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The immune system fighting cancer Flashcards

1
Q

What does an inadequate immune system predispose to?

A

Chronic infection

Cancer

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2
Q

What does an overactive immune system cause?

A

Autoimmune conditions

Type I diabetes
Arthritis
Scleroderma

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3
Q

What is immunotherapy?

A

Employing the immune system to

  • enhance immunity in patients with cancer and chronic infection
  • induce tolerance in autoimmune diseases
  • develop therapies for inherited diseases
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4
Q

What is the potential for immunotherapy in cancer?

A

Help develop a new generation of live medicine

Providing lasting clinical benefit for patients

Potential to replace chemotherapy and radiation therapy

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5
Q

What is cancer?

A

A genetic disease

Developing from normal cells

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6
Q

Describe the potential for cancer development

A

The individual probability for cancer to develop in a cell is small

However, since there are 10^13 cells in the body, the cumulative risk is relatively high

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7
Q

What do genes control?

A

Cell function

Cell shape

Cell growth

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8
Q

What is the consequence of mutated genes?

A

Uncontrolled cell growth

Production of new proteins

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9
Q

Why is cancer rare in individual cells?

A

Evolutionary mechanisms for eliminating of inactivating potentially dangerous cells

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10
Q

Describe the process of oncogenic evolution

A

Elimination:
Once a cancer cell has been formed, immune surveillance attempts to eliminate it

Equilibrium:
Some of the cancer cells develop immune resistance mechanisms, allowing them to escape the elimination phase.

The immune system keeps track of these cells, forming an equilibrium

Escape:
Some of the cells in equilibrium with the immune system escape from the immune syste, leading to progressive disease

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11
Q

When does the escape phase of oncogenic evolution take place?

A

When there is a change in the tumour cells or the microenvironment which causes the immune system to be switched off in some way to allow the tumour to grow

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12
Q

What is essential for the clinical manifestation of cancer to present?

A

Escape phase

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13
Q

Experimental evidence of immunoediting during oncogenic evolution

A

Immunogenic tumours (aka tumours that can be recognised by the immune system) arise in immunodeficient mice

Progressive tumour variants arise in normal mice (immunoedited so immune system can not recognise it)

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14
Q

Which cell is essential for cancer immunoediting?

A

T cell

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15
Q

Describe an important mouse study showing the importance of immunoediting for cancer cells

A

Cancer cells from an immunocompetent mouse was injected into an immunocompromised recipient = cancer developed

Cancer cells from immunocompromised mouse was injected into an immunocompetent recipient = no cancer

Cancer cells from immunocompromised mouse was injected into an immunocompromised recipient = cancer developed

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16
Q

Examples of prophylactic cancer vaccines

A

HBV vaccines

HPV vaccines

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17
Q

Have prophylactic cancer vaccines been effective in reducing the chances of developing cancer?

A

Yes

Vaccinating before viral infection

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18
Q

Which cancer does HBV vaccines protect against?

A

Liver cancer

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19
Q

Which cancer does HPV vaccines protect against?

A

Cervical cancer

20
Q

Example of a therapeutic vaccine used in cancer

A

Dendreon’s Provenge

Prostate cancer cell vaccine produced with patients own cells

21
Q

Have therapeutic vaccines been useful in cancer?

A

Not as effective as other immunotherapies

22
Q

Which cells play an important role in cancer protection?

23
Q

Describe the activation of T cells

A

TCR recognises the target cell through peptides presented on MHCs of APCs

This is called signal 1

On top of this, signal 2 is also needed

In the absence of costimulatory signals, signal 1 is ineffective

24
Q

What are the two types of T cell co-receptors?

A

Co-stimulatory -> cause T cell activation

Co-inhibitory -> prevent T cell activation

25
Examples of stimulatory co-receptors
PDL1 CD80/86 binding to CD28 CX40L CD70
26
Examples of inhibitory co-receptors
CD80/86 binding to CTLA4 PDL1 binding to PD1
27
How do cancers shut down the immune system?
Inhibit T cell activation following signal 1 by expressing inhibitory co-receptors like PD-1, or inhibitory molecules like CD80/86 binding to CTLA-4
28
What are immune checkpoint inhibitors?
Bind and block inhibitory receptors on T cells Induce immune system activation through blocking inhibitory receptors Including PD-1 and CTLA-4
29
Examples of checkpoint inhibitor drugs
Ipilumumab anti-PD-1
30
What is the only challenge of checkpoint inhibitors?
Autoimmune side-effects Global T cell activation due to the blocking of PD-1 and CTLA-4 Important regulators of normal immune balance
31
When are checkpoint inhibitors used?
In patients resistant to conventional therapies
32
Describe alternatives to conventional therapies currently being developed
Checkpoint inhibitors Tumour infiltrating lymphocytes Engineered T cells
33
Describe the idea behind using tumour infiltrating lymphocytes for cancer therapy
Extraction of T cells present in the tumour microenvironment and their subsequent expansion Since they have tumour specificity
34
How do we have to prepare the patient before using tumour infiltrating lymphocytes?
Reduce the levels of endogenous T cells before you inject the expanded T cells So the tumour-specific T cells don't have to compete for space
35
What is the advantage of tumour-specific T cells in cancer therapy?
They have multiple specificities against neo-antigens and tumour-associated antigens
36
What are the disadvantages of using tumour-specific T cells in cancer therapy?
Difficult to reliably obtain T cells from cancer patients Unknown fine specificity of T cells Generally unsuccessful in cancer types other than melanoma
37
Describe the process behind engineering T cells
Isolate T cells from peripheral blood Genetically engineer T cells to direct them towards cancer antigen using TCR or CAR Reinject the cells back into the patient
38
What is the difference between CAR and TCR?
CAR is the addition of the variable portion of antibody onto a chimeric antigen receptor Genetically engineer the T cell receptor to be specific to a certain antigen
39
What is the benefit of using TCR instead of CAR in engineering T cells?
TCR recognise intracellular peptides through the MHC presenting system due to the nature of TCR proteins CAR T cannot recognise intracellular peptides
40
Success of genetically engineered T cells
CAR T cells have been successful for acute lymphoid leukemia Genetically modified T cells have shown tumour regression in patients with metastatic synovial cell melanoma and sarcoma
41
Which mutations are targeted by T cell therapy?
Mutations present in the coding portions of the genome So it can be loaded on the HLA and presented to the lymphocytes
42
What is the biggest challenge in cancer therapy?
Every patient has a unique set of mutations This personalised therapy is a limitation
43
What is the current goal of cancer therapies?
Targeting tumour associated antigens present in all patients Removes the challenge of personalised therapy Biggest success = CD19
44
What are the disadvantages of targeting tumour associated antigens present in all patients?
Risk of autoimmune disease Induction of T celinl tolerance by normal tissues
45
Which type of mutations create novel protein sequences?
Non-synonymous Mutation causes a change in the protein expressed Since DNA is redundant, mutations are not always caused following DNA changes
46
What percentage of the genome is the protein coding exome?
1%

IMM005 (17 decks)

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