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.
what was the first immunotherapy
a) pertuzumab
b) Keytruda
c) Coley’s toxin
d) trastuzumab
Coley’s toxin
the antibody Fakeumab has just entered the market. What type of antibody is it?
a) fully human
b) humanized
c) fully mouse
d) chimeric
fully human
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
Rituximab
___ is a transmembrane protein that regulates an early step in activation of cell cycle initiation and differentiation
- expressed by normal ___ lymphocytes and ___ pre-B cells
- also expressed on > 90% of B-cell non - ___ lymphomas cells
___ is a fully human monoclonal antibody specific for CD20 originally developed to treat MS and now used in ___
Rituximab and Obinutuzumab are other CD20 antibodies currently approved for B-cell lymphomas (non-Hodgkin’s), that target ___ binding sites on CD20
- CD20
- B, immature
- Hodgkin’s
- Ofatumumab, CLL
- different
Daratumumab
- CD __ is a multifunctional transmembrane protein highly expressed on ___ B cells that make antibodies
- multiple myeloma is a cancer of malignant ___ cells
- antibodies for CD38 eliminate multiple myeloma cells by ___ or ___
- also eliminates ___ cells (main innate immune cell defense against virus)
- CD38, plasma
- plams
- ADCC, CDC
- natural killer
antibody drug conjugates (ADCs)
Ado-Trastuzumab Emtansine (T-DM1, Kadcyla)
Emtansine is a modified version of Mertansine, a ___ inhibitor
tubulin
ADCs - Trastuzumab Emtansine (T-DM1, Kadcyla)
T-DM1 is an antibody drug conjugate consisting of the cytotoxic agent emtansine linked to the monoclonal antibody trastuzumab
- trastuzumab binds to ___ /Ne receptor and leads to usual Herceptin response
- emtansine enters cell and inhibits microtubule ___
- emtansine toxicity significantly reduced because of selective ___ targeting
1st ADC to get FDA approval
- 2nd line treatment for HER2+ metastatic breast cancer
toxicities
- adverse effects of trastuzumab
- ___ and ___ (mertansine effect)
- HER2
- assembly
- HER2
- thrombocytopenia, hepatotoxicity
Trastuzumab-deruxtecan
the “tecans” are ___ inhibitors
Topo 1
the major goal and challenge of cancer immunotherapy is to direct the immune system to recognize and destroy cancer
- at the point where tumor has established, natural balance has fundamentally shifted against the ability to mount an effective immune response
Major issues for T-cell based immunotherapy
- central ___ : repertoire to self is irrevocably compromised
- immuno ___ / peripheral tolerance
- tolerance
- immunosuppresion
“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
overcoming central tolerance
Problem: all high avidity self-reactive T-cells have been ___
Goal: empower T-cells to kill cancers, which are often not very ___ from “self”
strategies
- redirect T cells to cancer using genetics
- redirect T cells to cancer using recombinant proteins
- ___ the threshold to allow for targeting neo-antigens
- deleted
- different
- lower
multiple intervention points are likely to be required for maximally effective implementation of immunotherapy
established tumors have developed a breadth of mechanisms to counterbalance anti-tumor immunity
- ___ therapies needed to address multiple steps in the immune process
combination
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
Blinatumomab
example of a ___ - target T cells to receptors highly expressed on cancers
- bind to CD ___ on T cell and physically bring active T cell into proximity with CD ___ , which is highly expressed on B cells and acute lymphoblastic leukemia
the activated T cell will then lyse the ___ cell
DONT CONFUSE WITH CHIMERIC ANTIBODIES
- BiTE
- CD3, CD19
- tumor
Mosunetuzumab (Epcoritamab)
BiTE that targets CD ___ and CD __ on ___ lymphomas, another type of B cell malignancy
SE
- ___ release syndrome when the immune system responds too aggressively. A problem for immunotherapies.
CD3
CD20
non-Hodgkin
cytokine
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
ipilimumab (Yervoy)
recombinant ___ monoclonal antibody with a ___ MOA
- cytotoxic T lymphocytes (CTLs) have the capacity to recognize and destroy malignant tumor cells
- tumor cell antigens recognized by dendritic cells, which present the antigens to the CTLs
- However, dendritic cells also deliver an ___ signal to CTLs via the ___ receptor
- ipilimumab binds to the ___ receptor and reverses the CTL inhibition
approved for treatment of advanced metastatic ___
severe immune-mediated adverse reactions generally related to ___ response
- GI tract - enterocolitis, hepatitis
- dermatitis, neuropathy, endocrinopathy
- may require high dose ___
human, unique
- CTLA-4
- CTLA-4
- melanoma
- inflammatory
- corticosteroids
Pembrolizumab(Keytruda), nivolumab, cemiplimab, ostarlimab, retifanlimab
monoclonal antibodies that bind the program death-1 (PD-1) receptor and blocks its interaction with PD-ligand 1 and 2 (PD-L1 and PD-L2_
- PD-1 is expressed on ___ cells
- PD-L1 is expressed on macrophages and ___ cells
- similar to CTLA-4 blockade, blockade of PD-1 prevents ___ signaling within T-cells, leading to enhanced ___ killing
approved for the treatment of advanced metastatic ___ following treatment with ___ and (if BRAf V600 mutation positive) a BRAF inhibitor
approved for NSCLC if the patients biopsy tests positive for ___
- T cells
- tumor
- inhibitory, tumor
- melanoma, ipilimumab
- PD-L1
Atezolizumab (Avelumab, Durvalumab)
monoclonal antibodies that bind ___ receptor and blocks interaction with ___
- PD-1 is expressed on T cells
- PD-L1 is expressed on macrophages and ___ cells
- challenge of identifying patients who will respond
exclusions:
- ___ disease
- medical conditions requiring ___ suppression
- PD-L1, PD-1
- tumor
- autoimmune
- immunosuppression
Cell Therapy
Sipuleucel-T (PROVENGE) is approved for metastatic ___ cancer
prostate
Myeloid cellular immunotherapy
Sipulcel-T (Provenge) is a ___ vaccine
- “drug” is PAP-GM-CSF, a recombinant human protein containing prostatic acid phosphatase (PAP) linked to granulocyte macrophage colony stimulating factor (GM-CSF), an immune cell activator.
- ___ collected from a patient via leukapheresis
- ___ then activated by ex vivo treatment with PAP-GM-CSF and the reinfused back into patient
Goal is to stimulate a patient;s own immune system to attack the cancer
indicated for the treatment of minimally symptomatic metastatic hormone-refractory prostate cancer
AE:
- flu like symptoms
- possible increased risk for stroke
- therapeutic
- APCs
- APCs
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
which antibody is effective against metastatic melanoma and targets CTLA-4?
a) ipilimumab
b) trastuzumab
c) daratumumab
d) blinatumomab
ipilimumab
which of the following proteins is used as a cancer biomarker test to determine eligibility for treatment of NSCLC with pembrolizumab
a) CD19
b) CTLA4
c) PDL1
d) PD1
PDL1
which of the following antigens is a common target for CAR-T therapy in B cell malignancy
a) CD4
b) CD19
c) CD28
d) CTLA4
CD19
what is the primary mechanism of action of bispecific T cell engagers in cancer immunotherapy
a) they inhibit PD1/PDL1 interaction
b) they bring T cells and cancer cells in close proximity to facilitate T cell mediated cytotoxicity
c) they stimulate the innate immune system to recognize tumor cells
d) they increase neoantigens
they bring T cells and cancer cells in close proximity to facilitate T cell mediated cytotoxicity
the future oof T cell therapy
- rn it is very dependent on finding a selective ___
- the best success have been with B-cell leukemias with a CAR specific for CD ___
- adopting this same approach into other tumor types has been a challenge due to ___ . Need a way to turn the CAR T-cells off after the tumor has been eliminated to reduce life-long toxicity
- antigen
- CD19
- toxicities
