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Cancer > TBL immunotherapy > Flashcards

TBL immunotherapy Flashcards

1
Q

State the four different types of immunotherapy. (the four Cs)

A

Checkpoint inhibitors using monoclonal antibodies
Cancer vaccines
Cytokines
CAR-T cell therapy

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2
Q

What does CAR-T cell therapy stand for?

A

Chimeric antigen receptor (CAR) T cells

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3
Q

What is the aim or purpose of immunotherapy?

A

Enhancing the body’s own immune system to fight off the cancer cells themselves by helping our own immune system recognise and attack cancer cells.

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4
Q

What are some of the effective ways tumour and cancer cells develop to avoid immune destruction?

A

Downregulate MHC-1, no antigens can be presented to T cells
Tumour induces inflammation and anti-inflammatory cytokines can be released suppressing the immune system
Grows too quickly for the immune system to be able to develop a response
Antigenic peptides do not prime the cytotoxic T cells in the correct way
Co-stimulatory molecule for T cell activation is not present

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5
Q

What are neoantigens?

A

They are tumour specific antigens generated and expressed on the surface of tumour cells when they undergo a series of tumour-specific mutations.

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6
Q

What do tumour cells specifically secrete to inhibit T cell activity?

A

Tumour cells secrete specific cytokines such as TGFβ and IL-10 which inhibit T-cell activity.

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7
Q

What is the role CD4+ T cell in the immune response to tumour cells?

A

Enhance CD8+ T cell (cytotoxic T cells) and macrophage response by producing pro-inflammatory cytokines.

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8
Q

Which specific pro-inflammatory cytokines does CD4+ T cells produce?

A

Interferon-γ and tumour necrosis factor (TNF)

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9
Q

What is the role of natural killer cells in the anti-tumour response?

A

Natural killer cells are able to detect the downregulation of MHC-1 in tumour cells and can then target them.

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10
Q

What specific CD8 (+) T-cells are found within humans/ animals with tumours?

A

Tumour specific CD8+ cytotoxic T lymphocytes

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11
Q

What do tumour infilitrating lymphocytes do?

A

Can recognise and kill cancer cells

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12
Q

What are tumour associated macrophages?

A

They are the macrophages found in the tumour-infiltrating leukocyte population and they kill tumour cells like how they would bacterium.

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13
Q

How many signals do T-cells require for activation?

A

Two

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14
Q

Describe the two specific signalling for T-cell activation.

A

The first signal is from the MHC with the TCR The second signal from a co-stimulatory molecule found on T cells which engages with CD80 or CD86 molecules which are expressed by the antigen-presenting cell.

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15
Q

Once both signals are present (T-cells) what happens next?

A

The T-cell growth factor IL-2 is secreted and clonal expansion begins.

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16
Q

Where are CD28, CD80 and CD86 found?

A

CD28 is found on T-cells and they engage with CD80, CD86 which are located on the antigen presenting cells.

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17
Q

How are CTLA-4 and CD28 similar and different?

A

CTLA-4 is a co-stimulatory molecule very similar to CD28 that can be expressed on the surface of T-cells, normally after T-cell activation.
CTLA-4 can also interact with CD80 and CD86.
Whilst engagement with CD28 results in activation of T-cells, CTLA-4 has an inhibitory effect on T-cell activity and proliferation.

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18
Q

How is CTLA-4 optimised in tumours?

A

Tumour cells can upregulate expression of proteins on their cell surface which can interact with CTLA-4 and hence inhibit further activity and proliferation of T-cells.

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19
Q

Aside from CTLA-4 which other protein is responsible for T-cell inhibition?

A

PD-1 (programmed cell death protein-1)

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20
Q

When PD-1 is expressed on the surface of proteins what does it interact with?

A

PDL-1 and PDL-2 which are expressed on antigen presenting cells. Once engaged they then cause inhibition of T-cell activity.

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21
Q

Overcoming CTLA-4 and PD-1 is known as what?

A

Checkpoint inhibitors.

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22
Q

What type of cells is CTLA-4 highly expressed?

A

Regulatory T cells

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23
Q

What is the normal role of regulatory T cells?

A

They suppress the immune system to prevent autoimmunity.

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24
Q

How would you expect population of T-regulatory cells to be different in a patient with cancer?

A

Increased population of T-regulatory cells, increased expression of CTLA-4 resulting in inhibition of T cell activity causing suppression of the anti-tumour immune response.

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25
Q

Explain the concept behind checkpoint inhibitors.

A

Checkpoint inhibitors compromise of monoclonal antibodies which inhibit two proteins expressed on the surface of T cells CTLA-4 and PD-1 from interacting with their ligands which can be expressed on tumour cells.

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26
Q

What are the downstream effects of checkpoint inhibitors?

A

With monoclonal antibodies blocking CTLA-4 and PD-1 engagement with ligands this prevents T-cell inhibiton and therefore anti-tumour immune responses can occur.

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27
Q

What is a secondary effect of using monoclonal antibodies blocking CTLA-4?

A

It depletes T regulatory cells and therefore prevents that immuno-suppressive response.

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28
Q

What are the types of cancer that can be treated with checkpoint inhibitors?

A

Melanoma
Lung carcinoma
Renal carcinoma
Bladder carcinoma
Colon carcinoma
Non-Hodgkins lymphoma

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29
Q

What are the two licensed checkpoint inhibitors that target PD-1 and PDL-1 and when were they discovered?

A

Nivolumab PD-1 (2014)
Atezolimumab PDL-1 (2016)

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30
Q

What licensed checkpoint inhibitor targets CTLA-4 and when was it discovered?

A

Ipilimumab (2011)

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31
Q

What checkpoint inhibitors are used to treat melanoma?

A

Nivolumab and ipilimumab (not incombination)

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32
Q

What type of cancer is ipilimumab used in combination with nivolumab?

A

Advanced renal cell carcinoma

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33
Q

Which types of cancer can be treated with Atezolimumab?

A

Urothelial carcinoma
Small and non-small cell lung cancer
Breast cancer

34
Q

What are the main adverse effects of checkpoint inhibitors?

A

They can produce autoimmune and inflammatory responses normally affecting the colon, lung, liver and endocrine glands.

35
Q

Explain how to manage some of the main cautions regarding checkpoint inhibitors.

A

Checkpoint inhibitor induced colitis / gastrointestinal CMV infection or reactivation.
Indicative symptoms may include diarrhea, abdominal pain and rectal bleeding.

For mild cases recommend loperamide in addition to having a bland diet. For more extreme cases discontinuation of medication may be required.

It is also important to rule out infections as the cause of colitis. This can be done by carrying out stool studies testing for Clostridioides difficile toxin, bacterial culture, ova and parasites and CMV infection.

36
Q

What drugs are used to treat checkpoint inhibitor induced colitis?

A

Prednisone
Infliximab
Vedolizumab

37
Q

Describe the prevalence of checkpoint inhibitor induced colitis with different the types.

A

0.7 – 1.6% for PD1 inhibitors
5.7 – 9.1% for CTLA-4 inhibitors
13.6% for combination therapy

38
Q

Aside from colitis what is the other major caution of ipilimumab?

A

Can cause severe cutaneous adverse reactions (SCARs), if a skin reaction does occur with the drug they should seek medical attention immediately.

Caution should be used before starting the drug if they have experienced a SCAR with another immuno-stimulatory antineoplastic drugs.

39
Q

What is the major caution associated with Atezolizumab?

A

Severe cutaneous adverse reactions

40
Q

List the cautions associated with nivolumab.

A

Gastrointestinal CMV infection or reactivation
Severe cutaneous adverse reactions
Organ transplant rejection

41
Q

What are the two types of cancer vaccines?

A

Preventative vaccines (HPV vaccine)
Vaccines to those already have tumours

42
Q

What is the purpose of vaccines in general and what is the thought behind cancer vaccines?

A

To boost the immune system’s sensitivity to a particular antigen and enhance the immune response. This can be applied to boosting an immune response to tumour cells in a patient with cancer.

43
Q

What specific immune cells do cancer vaccines boost?

A

The CD8 (+) T-cells response to tumour cells

44
Q

What three cell types can compose these cancer vaccines?

A

Killed tumour cells from the patient or
Dendritic cells or
Recombinant tumour antigens

45
Q

How are these vaccines prepared and work inside the body?

A

Firstly dendritic cells are extracted from the patient and incubated alongside tumour antigens before being injected back into the patient. These antigen presenting cells then present the tumour antigens to the T cells increasing the immune response.

46
Q

What is an example of a cancer vaccine that has already been licensed?

A

A vaccine for metastatic prostate cancer has been licensed in the US

47
Q

What is the licensed vaccine for prostate cancer composed of?

A

Dendritic cells that have been treated with a prostate specific antigen known as prostatic acid phosphatase and treated with GM-CSF which helps the maturation of dendritic cells.

48
Q

Why has there been limited success with the development of cancer vaccines?

A

The tumour through acquiring substantial mutations can continue to evade the immune response.

49
Q

How could cancer vaccines be more successful?

A

If given in combination therapy with checkpoint inhibitors.

50
Q

What do preventative vaccines consist of?

A

Viral antigens known to be oncogenic

51
Q

What is the aim of the HPV vaccine?

A

Reduce the incidence of precancerous lesions forming in the cervix, mouth and throat and the anus.

52
Q

Who is eligible for the HPV vaccine?

A

Girls born after 1st September 1991
Boys born after 1st September 2006

53
Q

When do boys and girls typically receive the HPV vaccine?

A

In England, girls and boys aged 12 to 13 years are routinely offered the 1st HPV vaccination when they’re in school Year 8. The 2nd dose is offered 6 to 24 months after the 1st dose

54
Q

What is the evidence base for using the HPV vaccine?

A

Trials undertaken show that the vaccine:
Prevents cancer-causing infections
Prevents ano-genital warts
Prevents cervical precancers

55
Q

How are tumour specific antibodies used in the treatment of breast cancer?

A

They can be used to target growth factors. For example, if HER2 (+) cases of breast cancer gene amplification of the EGFR receptor results in sustained proliferative signalling and so the antibody Herceptin or Trastuzumab can be used to target these receptors and prevent the downstream signalling pathway.

56
Q

How do tumour specific antibodies work?

A

They bind to the tumour cells and induce host immune effector responses such as complement-mediated cell lysis, phagocytosis by macrophages or NK cell mediated
cytotoxicity.

57
Q

What is the role of tumour specific antibodies in B cell lymphoma?

A

Anti-CD20 antibodies (e.g. Rituximab) can be used to deplete all cells expressing CD20 (a cell surface marker of B cells).

58
Q

What is the rationale behind using immune modulators?

A

They stimulate T-cells and NK cells and enhance the activation of dendritic cells, therefore driving the overall immune response.

59
Q

What are the two examples of cytokines used as immune modulators?

A

Interleukin-2
Interferon-alpha

60
Q

Which specific types of cancer is interleukin 2 prescribed for?

A

Melanoma and renal cell carcinoma

61
Q

What is the cause of some of the side effects associated with interleukin 2?

A

Interleukin 2 stimulates inflammatory mediators such as TNF-a and IFN-y which is the cause of the side effects.

62
Q

What is a clinical drug of IL-2?

A

Aldesleukin

63
Q

What is the primary purpose of immune modulator therapy?

A

Primarily used to shrink the tumour rather than increase survival

64
Q

What are some of the side effects associated with immune modulators?

A

Acidosis
Cardiovascular disorders
Hepatic disorders
Hypertension
Hyperglycaemia
Nerve disorders
Oral disorders
Respiratory disorders

65
Q

Which type of cancers use Interferon-a as a treatment?

A

Melanoma
Lymphoma
Leukemia

66
Q

How does interferon-alpha used in the treatment of cancer?

A

Increases the activity of NK cells in addition to upregulating MHC class I expression on tumour cells thus promoting the cytotoxic action of CD8+ T cells.

67
Q

Briefly outline what CAR T cell therapy involves?

A

A blood sample is taken from a patient with cancer and the T-cells are isolated and then injected. A modified and inactive virus is then injected into the T-cells and causes them to now express a chimeric antigen receptors. The genetically modified T-cells are then grown in a lab and infused back into the patient. These receptors are specific to an antigen expressed on the tumour cell and induce apoptosis.

68
Q

What do CAR receptors contain?

A

CARs are chimera’s (definition: something that contains pieces derived from
two or more sources) of an immunoglobulin variable gene and the cytoplasmic tails.
These tails include the intracellular signalling and co-stimulatory domains of the TCR such as ITAM (immunoreceptor tyrosine based activation motif) and the intracellular signalling domain of CD28.

69
Q

How are the genetically modified T-cells expanded in the lab?

A

They are stimulated to expand using antibodies to the CD3 complex and antibodies to the CD28 co-stimulatory molecule

70
Q

What is the main type of cancer that utilises CAR T cell therapy?

A

Lymphoma

71
Q

What are the six overall key steps of the CAR T cell process?

A

Leukapheresis
T-cell engineering
CAR T cell therapy
Chemotherapy
CAR T-cell infusion
CAR T cells attack the lyphoma

72
Q

Explain what is meant by leukapheresis?

A

Leukapheresis is the process of extracting blood to obtain specifically white blood cells. It is normally completed by IV and takes several hours (3-4 hrs).

73
Q

What happens once the white blood cells are extracted?

A

The rest of the blood cells are returned to the body.

74
Q

What happens in the T cell engineering process?

A

The extracted T-cells are then injected with an inactive modified virus which induces expression of chimeric antigen receptors on the T cells with the antigen receptor specific to the antigen protein specifically expressed on lymphoma cells.

75
Q

Once enough cells have be generated what happens next?

A

They are frozen for transport and delivered back to the treatment centre.

76
Q

Why is it essential to receive a low dose chemotherapy treatment before receiving CAR T cell therapy?

A

It suppresses the immune system from fighting against the CAR T cells and allows them time to proliferate and fight the lymphoma.

77
Q

What is the administration process of CAR T cell therapy?

A

CAR T cell therapy has an infusion time of approximately an hour and may be co administered with acetaminophen or diphenhydramine to prevent or relieve some of the side effects as they attack the lymphoma cells.

78
Q

How does CAR T cell therapy work for the treatment of lymphoma?

A

CAR T cells can recognise the CD19 B cell surface marker can eradicate all B cells from the patient (both tumour B cells and normal B cells).

79
Q

What is the Chimeric specific antigen specific to lymphoma?

A

Consists of CD28 and CD3 (squiggle) which recognises and binds to the CD19 present on B cells.

80
Q

What are some of the adverse effects associated with CAR T cell therapy?

A

Due to the high number of activated T cells injected back into the patient it can cause intense inflammatory responses or cytokine release syndrome.
There is also a number of reported neurological complications such as cerebral oedema which has led to fatalities.

Cancer (6 decks)

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