Lecture 8 - Tumour Immunity 2 Flashcards
Describe William Coley experiments with anti-tumour immunotherapy
1893
Coley observed a patient recover from cancer after a severe bacterial infection
He then isolated bacterial Ags: ‘Coley’s toxins’
When injected, Coley’s toxins induced tumour rejection
What is the key to the future of cancer therapy?
Immunotherapy
List some of the various approaches to cancer immunotherapy
- Preventative therapies
- Antibody therapy
- Cytokine therapy
- Immunisation w/ tumour Ags
- Adoptive cell transfer therapy
- Removal of immunosuppression
Discuss preventative immunotherapy against cancer
Immunise against viruses that can cause cancer
Examples:
• EBV
• HPV - Gardasil
• HBV
Which cancers do the following cause:
• EBV
• HPV
• HBV
EBV: Lymphoma, Non-Hodgkins Lymphoma
HPV: cervical cancer
HBV: hepatocellular carcinoma
Describe Ab therapy for cancer
Approach: • mAb generated against tumour Ags • mAbs injected and act through a variety of mechanisms: - Ligand blockade - Receptor blockade - Cell depletion - Ab-conjugates - ADCC
Describe the use of conjugated mAb as cancer immunotherapy
Certain molecules are conjugated to mAbs. Conjugates are internalised, killing the tumour cell
- Radioisotopes
• Delivers radiotherapy directly to tumour
• Diminishes radiation to healthy cells - Toxins e.g. Ricin
• Chemotherapy delivered directly to cancerous cells
• Diminishes off target effects - Immunocytokines
- Bipolar mAbs
• Specific for tumour cell as well as e.g. CTL
• Brings these two things into contact
What are the problems with antibody based immunotherapy?
- Specificity
• Abs binding to non-tumour cells - Penetration into large tumours
- Genetic instability of tumours
- Limited knowledge of dominant tumour Ags
Describe Rituximab
Rituxan (Rituximab)
• Anti-CD20 Ab
• Depletes all B cells in the body through ADCC and C’-dep. cellular cytotoxicity
Describe Trastuzumab
Herceptin (trastuzumab)
• Anti-HER2
• HER2 is a GF receptor present in many breast cancers
• Blocks GF signalling, inhibiting growth of the tumour
Describe Bevacizumab
Avastin (bevacizumab) • Anti-VEGF • VEGF is a GF for angiogenesis • mAb blocks angiogenesis, thus cutting off the blood supply to the tumour • esp. in colorectal cancer
Describe Brentuximab
Adcetris (brentuzimab) • Anti-CD30 • Antibody-drug conjugate • Targets CD30 on many lymphoma cells • Results in shrinkage of tumours in ALCL (anaplastic large cell lymphoma)
Give some examples of cytokine immunotherapy for cancer
List which cancers each can be used for, and the MOA
IL-2
• Melanoma, renal & colon cancer
• T and NK cell activation
IFNa
• Melanoma, lymphoma, renal cancer
• NK cell activation and increased MHC I expression
TNF
• Malignant ascites, sarcoma, melanoma
• Macrophage and lymphocytes activation
IL-12
• Melanoma
• NK and CTL activation
What are the problems associated with cytokine therapy?
- AEs when administered systemically
- Short half life
- Limited success with some tumour types
Describe the approach of immunisation against tumours
Describe the effectiveness of such an approach
Approach:
• Patient immunised with killed tumour cells / purified tumour Ags
• + Adjuvant (e.g. BCG)
Results:
• Works in animals as prophylactic
• Often less effective therapeutically
What are the problems associated with immunisation with tumour Ags?
- Problems identifying the dominant tumour antigen
* Antigen modulation of tumour cells
Describe adoptive cell therapy for cancer
What are the two approaches?
- Lymphocytes form blood or tumour infiltrate isolated from patient
- Lymphocytes expanded in culture with IL-2
- Lymphocytes transferred back into patient
- Hopefully, tumour regresses
Approaches:
1. LAK - Lymphokine activated killers
• Mainly NKs isolated from patient
• Limited success
- TIL - Tumour infiltrating lymphocytes
• Lymphocytes taken from within / around tumour biopsy
• This is more likely to include tumour specific CTLs and NKs
• Dramatic improvements in some patients
Why is autoimmunity often a good sign in cancer immunotherapy?
Indicates that the immune system has boosted its function
e.g. Vitiligo
• Immune system is destroying melanocytes
• Good indication in melanoma
Describe the process of immunisation with immunogenically enhanced, viable tumour cells
- Tumour cells isolated from patient
- Tumour cells transfected with immunogenic molecules
a. B7
• B7 activates naïve T cells
b. GM-CSF
• Induces DC development
• DCs mature and present tumour derive Ag to T cells in the lymphoid tissues - Tumour cells put back into the patient
- Transfected cells capable of generating T cell responses
- T cell response directed against all tumour cells, not just those that were enhanced immunogenically
- Tumour shrinks
Describe the rationale for ‘releasing the handbrake’ on the immune system
Describe how this can be done
Development of Tregs and expression of immunosuppressive cytokines ‘protects’ tumours from the immune system
Approaches:
1. Blocking CTLA-4
• Ipilimumab
• Blocks CTLA-4, the inhibitory molecule expressed by T cells
• T cells can no longer be inhibited
• Promising results in melanoma and prostate cancer patients
2. Depletion of Tregs • e.g. Ontak • IL-2-diptheria toxin conjugate • Binds and kills CD25+ Tregs • Mixed results in clinical trials
- Anti-PD-1
• PD-1: programmed cell death protein 1
• PD-1 expressed on T cells
• When ligated by PD-L1 on tumour cells, T cells are inhibited
Describe the function of B7?
Stimulates T cells through ligation of CD28
What is the function of GM-CSF?
In this case, it recruits DCs to the environment (the tumour), enhancing T cell activation
