Immunotherapy Flashcards
1
Q
Why immunotherapy for cancers?
A
- Specificity
- Immunological memory
- Adaptability
2
Q
Ipilimumab
A
- Monoclonal antibody
- CTLA-4 blockade
- Treats metastatic melanoma
3
Q
What are the mechanisms of actions of Anti-CTLA-4?
A
- Hard wired
- Targets CD28 pathway (T cell activation)
- Works during priming
- Expands clonal diversity
- Primarily effects CD4+ T cells
- Can move T cells into tumors
- Disease reoccurence after response is rare
4
Q
What are the mechanisms of actions of anti-PD-1?
A
- Induce resistance
- Targets TCR pathway (signaling pathway)
- Works during exhausted T cells
- Does NOT expand clonal diversity
- Primarily effects CD8+ T cells
- Does NOT move T cells in tumors
- Disease reoccurence after response is significant
5
Q
What is a biomarker of response to anti-PD-1 therapy?
A
- Tumor mutational burden
6
Q
What are some hormone gland side effects?
A
- Persistent or unusual headache
- Extreme tiredness
- Weight loss or gain
- Rapid heartbeat
- Increased sweating
- Hair loss
- Constipation
- Dizziness or fainting
7
Q
What are some skin side effects?
A
- Rashes
- Itching
- Blistering
- Painful sores or ulcers
8
Q
What are some liver side effects?
A
- Yellowing of the skin or the whites of the eyes
- Severe nausea or vomiting
- Pain on the right side of the stomach area
- Dark urine
- Bleeding or bruising more easily than normal
9
Q
What are some intestinal side effects (colitis)?
A
- Diarrhea or more bowel movements than usual
- Stools that have blood or are dark, tarry, or sticky
- Severe stomach-area pain
10
Q
What are some side effects of immunotherapy?
A
Most common:
* GI tract
* Endocrine glands
* Skin
* Liver
Less often:
* CNS
* Cardiovascular
* Pulmonary
* Musculoskeletal
* Hematological
11
Q
How do you diagnose and treat dermatitis?
A
- Clinical examination, skin biopsy
- Topical steroids, oral steroids
12
Q
How do you diagnose and treat endocrinopathy?
A
- TSH, T4, cortisol, ACTH
- Hormone replacement
13
Q
How do you diagnose and treat colitis?
A
- Clinical, endoscopy
- Oral steroids
14
Q
How do you diagnose and treat hepatitis?
A
- AST, ALT
- Oral steroids
15
Q
When do immune-related adverse events occur?
A
First few weeks to months after treatment but can occur anytime, even after treatment discontinuation
* Dermatologic adverse events are usually first to appear
16
Q
Are immune-related adverse events associated with the efficacy of immune-checkpoint blockade?
A
- Conflicting data are available
- The development of immune-related events is not required for treatment benefit
- Specific adverse events may be more clearly associated with treatment efficacy
17
Q
Does immunosuppression to treat such adverse events reduce the antitumor efficacy of treatment?
A
- Beneficial responses can persist despite the use of immunosuppression to treat immune-related events
18
Q
Is it safe to restart treatment after a major adverse event?
A
- Retrospective studies have shown that immune-related adverse events associated with one class of agent may not necessarily recur during subsequent treatment with another agent
- The safety of treatment probably depends on the severity of the initial immune-related adverse event
19
Q
What are the proposed mechanism of LAG-3?
A
- Attenuated cytokine secretion
- Inhibit via signal transduction
- Enhance the function of Tregs
20
Q
What are the main components of CAR T cell therapy?
A
- Antigen-recognition
- Transmembrane
- Intracellular domain
21
Q
Nivolumab
A
- Targets PD-1
- Melanoma, non-small cell lung cancer, Hodgkin’s lymphoma, squamous cell carcinoma, colorectal cancer
22
Q
Pembrolizumab
A
- Targets PD-1
- Melanoma, non-small cell lung cancer, Hodgkin’s lymphoma, squamous cell carcinoma, solid tumors with high MSI
23
Q
Dostarlimab
A
- Targets PD-1
- Endometrial cancer and solid tumors with mismatch repair deficient (MMR)
24
Q
Cemiplimab
A
- Targets PD-1
- Non-small cell lung cancer, basal cell carcinoma, cutaneous squamous cell carcinoma
25
Atezolizumab
Non-small cell lung cancer, **urothelial carcinoma**
26
Avelumab
* Targets PD-1
* Merkel cell carcinoma, urothelial carcinoma
27
Durvalumab
* Targets PD-1
* Urothelial carcinoma
28
Relatilimab
* Targets LAG-3
* Unresectable or metastatic melanoma given in combination with nivolumab
29
What are some limitations of checkpoint blockade?
* More basic science needed-identify the best rationale for blockade combinations
* T cell infiltration-getting antigen-specific T cells into tumors
* Will NOT be particularly beneficial for cancers with low mutational burden
30
Lymphodepleting chemotherapy
* Fludarabine at 30 mg/m2 IV daily for 4 days
* Cyclophosphamide at 500 mg/m2 IV daily for 2 days starting with the first dose of fludarabine
* Kymriah is infused 2 to 14 days after completion of lymphodepleting chemotherapy
31
What is the mechanism of lymphodepleting chemotherapy?
Mechanism is unknown
* Inudction of cytokines that promote CD3+ lymphocyte homeostasis
* Tumor burden reduction
32
What CAR T cells eliminate cancers of B cell lineage?
CD19-directed
33
What is the target and costimulatory domain of Tisagenlecleucel (Kymirah)?
* Target: CD19
* Co-stimulatory: 4-1BB
34
What is the target and costimulatory domain of Axicabtagene ciloleucel (Yescarta)?
* Target: CD19
* Co-stimulatory domain: CD28
35
What is the target and costimulatory domain of Brexucabtagene autoleucel (Tecartus)?
* Target: CD19
* Co-stimulatory domain: CD28
36
What is the target and costimulatory domain of Lisocabtagene maraleucel (Breyanzi)?
* Target: CD19
* Co-stimulatory domain: 4-1BB
37
What is the target and costimulatory domain of Idecabtagene vicleucel (Abecma)?
* Target: BCMA
* Co-stimulatory domain: 4-1BB
38
What is the target and costimulatory domain of Ciltacabtagene (Carvykti)?
* Target: BCMA x2
* Co-stimulatory domain: 4-1BB
39
Cytokine release syndrome (CRS)
* A common complication of CD-19-directed CAR T cellls
* Common first 2 weeks after infusion
40
Prodromal Syndrome
* Low-grade fever, fatigue, anorexia
* Treatment: Observe in person
41
Overt CRS
One or more of the following:
* High fever
* Hypoxia
* Mild hypotension
Treatment: Administer antipyretics, oxygen, intravenous fluids and/or low-dose vasopressors
42
Severe of Life-threatening CRS
One or more of the following:
* Hemodynamic instability despite intravenous fluids and vasopressor support
* Worsening respiratory distress
* Rapid clinical deterioration
Treatment: Administer high dose or vasopressors, oxygen, mechanical ventilation
* Administer tocilizumab
43
What is a common complications of CD19-directed CAR T cells?
Neurotoxicity
(not responsive to tocilizumab)
44
How do you treat a grade 2 and 3 neurotoxicity?
Dexamethasone 10 mg IV q6h
* continue until grade 1 than taper over 3 days
45
How do you treat grade 4 neurotoxicity?
Methylprednisolone 1000 mg IV for 3 days, then manage as above
