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
Why are TILs (tumour infiltration lymphocytes) important
- 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
How do TILs work in adoptive cellular therapy
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
What are the results of adoptive therapy with TILs
* 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
What are the disadvantages of adoptive therapy with TILS
* 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
How can we use peripheral blood T cells to carry out ACT
* 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
How does high affinity TCR transduction work
* 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
What are the problems associated with high affinity TCR transduction
* 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
What are Chimeric Antigen Receptors
* 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
