The immune system fighting cancer Flashcards
What does an inadequate immune system predispose to?
Chronic infection
Cancer
What does an overactive immune system cause?
Autoimmune conditions
Type I diabetes
Arthritis
Scleroderma
What is immunotherapy?
Employing the immune system to
- enhance immunity in patients with cancer and chronic infection
- induce tolerance in autoimmune diseases
- develop therapies for inherited diseases
What is the potential for immunotherapy in cancer?
Help develop a new generation of live medicine
Providing lasting clinical benefit for patients
Potential to replace chemotherapy and radiation therapy
What is cancer?
A genetic disease
Developing from normal cells
Describe the potential for cancer development
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
What do genes control?
Cell function
Cell shape
Cell growth
What is the consequence of mutated genes?
Uncontrolled cell growth
Production of new proteins
Why is cancer rare in individual cells?
Evolutionary mechanisms for eliminating of inactivating potentially dangerous cells
Describe the process of oncogenic evolution
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
When does the escape phase of oncogenic evolution take place?
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
What is essential for the clinical manifestation of cancer to present?
Escape phase
Experimental evidence of immunoediting during oncogenic evolution
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)
Which cell is essential for cancer immunoediting?
T cell
Describe an important mouse study showing the importance of immunoediting for cancer cells
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
Examples of prophylactic cancer vaccines
HBV vaccines
HPV vaccines
Have prophylactic cancer vaccines been effective in reducing the chances of developing cancer?
Yes
Vaccinating before viral infection
Which cancer does HBV vaccines protect against?
Liver cancer
Which cancer does HPV vaccines protect against?
Cervical cancer
Example of a therapeutic vaccine used in cancer
Dendreon’s Provenge
Prostate cancer cell vaccine produced with patients own cells
Have therapeutic vaccines been useful in cancer?
Not as effective as other immunotherapies
Which cells play an important role in cancer protection?
T cells
Describe the activation of T cells
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
What are the two types of T cell co-receptors?
Co-stimulatory -> cause T cell activation
Co-inhibitory -> prevent T cell activation
Examples of stimulatory co-receptors
PDL1
CD80/86 binding to CD28
CX40L
CD70
Examples of inhibitory co-receptors
CD80/86 binding to CTLA4
PDL1 binding to PD1
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
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
Examples of checkpoint inhibitor drugs
Ipilumumab
anti-PD-1
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
When are checkpoint inhibitors used?
In patients resistant to conventional therapies
Describe alternatives to conventional therapies currently being developed
Checkpoint inhibitors
Tumour infiltrating lymphocytes
Engineered T cells
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
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
What is the advantage of tumour-specific T cells in cancer therapy?
They have multiple specificities against neo-antigens and tumour-associated antigens
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
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
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
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
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
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
What is the biggest challenge in cancer therapy?
Every patient has a unique set of mutations
This personalised therapy is a limitation
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
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
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
What percentage of the genome is the protein coding exome?
1%
