Immunotherapy and cancer I Flashcards

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1
Q

why target the immune system?

A

Ehrlich stated that;
- early tumors never become apparent because they are destroyed by the immune system

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2
Q

examples of some immune modulators

A
  • Coley’s toxins
  • Cytokines
  • Pattern recognition receptor agonists
  • HSP
  • Ab therapy
  • Inflammation
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3
Q

what is Coley’s toxin?

A

a therapy developed after it was observed that some cancer patients experienced spontaneous remission after developing bacterial infections.

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4
Q

what does Coley’s toxin contain?

A

originally, streptococcus pyogenes and serratia marcesens ; heat killed and injected into cancer patients.

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5
Q

what is the idea behind Coley’s toxin?

A

immune system would be activated by the bacteria which would in turn attack the cancer cells

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6
Q

what is BCG?

A

bacillus calmette-guerin
- vaccine for TB
- good immunological adjuvant
- stimulaes the innate immune system
- used in bladded cancer

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7
Q

MOA of BCG

A

DC activation, direct NK activation, bystander T cell activation

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8
Q

Cytokines; interferons

A
  • Type I interferon
  • produced by virally infected cells
  • viral detection pathways within most cells
  • upregulates MHC class I, tumors antigens and adhesion molecules
  • activates T-cells, B cells and DC
  • used successfully in metastatic melanoma
  • nasty flu like side effects
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9
Q

what does DC refer to?

A

dendritic cells; immune cells , APCs

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10
Q

interleukins

A
  • T cell growth factor
  • success in RCC and melanoma
  • toxicity
  • LAK cells, PBMC treated with IL2 and reinfused into patients
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11
Q

what is GM-CSF?

A

granulocyte macrophage colony stimulating factor

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12
Q

what is the function of GM-CSF?

A

cytokine that promotes myeloid cell development and maturation, and dendritic cell differentiation and survival in vitro

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13
Q

success rate of cytokine therapy

A
  • interferons; 10-20%
  • IL2; 10-20%
  • IL2 + interferons; 40%
  • GMCSF; ?
  • GMCSF + IL2; 20%
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14
Q

pattern recognition

A
  • intra and extra cellular sensors pathogens associated molecular patterns (PAMPs)
  • conserved between species
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15
Q

4 families of pattern recognition

A
  • Toll-like receptors
  • Nucelotide-binding oligomerisation domain (NOD_-like receptors
  • Retinoic acid inducible gene (RIG)- like receptors
  • DNA sensors
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16
Q

pattern recognition receptors ; PRR

A
  • originally though of as sensors for infection but more recently receptors for endogenous ligands
  • Danger Associated Molecular Patterns (DAMPs)
  • cell injury, stress or cell death
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17
Q

what are toll-like receptors?

A
  • discovered in drosophila ; important in dorsoventral development but also in defence
  • PR molecs. for bacterial and viral ligands
  • stimulate cytokine relase
18
Q

TLR signalling pathway

A
  • recognise specific PAMPs present on pathogens.
  • receptor activated
  • adapter molecules recruited to TLR initiating signalling cascade
  • downstream signalling cascade = activation of various TFs
  • activated TFs translocate to nucleus and induce expression of pro-inflam. cytokines and chemokines.
  • inflam. response
  • TLR signalling downregulated to prevent excessive inflammation and maintain immune homeostasis
19
Q

TLR in cancer therapy

A
  • BCG used in adjuvants TLR2 and 4 mostly used in bladder cancer
  • MPL, IPS, TLR4 agonist
  • Stimuvex; MUC1 peptide and AS04 used in NSCLC
20
Q

intracellular PRR

A
  • Poly I;C, synthetic dsRNA. Direct effect on tumors causing cell death; induction of apoptosis
  • activated in immune response
  • used in glioma, prostate, breast, melanoma, ovarian
21
Q

T cells and DCs

A
  • induce death in a TC = correctly stimulate the DC which endocytoses it
  • TC will release signals = activate/mature the DC
  • correct presenation of the TC peptides by the DC to the adaptive response
22
Q

what are HSPs?

A

heat shock proteins
- some HSP are stress inducible, others are constitutively expressed
- some HSP are upregulated by specific stress type, others by many stresses

23
Q

HSP; effects on adaptive immune system

A

processing of peptide for presentation

24
Q

HSP; effects on innate immune system

A

cytokine production and upregulation of co-stimulatory molecules

25
Q

therapeutic use of HSP in cancer

A
  • isolated the proteins from many different tumors. From range of different immunogeneicties
  • all proteins identified were members of hsp70 and 90 families
  • HSP derived from tumor lines is protective whereas HSP derived from normal tissue isnt
26
Q

therapeutic use of HSP-peptide complexes

A
  • HSP is increased in tumor tissue
  • at present; 150 centres looking at the therapeutic use of HSP-peptides in cancer
  • most non-randomised trials
  • data so far is suggestive>definitive
27
Q

antigenics related to HSP

A
  • still no definitive results
  • trials; at phase I/II/III in RCC; melanoma, colorectal, non-Hodgkin;s lymphoma, pancreatic; gastric; b-cell lymphoma
  • all suggest some response
28
Q

methods of tumor killing

A
  1. direct tumor cell killing
  2. immune mediated tumor cell killing
  3. vascular and stromal cell ablation
29
Q

growth factor blocks; trastuzumab (herceptin)

A

targets ERBB2 (human epidermal growth factor) on breast cancer cells.
blocks ERBB2 signalling and allows targeting of ADCC

30
Q

what is ADCC

A

antibody-dependent cell-mediated cytotoxicity

31
Q

growth factor blockers; bevacizumab (avastin)

A

targets VEGF and block signalling.
Used against NSCLC, colon cancer, glioblastoma and kidney cancer

32
Q

what therapies induce apoptosis?

A
  • rituximab; anti CD20, used for CD20 positive Bcell non-hodgkin’s lymphoma and chronic lymphocytic lymphoma
  • alemtuzumab (campath); anti CD25; used for B-CLL
33
Q

immunomodulation

A

Ipilimumab (anti CTLA-4), blocks the inhibition due to CTLA-4 signalling.
used in metastatic melanoma.

34
Q

Yttrium-labelled ibritumomab tiuxetan

A

antibody to CD20 delivering radiotherapy to follicular B-cell NHL

35
Q

Brentuximab vedotin

A

antibody to CD30 delivering toxin to CD30+ B-cells in NHL

36
Q

ontak

A

IL2 delivering diphtheria toxin in T cell lymphoma

37
Q

new approaches; checkpoint inhibition

A
  • blockade of effect cell death
  • antibody against PD1
  • expressed on T cells and can induce apoptosis when bound by PDL-1
  • PDL-1 found oon timor cells
38
Q

targetting inflammation

A
  • can be both pro and anti tumrigenic
  • Coley’s toxin ; acute inflammation though to be good, chronic inflammation isn’t
39
Q

why is inflammation bad?

A
  • regulation of the immune response
  • Tregs induced which turn off response
  • Myeloid derived suppressor cells / M2 cells
  • Th2 switch
  • NKT cells make IL13 which induces myeloid cells to produce TGFb
40
Q

Th1 vs Th2

A
  • Th1 response is good and will resolve tumor, Th2 isn’t and won’t.
  • Aim of therapy is to resotre the Th1 response