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Carcinogensis + Anticancer drugs > Antibody immunotherapy > Flashcards

Antibody immunotherapy Flashcards

1
Q

Outline the basics of antibodies

A

Produced by B cells in response to specific antigens
5 classes (G,A,M,D,E)
Monoclonal are made from identical immune cells
Each Fab domain has variable (V) and constant (C)

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2
Q

What are murine therapeutic mAbs (o)

A

potentially most immunogenic and possibly less effective

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3
Q

What are chimeric therapeutic mAbs (xi)

A

human constant region with non-human (murine) variable regions

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4
Q

What are humanised therapeutic mAbs (zu)

A

human constant regions with some complementary determining regions replaced with non-human sequences

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5
Q

What are chimeric/humanised mAbs (xizu)

A

A combination of both antibodies structure

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6
Q

how are human (u) monoclonal antibodies derived

A

using transgenic mice or phage display

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7
Q

Explain how monoclonal antibodies are dosed

A
  • Dosed as either FIXED dose or by subject body weight (mg/kg), the frequency of administration is
    MAb-dependent
  • MAbs relatively stable in the circulation and can be given ~once per week or at greater intervals
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8
Q

How do humans receive mAbs

A

given by IV but some can be given by sub-cutaneously

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9
Q

Evaluate the different routes of administration for mAbs

A
  • IV is optimal administration route for most MAbs due to greater and more rapid bioavailability
  • SC administered MAbs are taken up by lymphatic channels and may not reach maximum plasma concentration for several days
  • Oral MAbs are large molecules, not highly lipophilic, unstable in GI environment
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10
Q

How do MAbs leave the circulation into tumours

A
  • leaves the vasculature by hydrostatic and osmotic pressure (may differ due to tissues)
  • There is complex penetration process into tumours
  • Volumes of distribution relatively small
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11
Q

Why might biopsied solid tumours show non uniform distribution of MAbs in tissues

A

Barriers to inward diffusion of mAbs =
- high interstitial pressure
- poor lumphatic drainage
- leaky vasculature
- hypoxic core
- Binding site barrier hypothesis

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12
Q

What is the binding site barrier hypothesis

A

MAbs with very high affinity for target Ag will bind to first Ag encountered in tumour and thus accumulate in regions surrounding tumour vasculature

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13
Q

Why might the volume of distribution by relatively small for mAbs

A
  • Indicates distribution restricted to blood and extracellular space compartments
  • Low tissue: blood ratio common: 0.1 – 0.5
  • Poor CNS penetration: CSF levels only 0.1 to 1% of respective serum levels
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14
Q

How are mAb eliminated

A

Most mAbs are eliminated by reticuloendothelial macrophages
(half-lives of MAbs are quite variable, from 2 days to several weeks)
Two general clearance pathways –
(i) Linear clearance via nonspecific catabolism
(ii) Target-mediated drug disposition (TMDD, target-mediated clearance)

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15
Q

Explain target-mediated drug disposition clearance

A

Drugs bind with high affinity to its biological target
= these drug-target complex are internalised and degraded
[membrane target = receptor-mediated endocytes] [Soluble targets = complex often eliminated by RES]
Saturable mechanism because finite amount of target in body

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16
Q

How does protein/target conc effect TMDD saturation therefore elimination of mAbs

A
  • If [protein] < [target]: no TMDD saturation
    (Higher CL and shorter half-life)
  • If [protein] > [target]: TMDD saturation
    (Lower CL and longer half-life)
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17
Q

What are the mechanism of action of mAbs (Direct effects of anti-tumour IgG)

A
  • Blocking binding of an activating ligand responsible for the survival of the cancer cell
  • Inhibiting dimerization of a receptor, thereby blocking an activation signal
  • Inducing an apoptotic signal by cross-linking a receptor
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18
Q

What are the mechanism of action of mAbs (Immune-mediated effects of anti-tumour IgG)

A
  • Mediate antibody dependent cellular cytotoxicity (ADCC) with natural killer cells, monocytes/macrophages or granulocytes acting as immune effector cells
  • Fixation of complement can opsonize the target cell and enhance lysis by monocytes and granulocytes
  • Complement mediated cytotoxicity - results directly in target cell death through development of a membrane attack complex
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19
Q

Successful mAb-based therapeutics have been based on a number of strategies such as

A
  • Anti-tumour IgG
  • Angiogenesis inhibition
  • Immune checkpoint blockade
  • Radio-immune therapy
  • Antibody-drug conjugate
  • Chimeric antigen receptor (CAR) T cells
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20
Q

How do anti-tumour IgG work

A

IgGs that bind to target cancer cells can (A) mediate Antibody dependent cellular cytotoxicityby immune effector cells, induce CMC, or result in direct signaling induced death of cancer cells (e.g. herceptin and rituximab).

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21
Q

Why can blocking immune checkpoint be a strategy to treat cancer using mAb

A

block inhibitory signals on T cells thereby resulting in a stronger anti-tumour T cell response

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22
Q

How does radio-immune therapy work

A

Radioimmunoconjugates deliver radioisotopes to the cancers cells

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23
Q

what do antibody drug conjugates do

A

deliver highly potent toxic drugs to cancer cells

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24
Q

How is antibody based retareting of cellualr immunity carried out ?

A
  • mAb variable regions are used to retarget immune effector cells towards cancer cells using bispecific mAb to recognise the cancer cells AND activating antigen on immune effect cells
  • Gene therapy approach where DNA for mAb variable region, fused to signalling peptide, is transferred to T cells making them chimeric antigen receptor T cells
25
Q

What is Rituximab

A

1st mAb approved to trwat cancer
- chimeric anti-CD20 mAb
used primarliy in the treatment of B-cell non Hodgkin lymphoma and chromic lymphocytic leukaemia

26
Q

Outline the benefits of using Rituximab with chemotherapy

A

[Often used with CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone)]
Progression free survival (PFS) greatly improved in patients with relapsed/resistant follicular lymphoma when rituximab added to CHOP (51.5 vs. 14.9 months, p<0.001, led to the FDA approval

27
Q

What is Trastuzumab (Herceptin)

A

A humanised anti HER2 Mab (binds to extracellular domain of HER2 receptors

28
Q

What is HER2

A

member of the erbB family of transmembrane tyrosine kinase receptors
= regulates cellular growth, differentiation and survival

29
Q

What is Trastuzumab used to treat? history?

A

Major impact on treatment of metastatic HER2+ breast cancer
Low response rates when used alone however when combined with chemotherapy, respponse rates is nealy 70%

30
Q

What can trastuzumab be used along side

A

Chemotherapy
Combined with taxane or docorubicin/cylophosphamide
Synergic activity with vinca alkaloids, platinums, capecitabine & gemcitabine

31
Q

Outline the HERA trial

A

Phase III trial = After 1 year of adjuvant herceptin treatment as SOC in early stage HER2+ BC
- 24% reduction in risk of death

32
Q

what are the toxicities surrounding trastuzumab and the contra-indications

A

Most significant: cardiotoxicity, incl. congestive heart failure
(may be related to HER2 expression on cardiac myocytes)
Synergistic effects when used with anthracyclines, so avoid combining
Measure ejection fraction before therapy, then every 3 months during treatment
Infusion reaction (40%): pre-treatment with acetaminophen, diphenhydramine
Give first dose over 90 minutes, subsequent doses over 30 mins if tolerated
Rare pulmonary complications: avoid in patients with pre-existing lung disease but not lung metastases

33
Q

What is Cetuximab (Erbitux)

A

Chimeric anti EGFR MAb
Binds to extracellular domain of EGFR → prevents ligand dependent signalling and receptor dimerisation
Also induces receptor internalisation and degradation, thus inhibiting cell growth and survival, induction ofapoptosis, and decreasedmatrix metalloproteinase andvascular endothelial growth factor production

34
Q

What is the EGFR

A

EGFR: epidermal growth factor receptor
EGF signalling pathway drives growth/differentiation of epithelial cells. EGFR belongs to ErB family of transmembrane receptor tyrosine kinases

35
Q

Why are 250mg/m3 doses of cetuximab needed

A

Non-linear PK
- Needed to saturate EGRF pools in the body

36
Q

what are the therapeutic uses of cetuximab

A
  • Metastatic colorectal cancer
    (single agent use in EGFR+ metastatic colorectal cancer in patients intolerant to irinotecan/ in combination with irinotecan in patients refractory to/ intolerant to oxaliplatin, irinotecan, and 5-FU)
  • Non-small cell lung cancer
  • Head and Neck SCC
37
Q

what are the toxicities involved with cetuximab use

A
  • Rash (greater than 50%) pruritus, nail changes, headache, diarrhoea
  • Rare but serious: interstitial lung disease, hypomagnesemia
38
Q

What is Panitumumab

A

Fully human anti-EGFR mAb
Binds to extracellular domain of EGFR similarly to cetuximab,

39
Q

What are the therapeutic uses of Panitumumab

A

Improves PFS in metastatic colorectal cancers with EGFR expressing tumours
Activity in lung and HPV+ head and neck cancer

40
Q

What are the adverse effects of Panitumumab

A

Advantage: fully human, so less likely than cetuximab to induce immunogenicity
Toxicity profile similar to cetuximab: rash, pulmonary fibrosis, electrolyte abnormalities

41
Q

What is Bevacizumab

A

Humanised anti-VEGF mAb
Binds and neutralises the biologically active forms of VEGF by recognising the binding sites for VEGF on endothelial cells (prevents VEGF from binding to its receptors)

42
Q

what is VEGF

A

vascular endothelial growth factor
- important role in tumour angiogenesis

43
Q

What are the therapeutic uses of bevacizumab

A

Metastatic colorectal cancer (in conjunction with 5-FU based chemo), Ovarian cancer, Cervical cancer, Non-squamous NSCLC (with atezolizumab, carboplatin and paclitaxel), Metastatic breast cancer (with paclitaxel)
Glioblastoma (single agent following prior therapy)
Unresectable HCC (with atezolizumab)

44
Q

What are the side effects of Bevacizumab

A

GI perforations – (Fatal GI perforation in 0.2-1% of ALL patients in trials)
GI fistula in 2% CRC patients and less in others
Delayed wound healing/complications – NOT give within 28 days of surgery - cannot be restarted until wound healed
Hypertension – all grades 34% of trial patients
Proteinuria – all grades 0.7 – 38% of trial patients G4 (nephrotic syndrome 1.4%)
Haemorrhage (including pulmonary haemorrhage or haemoptysis) severe < 5%
Arterial and venous thromboembolism – DISCONTINUE in anyone with an arterial thrombotic event caution in those with venous thrombotic event as at risk of further even if anti-coagulated
Posterior reversible encephalopathy syndrome – RARE reports

45
Q

What are immune checkpoints

A

To a group of proteins/pathways found on immune cells. They are hardwired into our immune systems and are essential to maintain self-tolerance
CTLA-4 & PD-1 are the most widely studied
= Many of these immune checkpoints are initiated by ligand–receptor interactions so could be readily blocked by antibodies or modulated by recombinant forms of the ligands or receptors.

46
Q

what are the 3 subtypes of immune checkpoint inhibitors

A

CTLA-4 inhibitors, PD-1 inhibitors and PD-L1 inhibitors
= Can block both CTA4 + PD-1 at the SAME time

47
Q

Inhibition of which checkpoint causes milder severe immune-related adverse effects

A

PD-1 vs CTLA-4
Monotherapy = 10% vs 50% develpoed Grade3/4 IrAE

48
Q

what are the common adverse effects associated with immune checkpoint inhibitors

A

Rash, Colitis, Hepatitis, Pneumonitis, Thyroiditis
The median time to onset of irAEs differs depending on the type of toxicity, can happen up to 2 years after last dose

49
Q

How is toxicity of immune checkpoint inhibitors fought

A

Steriods oral or IV
Sub-specialty teams used

50
Q

Explain what is known about Radioimmunotherapy conjugated mAbs
- Give names

A

Used in Haematological cancer
- 131I-tositumomab (Bexxar)
- 90Y-ibritumomab tiuxetan (Zevalin)

51
Q

Outline what is known about 131 l-tositumomab

A

Anti-CD20 murine mAb combined with cytotoxic beta-emitting isotope
Highly effective in treatment of relapsed or refractory low-grade, follicular, or transformed B-NHL (effective in rituximab-refractory disease)
Well-tolerated: toxicity primarily haematologic

52
Q

Outline what is known about 90 Y-ibritumomab tiuxetan

A
  • Anti-CD20 murine mAb combined with cytotoxic isotope
  • Sig prolongs time to progression in low grade or transformed NHL
  • Use restricted to patients having less than 25% malignant infiltration of bone marrow
  • Increased risk of myelosuppression in those having higher infiltration
53
Q

Outline what is known about antibody drug conjugates
Examples

A

Antibody-drug (cytotoxic agent) conjugate
ado-trastuzumab + emtansine (T-DM1)
= Kadcyla
Chemotherapy microtubule disrupting agent is delivered to HER2 overexpressing cancers cells
Kadcyla is licensed for the treatment of HER2 +ve metastatic breast cancer following failure of trastuzumab alone

54
Q

Describe the EMILIA trials

A

978 patients with HER2+ BC previously treated with trastuzumab and a taxane
- either assigned to (ado-trastuzamab emtansine) or (capecitabine + lapatinib)
An improvement in both progression free survival and overall survival in antibody group
[clinically sig improvement in the overall response rate 44 vs 31]

55
Q

Outline CAR T-cell therapy

A
  • Blood from patient is removed to get T cells
  • CAR T cells are made and grown
  • CAR T cells are infused into patients
  • CAR T cells bind to cancer cells and kill them
56
Q

What can be used as Adoptive cell transfer therapies

A
  • Chimeric antigen receptor T cell therapy = uses portions of synthetoc Ab that can recognise specific antigens
  • Tumour infiltrating lymphocytes
  • Engineer patient T cells to express a specific T-cell receptors which recognise antigens that are inside tumour cells
57
Q

Why would Tisagenlecleucel Chimeric Antigen Receptor T Cell (Kymriah)
be used

A

Where all other treatment options have been unsuccessful for relapsed or refractory B-cell acute lymphoblastic leukaemia (ALL).

58
Q

why would Axicabtagene Ciloleucel (Yescarta) [CAR Tcell] be used

A

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after 2 or more systemic therapies

59
Q

what toxicites are associated with CAR T cells

A

Cytokine release syndrome = significant fever & hypotension main presenting features; treat with anti-IL6 mAb if severe (e.g. Tocilizumab. Response to therapy can be compromised.)
Neurotoxicity = Often reversible though can be prolonged

Carcinogensis + Anticancer drugs (16 decks)

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