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Microbiology And Immunology > Anti Tumour Immunity and Immunotherapy for Cancer > Flashcards

Anti Tumour Immunity and Immunotherapy for Cancer Flashcards

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1
Q

Background of cancer cells
State features of cancers cells that make it different from normal cells?

A
  • Rapid uncontrolled growth
  • Increased mobility
  • Invade tissue
  • Evade immune system
  • Metastasize
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2
Q

Describe how immune system can cause cancer?

A

Imbalance in IS -> Immunodeficiency + IF conditions -> Cancer + tumour formation -> tumours infiltrated with lymphocytes have better prognosis

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3
Q

Can the body defend against cancer?

A
  • Immunosurveillance:
  • Immune system (lymphocytes) recognise cancerous and precancerous cells leading to their elimination before they can cause damage
  • Demonstrated anti-tumour immune response (CD8+), production of immune memory + specificity of individual tumours (tumour antigens)
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4
Q

Immunoediting
Describe the process of tumourigenesis?

A
  • Normal cells undergoing change via exposure to harmful factors
  • Develop abnormal tumour antigens.
  • Expresses Danger signals (ECM products)
  • Tumour cells recognise DS + action via immunoediting
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5
Q

Describe the process behind immunoediting of the immune system (3)?

A
  • Elimination
  • Equilibrium
  • Escape
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6
Q

Describe Eliimination

A
  • Nks, NKTs, Macs + DCs + Tumour-specific CD4+ + CD8+ T cells : Eliminate Tu. cells -> INF gamma + chemokines cause tumour death
  • Tumour specific DCs activate adaptive immunity in draining lymph nodes
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7
Q

Describe equilibrium

A
  • incomplete Elimination
  • Tumor cells lie dormant + modulate tumour antigen expression + stress signals
  • IS eliminates susceptible tumour clones (-> prevent tumour expansion) -> tumour heterogeneity -> ‘darwinian selection’ -> allows for escape mutants to arise
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8
Q

Describe escape

A
  • Immune system unable to control tumour growth
  • Tumour progression
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9
Q

Immunomodulation
Describe the use of Bacillus calmette-Guerin (BCG) and how it acts as a immunemodulator?

A
  • Vaccine for TB -> immunological adjuvant + stimulates innate IS (via TLRs)
  • Used in bladder cancer- intravessicular injection -> Possible mechanism of action: Activation of DC + NK - bystander T cell activation.
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10
Q

State examples of cytokines which can be used as modulators?

A
  • Main ones: Interferon, IL-2, GM-CSF
  • Others: IL-1; IL-4; IL-7; IL-12; gIFN.
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11
Q

Describe the use of Interferon as an immunomodulator?

A

Type I interferon (alpha + beta)
- Produced by virally infected cells via Viral detection pathways
- Upregulates MHC Class 1, tumour antigens + adhesion molecules
- Activates T cells, B cells + DC
- Used in metastatic melanoma
- Nasty side-effects (‘flu-like symptoms)

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12
Q

Describe the use of Interleukin-2 as an immunomodulator?

A
  • T cell growth factor
  • Success in Renal Cell Carcinoma + melanoma
  • Toxicity
  • LAK cells, PBMC treated with IL-2 + re-infused into patients
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13
Q

Describe the use of GM-CSF as an immunomodulator?

A
  • GM-CSF stimulates APC
  • Trialled in melanoma (some success)
  • Maybe better if used with IL-2
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14
Q

Antibody therapy
State the 3 general mechanisms in how antibodies kill tumours?

A
  • Direct tumour cell killing
  • immund-mediated tumour cell killing
  • Vascular and stromal cell ablation
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15
Q

Blockade of growth factors
Describe the use of trastuzumab as an AB therapy drug against cancer?

A
  • Herceptin
  • Targets ERBB2 (human epidermal growth factor) on breast cancer cells
  • Blocks ERBB2 signalling
  • Allows targeting of ADCC
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16
Q

Describe the use of Bevacizuman as an AB therapy drug against cancer?

A
  • Avastin
  • Targets VEGF + blocks signalling
  • Used against colon cancer, NSCLC, glioblastoma + kidney cancer
17
Q

Apoptosis induction
Describe the use of rituximan as an AB therapy drug against cancer?

A
  • Anti-CD20
  • used for CD20 positive B cell
  • Non-Hodgkin’s Lymphoma + Chronic Lymphocytic Lymphoma.
18
Q

Describe the use of Alemtuzumab as an AB therapy drug against cancer?

A

Campath -> anti CD52 -> used for B-CLL

19
Q

Immunomodulation
Describe the use of Ipilimumab as an AB therapy drug against cancer?

A
  • Anti CTLA-4
  • Blocks the inhibition via CTLA-4 signalling
  • Metastatic melanoma
  • Non-specific
  • Immune related adverse events
  • Kkin, GI + treated with corticosteroids.
20
Q

Delivery
Describe the use of 90Yttrium-labelled ibritumomab tuxetan as an AB therapy drug against cancer?

A

Antibody to CD20 delivering radiotherapy to follicular B-cell NHL

21
Q

Describe the use of Brentuximab vedotin as an AB therapy drug against cancer?

A

antibody to CD30 delivering toxin (Aurostatin) to CD30+ B cells in NHL

22
Q

Describe the use of Ontak as an AB therapy drug against cancer?

A

IL-2 delivering diphtheria toxin in T cell lymphoma (not antibody but a similar principle!)

23
Q

Checkpoint inhibition
Name AB therapy drugs involed in chekpoint inhibition against cancer and how this works?

A
  • Nivolumab (also no PDL-1 on tumour!) + pembrolizumab -> Combination therapy with Ipilimumab
  • Action -> Blockade of effector cell death -> Antibody against programmed cell death protein 1 (found on tumour cells. -> Expressed on T cells + induces apoptosis when bound by PDL-1
24
Q

Cell therapy
State cells that therapies can be made from for use against cancer?

A
  • Lymphocyte-activated killers
  • NK-T cells
  • Gamma-delta T cells
  • DC
  • Tumour-infiltrating lym.
  • chimeric AB receptors
25
Q

Innate cell therapy
Describe how LAK cells: Lymphokine Activated Killers are used as a cell therapy?

A
  • Peripheral blood mononuclear cell taken from patients + cultured with IL-2 in vitro -> Heterogeneous population of NK (mostly), NKT + T cells (CD25+)
  • Normal anti-tumour activity -> target NK resistant tumour cell
26
Q

Describe how Natural Killer cells are used as a cell therapy?

A
  • Recognise lack of MHC1
  • About 5-10 % of human peripheral blood lymphocytes
  • Majority are CD3- CD56+ (-> subsets CD56 bright and CD56 dim - CD16+/CD16- (Fc gamma RIII)
  • Found in blood, BM, spleen + liver
27
Q

Describe how NK-T immunotherapy is used as a cell therapy?

A
  • Recognises alpha-galactosyl ceramide
  • Used for in vitro expanded NKT based vaccines
  • Used alpha-gal cer pulsed DCs
  • Well tolerated, Induce expansions of NKTs in vivo
28
Q

Describe how gamma-delta cell is used as a cell therapy?

A
  • TC structurally similar to alpha-beta
  • May not need normal antigen presentation mechanisms (ie normal numbers in MHC1 and 2 ko mice)
  • May not recognise peptides + no need for protein processing
  • Detect stress, or small organic molecules which signify infection
  • Responds to MICA + MICB expressed on stressed cells
  • Recognises small organic molecules secreted by bacteria: eg HMBPP (from mycobacteria
29
Q

Adaptive immunity therapy
What is a therapeutic vaccination and describe its method as a form of adaptive immune therapy?

A
  • Induces a long lasting response against tumour
  • Use professional APC such as Dendritic Cells
  • Stimulate the adaptive arm of the immune response
30
Q

Adoptive cell therapy
Why is the manipulation of tumour-infiltrating lymphocytes important?

A
  • Presence of lymphocytes has prognostic significance
  • Increase TILs, CD8+ cells, CD8+/Treg ratio
  • Pre-existing antigen specificity of TILs has been correlated with outcome in immunotherapy of melanoma
31
Q

Describe the method + results of using tumour-infiltrating lymphocytes?

A
  • Assumes that TILs already have knowledge of tumour antigens
  • Method: Tumour biopsy -> In vitro polyclonal stimulation (IL-2 and anti-CD3 AB) -> Lymphodepletion of patient (increase persistence of transferred T cells) -> Stimulated T cells reintroduced into the patient.

Results: Cytotoxicity against tumour cells in culture -> Homing of transferred T cells to tumour in vivo.
• >50% objective response rate
- Best results when patients are pre-treated with peripheral lymphodepletion regimen of total body irradiation

32
Q

What are disadvantages of using tumour-infiltrating lymphocytes?

A
  • Need enough tumour to generate sufficient CTL
  • TILs may be refractory to stimulation (about 30%), Time consuming and labour intensive - requires infrastructure, Culture time may be too long + influence quality of T cells. -> High failure rate of culture.
33
Q

Describe the use of ACT using peripheral blood derived T cells?

A
  • Clonal expansion against a known antigen
  • Advantage of easy availability of large numbers of T cells
  • Peripheral blood contains many precursors with TAA reactivity.
  • Method: 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) + haematologic malignancies
  • Cloning and culture takes a long time.
34
Q

Describe the use of high affinity TCR transduction method?

A

TCRs reactive to Tumour Associated Antigen (MART-1, gp-100, NY-ESO and p53) characterised + cloned -> Alpha + beta chains of TCR are engineered into a retroviral vector. -> Patient’s CD8+ T cells from peripheral blood are removed + transduced with TCR-virus -> Adoptive transfer back into patients.

35
Q

State problems with the use of high affinity TCR transduction method?

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.
36
Q

Describe what chimeric antigen receptors are and its use?

A
  • Similar in nature 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 + high affinity

Microbiology And Immunology (32 decks)

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