What are checkpoint inhibitors?
- Type of immunotherapy that targets checkpoint proteins CTLA-4 and PD1
- Doing so minimizes damage to healthy cells and restores immune response to tumor cells (re-actives T-cells)
- Success with advanced melanoma and lung Ca
- Based on premise that an active immune system continuously recognizes and eliminates the vast majority of Ca cells before they form a tumor mass
What is the PD-1 pathway?
- PD-1 = programmed death-1 receptor on t-cells
- PDL1 is a receptor on Timor’s
- When t-cells with PD-1 binds with PD-L1 on tumors the T-cell is inactivated
- The higher the PD-L1 expression = poorer prognosis
What is the CTLA-4 cell surface receptor?
- Present on T-cells that is used to turn off T-cells, intended to prevent attacking healthy cells
- Inhibitors of CTLA-4 release the ‘brakes’ created by the CTLA-4 protein
How do tumors change checkpoint pathways?
Tumors use and abuse these pathways to avoid detection by:
Increase PD-L1 protein expression on their tumors to inactive larger amounts of T-cells
What are CTLA-4 inhibitors?
- Allows more T-cells to be activated and for longer to fight tumor cells
- ex. ipilimumab, tremelimumab
What are PD-1 inhibitors?
- Tumor proteins PD-L1 bind with the PD-1 protein on T-cells to prevent the T-cell from attacking them
- Inhibitors block this action, preventing T-cells from being turned off by tumor cells (blocks ligand binding)
- Prolong and enhance immune response against tumors
What are the adverse effects of checkpoint inhibitors?
- Inflammation based, immune-related adverse events
- Because these inhibitors affect T-cells, all throughout the body, any system can be affected
- Fatigue and rash/pruritis ** are most common with PD-1 inhibitors
- Diarrhea/enterocolitis **
- Pneumonitis (rare)
- Endocrinopathies (eg. thyroiditis, hypopituitarism)
- Neurologic (neuropathy, arthralgia, myalgia)
- Immune related adverse events usually occur within first few months and prolonged exposure does not seem to increase incidence
- Adverse events can be rapid and often occur during induction period, but can be at any time in tx period
How are immune related adverse events (irAE’s) managed?
- Management reflect the inflammatory nature, often involving steroids, symptom management based on the organ toxicity and severity, and interrupting treatment *
- Usually steroids are IV or oral and tapered
- Consider ABX prophylactically for opportunistic infections
- Evaluate and rule out non-inflammatory conditions (eg. assess for cdiff as well if diarrhea present)
- Monitor labs for events that can be asymptomatic (eg. hepatitis, early thyroiditis, drug induced liver injury)
- Some effects can be managed with NSAID’s (eg. myalgia’s)
- Some endocrine reactions may require lifelong hormone replacement therapy (eg. synthroid for hypothyroidism)
- Make consults as needed (eg. dermatology, surgery) and hospitalize as necessary (eg. hospitalize if pulmonary disease occurs)
- Prompt recognition and early intervention is the best management strategy
- Managing irAE’s is different from other interventions because the focus is to decrease inflammation *
What are targeted agents designed for?
To inactivate specific mutations that are over-expressed in tumor cells, or to restrict blood flow to the tumor
What are the three phases of immuno-editing?
Immuno-editing = The process of how the Ca cells not sensed by the immune system grow to become more prevalent and therefore a tumor not detected by the immune system
1) Elimination: successful recognition and elimination of malignant cells by the immune system
2) Equilibrium: control of Ca growth without completely eliminating the transformed cells
3) Escape: tumor cells not susceptible to destruction in the first two phases continue to divide and grow
Immunotherapy focuses on attacking malignancies before it reaches the escape phase
What are the three FDA approved checkpoint inhibitor therapies?
1) Anti-CTLA-4 (eg. Ipilimumab)
2) Anti-PD-1
3) Anti-PD-L1
What type of therapy is checkpoint inhibition?
Immunotherapy
What makes checkpoint inhibition adverse events different compared with chemo adverse events?
Checkpoint inhibition has its own side effects, known as immune-related adverse events, which are inflammatory and autoimmune in nature
Chemo adverse effects are the result of death of healthy cells on top of Ca cells
What is the basic difference between innate and adaptive immune systems?
Innate = rapid, non-specific Adaptive = slow, antigen specific **
Define antibodies
Proteins produced by immune system in response to foreign substances
What cell produces antibodies?
B-cells
What do dendritic cells do?
Antigen presenting cells, messengers between adaptive and innate immune response (while separate responses they do have some overlap in cells)
what cells attack infected cells?
T-cells
What is an example of a CTLA-4 inhibitor?
Ipilimumab
Immunotherapy can involve any organ system because T-cells are present throughout the body. What systems are most likely to be involved in an irSE?
- Endocrine (lethargy, mental status changes)
- GI and liver
- Skin
- Pulmonary
- CTLA-4 inhibitors tend to cause more side effects (often diarrhea, rash and fatigue)
- Can appear any time, but rash and diarrhea tend to be around cycle 2
What are the most common irSE of PD-1 inhibitors?
- Fatigue and rash
- Diarrhea less common
- Tend to be more tolerable than CTLA-4
Why is patient education crucial with checkpoint inhibitors?
- Serious irAE’s are infrequent and treatable, but early recognition is crucial for effective treatment
- Patient education is crucial in begin aware of irAE’s before therapy so they can identify the need for treatment before it progresses to potentially fatal consequences
What are the important aspects of patient education?
- irAE’s may be delayed by weeks or months, unlike other therapies
- Discuss how the reactions are d/t inflammation of any organ system (and maybe multiple at once)
- Importance of following dr recommendations for follow-up exactly (eg. some irAE’s may only show in the beginning with lab changes, so important to be checked even when feeling well)
- Report changes no matter how subtle
What irAE can be seen with the dermatologic system?
- Rash (+/- itching)
- Blistering or peeling
- Xerostomia
- Oral mucositis
- Loss of pigmentation
- Rare cases = Stevens-Johnson syndrome
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Pathophysiology Review46
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Medication Profiles41
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Diagnosis & Staging21
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Science of Antineoplastic Drugs66
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Antineoplastic Drugs30
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Bio therapy and Targeted Therapy52
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Checkpoint Inhibitors32
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Administration of Chemo drugs & safe drug handling22
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Toxicities: Long term37
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Systemic Effects of Chemo33
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Safe Handling of Hazardous Drugs9
