Immunotherapy Flashcards
Why immunotherapy for cancers?
- Specificity
- Immunological memory
- Adaptability
Ipilimumab
- Monoclonal antibody
- CTLA-4 blockade
- Treats metastatic melanoma
What are the mechanisms of actions of Anti-CTLA-4?
- 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
What are the mechanisms of actions of anti-PD-1?
- 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
What is a biomarker of response to anti-PD-1 therapy?
- Tumor mutational burden
What are some hormone gland side effects?
- Persistent or unusual headache
- Extreme tiredness
- Weight loss or gain
- Rapid heartbeat
- Increased sweating
- Hair loss
- Constipation
- Dizziness or fainting
What are some skin side effects?
- Rashes
- Itching
- Blistering
- Painful sores or ulcers
What are some liver side effects?
- 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
What are some intestinal side effects (colitis)?
- Diarrhea or more bowel movements than usual
- Stools that have blood or are dark, tarry, or sticky
- Severe stomach-area pain
What are some side effects of immunotherapy?
Most common:
* GI tract
* Endocrine glands
* Skin
* Liver
Less often:
* CNS
* Cardiovascular
* Pulmonary
* Musculoskeletal
* Hematological
How do you diagnose and treat dermatitis?
- Clinical examination, skin biopsy
- Topical steroids, oral steroids
How do you diagnose and treat endocrinopathy?
- TSH, T4, cortisol, ACTH
- Hormone replacement
How do you diagnose and treat colitis?
- Clinical, endoscopy
- Oral steroids
How do you diagnose and treat hepatitis?
- AST, ALT
- Oral steroids
When do immune-related adverse events occur?
First few weeks to months after treatment but can occur anytime, even after treatment discontinuation
* Dermatologic adverse events are usually first to appear
Are immune-related adverse events associated with the efficacy of immune-checkpoint blockade?
- 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
Does immunosuppression to treat such adverse events reduce the antitumor efficacy of treatment?
- Beneficial responses can persist despite the use of immunosuppression to treat immune-related events
Is it safe to restart treatment after a major adverse event?
- 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
What are the proposed mechanism of LAG-3?
- Attenuated cytokine secretion
- Inhibit via signal transduction
- Enhance the function of Tregs
What are the main components of CAR T cell therapy?
- Antigen-recognition
- Transmembrane
- Intracellular domain
Nivolumab
- Targets PD-1
- Melanoma, non-small cell lung cancer, Hodgkin’s lymphoma, squamous cell carcinoma, colorectal cancer
Pembrolizumab
- Targets PD-1
- Melanoma, non-small cell lung cancer, Hodgkin’s lymphoma, squamous cell carcinoma, solid tumors with high MSI
Dostarlimab
- Targets PD-1
- Endometrial cancer and solid tumors with mismatch repair deficient (MMR)
Cemiplimab
- Targets PD-1
- Non-small cell lung cancer, basal cell carcinoma, cutaneous squamous cell carcinoma
Atezolizumab
Non-small cell lung cancer, urothelial carcinoma
Avelumab
- Targets PD-1
- Merkel cell carcinoma, urothelial carcinoma
Durvalumab
- Targets PD-1
- Urothelial carcinoma
Relatilimab
- Targets LAG-3
- Unresectable or metastatic melanoma given in combination with nivolumab
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
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
What is the mechanism of lymphodepleting chemotherapy?
Mechanism is unknown
* Inudction of cytokines that promote CD3+ lymphocyte homeostasis
* Tumor burden reduction
What CAR T cells eliminate cancers of B cell lineage?
CD19-directed
What is the target and costimulatory domain of Tisagenlecleucel (Kymirah)?
- Target: CD19
- Co-stimulatory: 4-1BB
What is the target and costimulatory domain of Axicabtagene ciloleucel (Yescarta)?
- Target: CD19
- Co-stimulatory domain: CD28
What is the target and costimulatory domain of Brexucabtagene autoleucel (Tecartus)?
- Target: CD19
- Co-stimulatory domain: CD28
What is the target and costimulatory domain of Lisocabtagene maraleucel (Breyanzi)?
- Target: CD19
- Co-stimulatory domain: 4-1BB
What is the target and costimulatory domain of Idecabtagene vicleucel (Abecma)?
- Target: BCMA
- Co-stimulatory domain: 4-1BB
What is the target and costimulatory domain of Ciltacabtagene (Carvykti)?
- Target: BCMA x2
- Co-stimulatory domain: 4-1BB
Cytokine release syndrome (CRS)
- A common complication of CD-19-directed CAR T cellls
- Common first 2 weeks after infusion
Prodromal Syndrome
- Low-grade fever, fatigue, anorexia
- Treatment: Observe in person
Overt CRS
One or more of the following:
* High fever
* Hypoxia
* Mild hypotension
Treatment: Administer antipyretics, oxygen, intravenous fluids and/or low-dose vasopressors
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
What is a common complications of CD19-directed CAR T cells?
Neurotoxicity
(not responsive to tocilizumab)
How do you treat a grade 2 and 3 neurotoxicity?
Dexamethasone 10 mg IV q6h
* continue until grade 1 than taper over 3 days
How do you treat grade 4 neurotoxicity?
Methylprednisolone 1000 mg IV for 3 days, then manage as above
