastic anaemia
chronic leukaemia
hemoglobinopathies
hodgkin’s lymphoma
immune deficiencies

71
Q

what does allogeneic BMT involve

A

transplantation of bone marrow from a reasonably compatible MHC donor - results in graft versus leukaemia effect

72
Q

what is graft versus host disease (complication of allogeneic BMT)

A

graft also launches an attack on the recipient

Immunology (13 decks)

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