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Microbiology and Immunology - SGUL (Sem 4) > Anti-tumour Immunity and Immunotherapy for Cancer > Flashcards

Anti-tumour Immunity and Immunotherapy for Cancer Flashcards

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1
Q

How are cancer cells different from normal cells

A
  • Rapid uncontrolled growth
  • Increase mobility
  • Invade tissue
  • Evade immune system
  • Metastasize
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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.
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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
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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.
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5
Q

What are the 3 phases of immunoediting (immunosurveillance)

A
  • Elimination
  • Equilibrium
  • Escape
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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.
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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’
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8
Q

Describe the escape phase

A

Immune system is unable to control the tumour growth leading to tumour progression

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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.
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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)
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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
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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.
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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
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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.
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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
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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

Microbiology and Immunology - SGUL (Sem 4) (30 decks)

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