9 - MAb in Cancer Flashcards
1
Q
Classes of monoclonal antibodies for cancer
A
- CD antigens (alemtuzumab)
- Vascular endothelial growth factor inhibitors (bevacizumab)
- Epidermal growth factor receptor inhibitors (trastuzumab)
- Immune checkpoint inhibitors (nivolumab)
2
Q
Describe the general mechanism of cancer
A
- Multistep carcinogenesis model
- Discovery of oncogene and tumour suppressor gene (c-myc, c-fos; Rb, p53)
- Two-hit hypothesis (Knudson hypothesis)
- - Activator of pro-oncogene
- - Inactivation of tumour suppressor gene - Multiple-hit hypothesis aka hallmarks of cancer (from 6 hallmarks to 10 hallmarks)
3
Q
Mechanisms of antibodies in cancer
A
- Direct tumour cell killing
- Receptor antagonist, receptor agonist
- Conjugated antibody
- Antibody + enzyme bind to tumour cell - Immune-mediated tumour cell killing
- Phagocytosis, complement, ADCC, cross-presentation and T cell activation - Vascular and stromal cell ablation
- Antibodies inhibits growth of blood vessel or growth of stroma cell (present in tumour)
4
Q
Target and indication for trastuzumab
A
- Target = ERBB2
- Indication = ERBB-2+ breast cancer, as a single agent or in combo w/ chemo for adjuvant or palliative tx; ERBB-2+ gastric or gastroesophageal junction carcinoma as first-line tx in combo w/ cisplatin & capecitabine or 5-fluorouracil
5
Q
Target and indication for bevacizumab
A
- Target = VEGF
- Indication = first-line or second-line tx of metastatic colon cancer in combo w/ 5-fluorouracil-based chemo; first-line tx of advanced NSCLC in combo w/ carboplatin and paclitaxel in px who haven’t yet received chemo; in conjunction w/ IFNs to treat metastatic kidney cancer
6
Q
Target and indication for cetuximab
A
- Target = EGFR
- Indication = in combo w/ radiation for initial tx of locally or regionally advanced SCCHN
7
Q
Target and indication for panitumumab
A
- Target = EGFR
- Indication = single agent for tx of pretreated EGFR-expressing metastatic colorectal carcinoma
8
Q
Target and indication for alemtuzumab
A
- Target = CD52
- Indication = single agent for tx of B cell chronic lymphocytic leukemia
9
Q
Purpose of MAb and how are they organized?
A
- Purpose = can be used to improve overall survival, increase time to progression, and delay time to recurrence of many oncologic diseases
- Organized based on their target:
- CD cell surface antigens (CD20, CD52)
- Vascular endothelial growth factor (VEGF) receptor
- Epidermal growth factor receptor (EGFR, HER2)
- Immune checkpoint (CTLA-4, PD-1)
10
Q
Classes of Mab – CD antigens
A
- Cluster of differentiation (cluster of designation), often called CD, is a protocol used for the identification and investigation of cell surface molecules present on leukocytes
- CD molecules can act in numerous ways, often acting as receptors or ligands important to the cell
- Signal cascade is usually initiated, altering the behaviour of the cell
- Some CD proteins don’t play a role in cell signalling, but have other functions, such as cell adhesion
- Around 250 different proteins
11
Q
Alemtuzumab – target, function, and use
A
- Unconjugated, humanized, IgG1 kappa monoclonal Ab directed against the 21-28 kDa cell surface glycoprotein CD52
- CD52 is not shed or internalized so making it an excellent therapeutic target
- CD52 is highly expressed in certain cancer cells (chronic lymphocytic leukemia, CLL)
- Compound exerts its effect by binding to CD52 antigenic sites and stimulating cross-linking by Abs
- Complement dependent cytotoxicity (CDC)
- Direct cellular apoptosis via NK activity
- As a single agent for the tx of B cell chronic lymphocytic leukemia
12
Q
Alemtuzumab – dosage and administration
A
- Administered according to a dose-escalation schedule
- Single doses of > 30 mg and weekly doses > 90 mg are not recommended, due to risk of severe pancytopenia
- Should be infused through IV line that doesn’t contain any other drug substances
13
Q
Classes of Mab – vascular endothelial growth factor inhibitors
A
- Folkman theory -> development of new blood vessels (angiogenesis) must occur for tumour growth beyond 1-2 mm^3
- As tumours enlarge, the centers become hypoxic and stimulate angiogenic growth factors
- VEGF is thought to be one of the most potent growth factors and has been shown to induce neovascularization for malignant cells in an autocrine fashion
- Levels of VEGF in blood have been correlated w/ poor prognosis, disease recurrence, and metastases in a variety of neoplasm
14
Q
Steps of angiogenesis in cancer formation and metastasis
A
- Premalignant stage = avascular tumour
- Malignant tumour -> angiogenic switch
- Tumour growth – vascularized tumour
- Vascular invasion -> tumour cell intravasation
- Dormant micrometastasis -> seeding in distant organs
- Overt metastasis -> secondary angiogenesis
Angiogenesis plays a role in tumour progression at stages 2, 3, 4, and 6
15
Q
Bevacizumab – target and function
A
- Currently the only FDA approved VEGF inhibitor available
- Humanized MAb that consists of a normal human IgG and the VEGF binding residues from a murine neutralizing Ab
- Designed to block a protein called vascular endothelial growth factor (VEGF) which promote growth of blood vessels
- Once a tumour reaches a critical size (0.5-2 mm) more blood vessels are required for more nutrients and oxygen to grow
- Unlike chemo that attacks the cancer cells, bevacizumab starves tumour cells (anti-angiogenesis) from growth
- Has demonstrated both cytostatic and cytotoxic effects
16
Q
Bevacizumab indications
A
- Metastatic colon cancer -> first-line and second-line tx in conjunction w/ 5-fluorouracil-based chemo
- Non-small cell lung cancer -> first-line tx of advanced NSCLC in combo w/ carboplatin and paclitaxel in px who haven’t received chemo
- Glioblastoma -> single agent in px whose tumour has progressed after initial tx
- Kidney cancer -> conjunction w/ IFNs
17
Q
Bevacizumab dosage and administration; most common SE
A
- Preparation w/ NS for infusion
- Dextrose solutions should never be used as diluents or administrated concomitantly
- Infusion time can be 90, 60, or 30 mins
- Most common SE = back pain, proteinuria, dry skin, headache
18
Q
Epithelial growth factor receptor inhibitors
A
- EGFR/ HER-1 or EGFR 2/HER-2 are transmembrane glycoproteins constitutively expressed in many normal epithelial tissues including skin and hair follicle
- EGFR and HER are members of Erb family of receptors that play a role in normal cell growth and differentiation
- HER-2 protein overexpression can occur in up to 30% of px w/ metastatic breast cancer and is often associated w/ more aggressive disease, a faster relapse time, and overall poor prognosis
- Trastuzumab (Herceptin) is a recombinant DNA-derived humanized MAb that selectively binds to the extracellular domain of the human HER-2 receptor w/ high affinity
19
Q
Function of EGFR inhibitors
A
- Inhibit angiogenesis
- Inhibit cell migration and invasion
- Inhibit cell proliferation
- Enhance apoptosis
20
Q
Trastuzumab – indication
A
- Indicated for HEB2 overexpressing breast cancer
- Single agent for tx of px w/ HER-2 over-expressing metastatic breast cancer and who had previously been treated w/ chemo
- In combo w/ paclitaxel in px w/ HER-2 over-expressing metastatic breast cancer and hadn’t received any prior chemo
- Herceptin indicated for HER-2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma in combo w/ cisplatin and capecitabine or 5-fluorouracil for those who haven’t received prior tx
21
Q
How is HER2 positive breast cancer diagnosed?
A
- Immunohistochemistry (IHC) test
- - Most commonly used test
- - Determines amount of HER2+ receptor protein on cancer cell surfaces
- - Scale of 0 to 3+ is used => 0 or 1+ = HER2-; 2+ = should be retested using the FISH test; 3+ = HER2+ - Fluorescence in situ hybridization (FISH) test
- - Most accurate test
- - Determines if the tumour cells have a normal number of HER2 genes (compares # of HER2 genes w/ the # of normal genes in the tumour cells)
- - The tumour is HER2+ if there are 2 or more HER2 genes for every normal gene in the cells
22
Q
Trastuzumab dosage
A
- Initial dose = 4 mg/kg over 90 min infusion
- Weekly maintenance dose = 2 mg/kg over 30 mins
- Tx duration = indefinitely (or until disease progression) in metastatic breast cancer; 52 weeks as adjuvant tx
23
Q
Trastuzumab safety issues
A
- Heart problems – CHF, reduced heart function w/ or w/o sx, highest in people w/ both Herceptin and anthracycline
- Infusion reactions -> fever and chills, N/V, headache, dizziness, SOB
24
Q
What are the 3 sites for therapeutic intervention w/ immune checkpoint inhibitors?
A
- Promoting antigen presentation functions of dendritic cells
- Promoting production of protective T cell responses
- Overcoming immunosuppression in the tumour bed
25
Q
Immune checkpoint inhibitors – function; describe the normal immune response vs. tumour immune evasion
A
- Immune checkpoint consists of several proteins on cell surface of both cytotoxic T lymphocytes and cancer cells
- These proteins can either stimulate or inhibit cytotoxic T lymphocytes
- Cancer cells are able to express proteins that inhibit cytotoxic T lymphocyte
- PD-1 is a protein on the surface of activated T cells
- PD-L1 or PD-L2 bind to PD-1, which inactivates the T cell
- PD-1 receptor = nivolumab, pembrolizumab, pidilizumab
- PD-L1 ligand = atezolizumab
- Normal immune response = T-cell activation and tumour attack
- Tumour immune evasion = T-cell inactivation through the PD-1 immune checkpoint
- Normal immune response restored = T-cell reactivation and decreased tumour growth through PD-1 immune checkpoint inhibition; while having an effect on the tumour, this could also affect normal cells
26
Q
Nivolumab – function
A
- A human IgG4 anti-PD-1 MAb
- Doesn’t exert direct effect on tumour by cytotoxic or tumour growth inhibition
- Blocks a negative regulator of T-cell activation and response thus allowing the immune system to attack the tumour
- Normally, PD-L1 and PD-1 interaction is one way that the body regulates the immune system to avoid an overreaction
- Many cancer cells make PD-L1 which inhibits T cells from attacking the tumour
27
Q
Nivolumab dosage, administration, and SE
A
- IV infusion over 60 mins
- Indicated for unresectable or metastatic melanoma, metastatic non-small cell lung cancer, and advanced renal cell carcinoma
- Can be used w/ ipilimumab for melanoma
- Immune-mediated diseases -> pneumonitis, colitis, hepatitis, skin adverse reactions
- Serious SE = pneumonia, PE, dyspnea, pleural effusion
- Common SE = fatigue, MSK pain, cough, dyspnea, decreased appetite
