Oncology Immunotherapy Flashcards
which of the following is used to describe a cancer derived from pigment producing cells of the eye
a) teratoma
b) papilloma
c) sarcoma
d) melanoma
e) all of the above
melanoma
which of the following is NOT a hallmark of cancer
a) resisting cell death
b) evading growth suppressors
c) enabling replicative immortality
d) activating invasion and metastasis
e) increasing in cell size
increasing in cell size
molecular pathology is different from traditional pathology because…
It uses some kind of genetic testing to indicate therapy or
predict for tumor recurrence
which of the following terms is associated with substituition of tissue type of another
a) hyperplasia
b) dysplasia
c) metaplasia
d) desmoplasia
metaplasia
which is an example of a tumor suppressor
a) BRCA
b) HER2
c) CDK4/6
d) HPV
BRCA
Coley’s toxin
sometimes referred as MBV for mixed bacterial vaccine
- first attempt to use ___ and hyperthermia against cancer
- promotes a non-specific inflammatory response in the hopes of activating the immune system to kill cancer cells
- not FDA apploved
immunotherapy
B cells are ___ producing cells
- ___ arm of the immune system
antibody
humoral
“humanization” of antibodies
- antibodies produced in mice need to be changed to mimic a human protein or they will be recognized as ___ by the patients immune system
- using molecular biology and protein expression one can construct a cell line that secretes antibodies that are mostly human except for complementarity determining region (CDR); ___
- there are transgenic mice that have been constructed to express the human VDJ regions of the genome so they produce fully ___ antibodies
- foreign
- humanized
- human
stem of all monoclonal antibodies is ___
___ = o
chimeric = ___
___ = zu
fully human = ___
- mab
- mouse
- xi
- humanized
- u
antibody binding alone can lead to several anticancer events
- binding of antibodies to cell surface receptors often times will inhibit their function
- binding of several antibodies to receptor on surface of cancer cell can lead to ___ dependent cytotoxicity (CDC) and ___-dependent cellular cytotoxicity (ADCC) and ___ elimination of the tumor cell by the immune system
- this 2 tiered effect may be why blocking antibodies have unique effects over kinase inhibitors
complement
antibody
selective
HER2 is genomically ___ in breast cancer
amplified
T or F: HER2 has a ligand
FALSE
- does not require ligand
targeting cell signaling in drug development
good figure to know
Trastuzumab (Herceptin)
recombinant ___ monocolonal antibody specific for ___
- contains receptor binding domain of mouse mab linked to a human IgG framework
- human framework reduces immune respone to antibody
HER2 protein is overexpressed in 25-30% of all breast cancers
Herceptin binds to the receptor and induces ___ dependent cellular cytotoxicity
- also induces receptor ___ and ___
Primary indication for HER2 + cancer
toxicities
- flu like symptoms
- risk of cardiomyopathy/CHF
- no intrinsic myelosuppression but increases in combo with chemo
- risk of hypersensitivity reactions
- humanized, HER2
- antibody
- internalization, degradation
Pertuzumab (Perjeta)
recombinant ___ monoclonal antibody specific for ___
Pertuzumab binds to HER2 and inhibits ___
- HER2 dimerization is an important element of optimal HER2 response
used in combo with ___ (CLEOPATRA)
- humanized
- dimerization
- trastuzumab
__ engineering can improve immune activation by therapeutic antibodies
- basically margetuximab is a slightly better version of ___
- SOPHIA trial
Fc
- trastuzumab
Cetuximab (Erbitux)
recombinant ___ monoclonal antibody that binds specifically to the extracellular domain of the ___ receptor
- ___ inhibits binding of EGF and TGF-alpha
- blocks phosphorylation and activation of receptor-associated ___
- leads to inhibition of cell growth and induction of apoptosis
EGF receptor is ___ expressed in many normal epithelial tissues
- receptor is over-expressed in many human cancers
primary indication is in the treatment of ___ and ___ / ___ cancers
toxicities
- WARNING - severe ___ reaction in 3% of patients usually on the first dose
- acneiform rash
- asthenias
- fever
- chimeric, EGF
- competitively
- kinases
- constitutively
- colorectal, head/neck
- infusion
panitumumab (Vectibix)
fully ___ monoclonal antibody that binds specifically to the extracellular domain of the ___ receptor
- ___ inhibits binding of EGF and TGF-alpha
- blocks phosphorylation and activation of receptor-assocaited ___
- leads to inhibition of cell growth and induction of apoptosis
given every 2 weeks
SE
- rash and other cutaneous SE (predictive of ___ clinical outcome)
- diarrhea
primary indication is in the treatmnet of ___ cancer
does not carry ___ toxicities
- humanized, EGF
- competitively
- kinases
- better
- colorectal
- infusion
a bevy of inhibitors against the ErbB family
just a good summary slide
bevacizumab (Avastin)
recombinant ___ monoclonal antibody specific for ___ endothelial growth factor
- binds ____ and blocks its interaction with endothelial receptors
- blocks endothelial cell proliferation and new blood vessel formation
- inhibits solid tumor growth via anti-angiogenic effect
No evidence of efficacy as ___ agent
used in combo with ___ based chemo for first line treatment of metastatic ___ cancer
bevacizumab binds the ligands, ____ binds the receptor
- there are an array of small molecules that inhibit the ___ activity
- humanized, vascular
- VEGF
- single
- 5-FU, colorecta;
- ramucirumab
- kinase
which of the following antibodies targets HER2?
a) neratinib
b) cetuximab
c) lapatinib
d) pertuzumab
pertuzumab
explain the two tiered targeting affect of antibody therapy as compared to small molecule kinase inhibitors?
In general antibodies binding to their targets on the surface
of tumor cells will inhibit the function of that molecule.
This along with activation of the ADCC can lead to
differential therapeutic outcomes when using antibodies
as compared to the small molecules.
desribe why the combined use of pertuzumab and trastuzumab both defies and complies withe general rules of combination therapy
Against: Shared target equals shared toxicities.
For: Different bindings sites on HER2, different mechanisms of HER2 inhibition, enhanced activation of the ADCC
B Cell markers
CD ___
CD ___
CD22
CD27
CD38
CD19
CD20
targeting CD20 in B-Cell Lymphoma
- CD __ works with the B-Cell Receptor (BCR) to drive the proliferation of B-cells
- also plays a role in the proliferation of B-cell lymphomas
- antibody binding to CD20 inhibits B cell ___ AND induces ___
CD20
- proliferation, ADCC
ADCC = antibody dependent cellular cytotoxicity
antibody drug conjugates (ADCs)
Ado-Trastuzumab Emtansine (T-DM1, Kadcyla)
Emtansine is a modified version of Mertansine, a ___ inhibitor
tubulin
Trastuzumab-deruxtecan
the “tecans” are ___ inhibitors
Topo 1
“Tolerance” of T-cells to avoid autoimmunity
Central Tolerance - ___ selection of T-cells that bind to ___ peptides in the ___
Peripheral Tolerance - ___ reactive T-cells that escape the thymus into peripheral tissues are inactivated to an unresponsive state by ___ or fail to be properly stimulated by ___
- negative, self, thymus
- self, T-regs, APCs
T-cell Activation
require antigens (small peptides) to be presented to them by MHC
Steps
1) naive T-cell enounters antigen in combo with MHC
2) if the T-cell receptor (TCR) recognizes the antigen, it will become activated. A cytolytic T-cell will kill that cell and proliferate, creating a population of antigen ___ T-cells
3) once an infection (tumor) is cleared, the T-cell population will die down to a ___ population well suited to combat that antigen again (long term immunity)
- specific
- memory
bispecific T-cell engager (BiTE)
binds simulatanously to CD ___ on B cell lymphomas and CD ___ which is present on alll T cells
example drug: ___
CD19
CD3
Blinatumomab
BiTEs
Teclistamab - BiTE that targets CD __ on T cells and B-cell ___ antigen (BCMA) on multiple myeloma (MM) cells
Taquetamab - BiTE that targets CD ___ on T cells and human ___ coupled receptor family C group 5 member D (GPCR5D) on multiple myeloma (MM)cells
CD3, maturation
CD3 - G protein
Removing the emergency brake
CTLA-4 and PD1 act as brakes/checkpoints on the immune sytem
- blocking these interactions with antibodies can reactivate ___ cells
T cells
Cell Therapy
Sipuleucel-T (PROVENGE) is approved for metastatic ___ cancer
prostate
CAR T-cell Therapy
just a good diagram to be familiar with
T cell activation is a complex series of events
- Use ___ to mimic those events to activate T-cells against tumor cells
CARs
chimeric antigen receptor
CD19 CAR T treatments
- ___ cells isolated from the patient
- shipped to a lab where they are grown, and the CAR to target CD ___ is stably expressed
- these CAR-T cells are shipped back and engrafted into the patient
- the patient is essentially immunized against CD ___
- all immature B-cells are ___
- the T-cells live on ___
- T cells
- CD19
- CD19
- eliminated
- indefinitely
