Exam 1 lecture 6 Flashcards
What is the first attempted immunotherapy? how did it work?
Coleys toxin. Promotes non specific inflammatory response
What are the types of cells that show adaptive immunity? WHich ones produce antibodies?
T cells, B cells, Plasma cells
B cells promote antibodies
Why do antibodies produced by mice need to be changed
They need to be changed to mimic a human orotein or they will be recognized as foreign by the patients immune system
Explain the nomenclature of antibodies with exapmles
-o = mice
-Xi= chimeric (cetuximab)
-Zu= humanized (trastuzumab)
-U= fully humanized (ramucirumab)
What are the two ways antibody binding to cell surface receptor affect the cell? Compare with Kinase inhibitor
- Binding of large proteins to cell surface receptors will inhibit function
- It will also activate complement (ADCC)
Antibody activates complement AND blocks binding. Kinase only does one (blocks binding)
How does the amount of HER2 in a cell matter
Normal amount of HER2 send signals telling cells to grow and divide
Too many HER2 receptors send more signals, causing cells to grow too quickly (HER2 overexpressed in 30% of all breast cancers)
Trastuzumab (herceptin) MOA, indication and toxicity
Specific for HER2 and immune response to antibody is reduced by human framework of IgG
Herception binds to receptor and induces antibody dependent cytotoxicity. Also induces receptor internalization and degradation.
primary indication- Tx of breast cancers that overexpress HER2
toxicity- Risk of hypersensitivity
FLu like symptoms
Cardiomyopathy
MOA of pertuzumab?
Also binds HER2, but does it differently to trastuzumab.
Pertuzumab binds to HER2 and inhibits dimerization
What drug is pertuzumab used in combination with?
Trastuzumab. Due to different mechanisms of effecting HER2.
Cetuximab MOA, indication and toxicity
MOA- EGFR antibody competitive inhibitor that inhibits binding of EGF and TGF-alpha. It also blocks phosphorylation and activation of kinases. These lead to inhibition of cell growth and induction of apoptosis.
Primary indication- Colorectal and head and neck cancer
Toxicity- WARNING!!! SEVERE infusion reaction in 3% of patients. usually 1st dose.
Rash
Fever
Why would we expect the toxicities associated with cetuximab
EGFR is important for skin maintenance. This forms rash. Rash=better prognosis
Infusion rxn comes from non specific immune response to antibodies
What are the two antibodies that target EGFR?
Cetuxumab
panitumab
No infusion side effect with panitumumab
Panitumab MOA, toxicity, indication
MOA- competitively inhibits EGF and TGF-a. This blocks phosphorylation of kinases and leads to inhibition of cell growth and apoptosis
side effects- skin rash, diarrhea
indication- treatment of colorectal cancer
MOA of bevacizumab? Indication?
Specific for VEGF
Binds to VEGF and blocks its interaction with endothelial receptors.
Blocks endothelial cell proliferation
Used in combo with 5-FU based chemo for 1st line tx of colorectal cancer
Is there efficacy of bevacizumab as single agent
No
Difference between bevacizumab and ramucirumab
Bevacizumab binds ligand, ramucirumab binds receptor
Explain the 2 tiered targeting effect of antibody therapy compared to small molecule kinase inhibitor
- bind to target and inhibit function
- activate ADCC (complement).
Complement leads to different outcome compared to small molecule
describe why combining uses for pertuzumab and trastuzumab both defy and comply wuth general rules
against- shared target= shared toxicity
For- Different binding sites of HER2, different mechanism of inhibition, enhanced ADCC
What is CD 20 and what does it do?
CD20 works with B cell receptor to drive proliferation of B cells
What happens when antibody binds to CD 20
antibody binding to CD20 inhibits B cell proliferation and induces antibody dependent cytotoxicity
What are the drugs that target CD 20
Rituximab
ofatumumab
Rituximab MOA
Binds Cd 20 .
CD 20 is expressed on normal B cells, but also90% of B cell non-hodgkins lymphoma cells
Where are CD-38 found
Plasma cells
Name CD 38 antibodies
Daratumumab
What cells do antibodies for CD 38 like daratumumab eliminate?
Multiple myeloma cells (via ADCC or CDC)
Also eliminated NK cells
Name an antibody drug conjugate
Ado-trastuzumab emtasine (TDM1)
MOA of TDM1
Trastuzumab binds to HER/Neu receptor and leads to usual herceptin response.
Emtasine enters cell and inhibits microtubule assemble.
What happens to emtasine toxicity in TDM1
Emtasine toxicity significantly reduced due to selectivity to HER2
toxicity of TDM1
Adverse effects of trastuzumab
hepatotoxicity
Explain central tolerance
Negative selection of T cells that bind to “self” peptides.
If cells have no interaction with self or too tightly to self leads to apoptosis
explain peripheral tolerance
Self reactive T cells that escape the thymus into peripheral tissues are inactivated to an unresponsive state
How are T cells activated
T cell encounters antigen in combination with MHC
If T cell recognizes antigen it will be activated. A cytolytic T cell will kill that cell and proliferate creating a population of antigen specific T cells
Once infection clears they turn to memory cells.
What is BiTe (Bi-specific T cell engager)
Binds simultaneously to CD 19 on B cell and on CD-3 which is present on T cell and forces them together
Name the BiTe drugs
Blinatumomab
Mosenutuzumab
Teclistamab
Taquetamab
MOA of blinatumomab
BiTe that targets T cells present on cancer.
Binds CD-3 to physically bring an activated T cell into proximity with CD 19 expressed on B cells
Mosenutzumab MOA
BiTe targeting CD3 and CD20 on non hodgkins lymphoma
side effects of mosenutzumab
Cytokine release syndrome
Teclistamab MOA
Targets BCMA (b cell maturation antigen) on multiple myeloma
Taquetamab MOA
BiTe on GPCR Targeting multiple myeloma cells
What do CTLA-4 and PD-1 do
They act as brakes or checkpoints on immune systems.
What happens when we block CTLA 4 and PD-1
they can reactivate T cells
What are CTLs
cytotoxic T lymphocytes. They have the capacity to recognize and destroy malignant tumor
Ipilimumab MOA
Binds CTLA-4 receptor and reverse CTL inhibition
How is CTL inhibited
Tumor cell antigen recognized by dendritic cells which present antigens to CTLs.
dendrtitic cells deliver inhibitory signal to CTLs via CTLA-4 receptor
pembrolizumab MOA
monoclonal antibody that binds PD-1 receptor and blocks its interaction with PDL-1 and 2
Where is PD-1 expressed?
T cells
Where is PD-L1 expressed?
Macrophages and tumor cells
What happens when CTLA-4 and PD-1 are blocked
CTLA-4 and PD-1 blockade prevents inhibitory signal within T cells leading to enhanced tumor cell killing
Atezolizumab MOA? Who would be excluded?
Binds PD-L1 and blocks interaction with PD-1
people with autoimmune disease and medical conditions requiring immunosuppressions are excluded
sipuleucel (provenge) MOA? Indication?
Not a drug- more like a process.
Activates APCs collected from patient and reinfused into patient
used for metastaic prostate cancer
CAR T cell therapy MOA
Programming T cells by genetically entering receptors that bind cancer
Which antibody is effective against metastatic melanoma and targets CTLA4
Ipilimumab
Which protein is used as a cancer biomarker test to determine eligibility for treatment of NSCLC with pemrolizumab
PDL-1
Common target for CAR-T
CD-19
MOA of bispecific T cell enzymes
They bring T cells and cancer cells in close proximity to facilitate T cell mediated cytotoxicity
