Anti-tumour Immunity and Immunotherapy for Cancer Flashcards
1
Q
How are cancer cells different from normal cells
A
- Rapid uncontrolled growth
- Increase mobility
- Invade tissue
- Evade immune system
- Metastasize
2
Q
How does the immune system play an integral role in cancer
A
- Imbalance in the immune system in a critical contributory factor.
- Immunodeficiency lead to tumour formation eg. kaposi sarcoma, lymphoma.
- Inflammatory conditions lead to cancers too eg. ulcerative colitis and colon cancer
- Tumours infiltrated with lymphocytes have a better prognosis.
3
Q
How was it discovered that CD8 cells can cure cancer (mouse experiment)
A
- Mouse treated with methylcholanthrene and induce a sarcoma
- Surgically remove the tumour mass and culture the cells
- When tumour placed in same mouse it didn’t grow
- When the tumour placed in an identical mouse the tumour grows
- When tumour placed in identical mouse with CD8 cells the tumour doesn’t grow
4
Q
Describe tumour immunosurveillance
A
- Immunosurveillance’ coined by Burnet & Thomas in 1957 to describe a process where the immune system, namely lymphocytes, continually recognise cancerous and pre cancerous cells leading to their elimination before they can cause damage.
- But Tumours do develop highlighting the fact that immunosurveillance is not perfect.
5
Q
What are the 3 phases of immunoediting (immunosurveillance)
A
- Elimination
- Equilibrium
- Escape
6
Q
Describe the elimination phase
A
- NKs, NKTs, Macs and DCs (Innate).
- INFγ and chemokines lead to tumour death.
- Tumour specific DCs activate adaptive immunity in draining lymph nodes.
- Tumour specific CD4+ and CD8+ T cells join.
7
Q
Describe the equilibrium phase
A
- Elimination phase is incomplete.
- Tumour cells lie dormant and may modulate tumour antigen expression and stress signals.
- The immune system eliminates susceptible tumour clones when possible sufficient to prevent tumour expansion.
- Tumour heterogeniety resulting in ‘Darwinian selection’
8
Q
Describe the escape phase
A
Immune system is unable to control the tumour growth leading to tumour progression
9
Q
How is BCG being used to treat cancers
A
- Vaccine for TB
- Good immunological adjuvant
- Stimulates the innate immune system TLRs
- Used in bladder cancer- intravesicular injection
- MOA? DC activation, direct NK activation, bystander T cell activation.
10
Q
How can we use cytokines be used to treat cancer - Interferons
A
- Type I interferon (a and b)
- Produced by virally infected cells
- Viral detection pathways within most cells
- Upregulates MHC Class 1, tumour antigens and adhesion molecules.
- Activates T cells, B cells and DC
- Used successfully in metastatic melanoma
- Nasty side-effects (‘flu-like symptoms)
11
Q
How is interleukin-2 to treat cancer
A
- It is a T cell growth factor
- Success in RCC and melanoma
- Toxicity
- LAK cells, PBMC treated with IL-2 and re-infused into patients
12
Q
How are GM-CSF being used to treat cancer
A
- GM-CSF stimulates APC
- Trialled in melanoma, evidence of some success
- May be of benefit if used in conjunction with IL-2
- Other used include: IL-1; IL-4; IL-7; IL-12; gIFN.
13
Q
How can we use antibody therapy to target tumours
A
- Direct tumour cell killing
- Immune-mediated tumour cell killing
- Vascular and stromal cell ablation
14
Q
How doe growth factor blocking work and what agents are used
A
- Trastuzumab (Herceptin) targets ERBB2 (human epidermal growth factor) on breast cancer cells. Blocks ERBB2 signalling and allows targetting of ADCC
- Bevacizumab (Avastin) targets VEGF and blocks signalling. Used against colon cancer, NSCLC, glioblastoma and kidney cancer.
15
Q
How can we induce apoptosis and what agents are used
A
- Rituximab: anti CD20, used for CD20 positive B cell Non Hodgkin’s Lymphoma and Chronic Lymphocytic Lymphoma.
- Alemtuzumab (Campath): anti CD52, used for B-CLL
- They target all B cells which can reduce normal immune function
16
Q
How can we induce immunomodulation and what agents are used
A
- Ipilimumab (anti CTLA-4), blocks the inhibition due to CTLA-4 signalling.
Used in metastatic melanoma. - Problems with non specific actions. Immune related adverse events! Mainly skin and GI and treated with corticosteroids. Autoimmunity?
17
Q
How are antibodies delivered for tumour supression
A
- 90Yttrium-labelled ibritumomab tiuxetan. Antibody to CD20 delivering radiotherapy to follicular B-cell NHL
- Brentuximab vedotin: antibody to CD30 delivering toxin (Aurostatin) to CD30+ B cells in NHL
- Ontak: IL-2 delivering diphtheria toxin in T cell lymphoma (not antibody but a similar principle!)
18
Q
What new approaches are being used
A
- Checkpoint inhibition
- Blockade of effector cell death
- Antibody against PD 1 (programmed cell death protein 1)
- Expressed on T cells and can induce apoptosis when bound by PDL-1.
- PDL-1 can be found on tumour cells.
- Nivolumab (but also works if no PDL-1 on tumour!) and pembrolizumab.
- Combination therapy with Ipilimumab
19
Q
What cell based therapies do we have for cancers
A
- LAK
- NK-T cells
- gamma-delta T cells
- DC
- TIL
- CAR
20
Q
Describe how LAK cells work to suppress cancer
A
- PBMC taken from patients and cultured with IL-2 in vitro.
- Heterogeneous population
- NK, NKT and T cells (CD25+)
- Predominantly NK cells
- Higher than normal anti-tumour activity
- Can target NK resistant tumour cells
21
Q
Describe how does NK-T immunotherapy works
A
- a-galactosyl ceramide
- Used for in vitro expanded NKT based vaccines
- Used a-gal cer pulsed DCs
- Well tolerated
- Induce expansions of NKTs in vivo
- Some stable disease in a variety of cancers
22
Q
Describe how game-delta T cells works in tumour supression
A
- TCR structurally similar to ab
- May not need normal antigen presentation mechanisms (ie normal numbers in MHC1 and 2 ko mice)
- May not recognise peptides and therefore no need for protein processing
- May detect stress, or small organic molecules which signify infection
- Can respond to MICA and MICB expressed on stressed cells
- Can recognise small organic molecules secreted by bacteria: eg HMBPP ((E)-4 hydroxy-3-methyl-but 2-enyl pyrophosphate) from mycobacteria
23
Q
What is therapeutic vaccination
A
- To induce a long lasting response against tumour.
- Stimulate the adaptive arm of the immune response
- Use professional APC such as Dendritic Cells
24
Q
How does dendritic cell vaccinations works
A
- Isolate monocytes from patient
- Generate immature dendritic cell from the monocyte population
- Load dendritic cell with whole cell tumour-lysate
- Mature the antigen-presenting dendritic cell
- Put back into the patient
- Gain a population of dendritic cells that is good and presenting tumour proteins
25
Q
Why are TILs (tumour infiltration lymphocytes) important
A
- Presence of lymphocytes has prognostic significance
- Large numbers of TILs in many tumours
- High numbers of CD8+ cells also has prognostic significance
- High CD8+/Treg ratio.
- Pre-existing antigen specificity of TILs has been correlated with outcome in immunotherapy of melanoma
26
Q
How do TILs work in adoptive cellular therapy
A
Assumes that TILs already have knowledge of tumour antigens
Method:
- Tumour biopsy
- In vitro polyclonal stimulation (IL-2 and anti-CD3
antibody) - Lymphodepletion of patient (enhances persistence
of transferred T cells). - Stimulated T cells reintroduced into the patient.
27
Q
What are the results of adoptive therapy with TILs
A
- Cytotoxicity against tumour cells in culture.
- Homing of transferred T cells to tumour in vivo.
- > 50% objective response rate (best alternative immunotherapy
= approx 20%). - Best results when patients are pre-treated with peripheral
lymphodepletion regimen of total body irradiation (improved
survival benefit)
28
Q
What are the disadvantages of adoptive therapy with TILS
A
- Need enough tumour to generate sufficient CTLs
- TILs may be refractory to stimulation (about 30%)
- Time-consuming and labour-intensive – requires infrastructure.
- Culture time may be too long
- Culture time MAY influence quality of T cells.
- High failure rate of culture.
29
Q
How can we use peripheral blood T cells to carry out ACT
A
- Isolate peripheral blood PBMCs/PBLs
- Stimulate in vitro with autologous DC + antigen (+ IL-2)
- grow out tumour reactive clones / polyclonal pool.
- used extensively for treatment of post-transplant lymphoproliferative diseases (targeting EBV).
- Used in haematologic malignancies with some success.
- BUT… Cloning and culture takes a long time.
- Easy availability of large numbers of T cells
30
Q
How does high affinity TCR transduction work
A
- TCRs reactive to TAAs (earliest examples include MART-1, gp-
100, NY-ESO and p53) characterised and cloned. - Alpha and beta chains of TCR are engineered into a retroviral
vector. - Patient’s CD8+ T cells from peripheral blood are removed
and transduced with TCR-virus. - Adoptive transfer back into patients.
31
Q
What are the problems associated with high affinity TCR transduction
A
- Initial results 2/15 patients with clinical response.
- T cells remain in peripheral blood for up to one year.
- Epitopes need to be characterised and matched to HLA
- Must be present in the tumour.
- Becomes a patient-specific therapy
- Autoimmunity? Off-target hits, have lead to death eg MAGE
specific TCR have recognized cardiac and brain tissue.
32
Q
What are Chimeric Antigen Receptors
A
- Similar to TCR transgenics, but NOT MHC restricted
- Composed of:
Antibody recognition domains, cytoplasmic tail with multiple signalling domains that activate T cells. - Advantages of specificity and high affinity
