Checkpoint Inhibitors Flashcards

1
Q

What are checkpoint inhibitors?

A
  • 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
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2
Q

What is the PD-1 pathway?

A
  • 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
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3
Q

What is the CTLA-4 cell surface receptor?

A
  • 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
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4
Q

How do tumors change checkpoint pathways?

A

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

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5
Q

What are CTLA-4 inhibitors?

A
  • Allows more T-cells to be activated and for longer to fight tumor cells
  • ex. ipilimumab, tremelimumab
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6
Q

What are PD-1 inhibitors?

A
  • 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
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7
Q

What are the adverse effects of checkpoint inhibitors?

A
  • 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
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8
Q

How are immune related adverse events (irAE’s) managed?

A
  • 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 *
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9
Q

What are targeted agents designed for?

A

To inactivate specific mutations that are over-expressed in tumor cells, or to restrict blood flow to the tumor

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10
Q

What are the three phases of immuno-editing?

A

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

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11
Q

What are the three FDA approved checkpoint inhibitor therapies?

A

1) Anti-CTLA-4 (eg. Ipilimumab)
2) Anti-PD-1
3) Anti-PD-L1

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12
Q

What type of therapy is checkpoint inhibition?

A

Immunotherapy

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13
Q

What makes checkpoint inhibition adverse events different compared with chemo adverse events?

A

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

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14
Q

What is the basic difference between innate and adaptive immune systems?

A
Innate = rapid, non-specific
Adaptive = slow, antigen specific **
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15
Q

Define antibodies

A

Proteins produced by immune system in response to foreign substances

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16
Q

What cell produces antibodies?

A

B-cells

17
Q

What do dendritic cells do?

A

Antigen presenting cells, messengers between adaptive and innate immune response (while separate responses they do have some overlap in cells)

18
Q

what cells attack infected cells?

A

T-cells

19
Q

What is an example of a CTLA-4 inhibitor?

A

Ipilimumab

20
Q

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?

A
  • 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
21
Q

What are the most common irSE of PD-1 inhibitors?

A
  • Fatigue and rash
  • Diarrhea less common
  • Tend to be more tolerable than CTLA-4
22
Q

Why is patient education crucial with checkpoint inhibitors?

A
  • 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
23
Q

What are the important aspects of patient education?

A
  • 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
24
Q

What irAE can be seen with the dermatologic system?

A
  • Rash (+/- itching)
  • Blistering or peeling
  • Xerostomia
  • Oral mucositis
  • Loss of pigmentation
  • Rare cases = Stevens-Johnson syndrome
25
Q

What irAE can be seen with the GI system?

A
  • Inflammation of GI lining (colitis) can cause perforations or tears, and they can cause the symptoms below:
  • Abd pain
  • Diarrhea
  • Increased frequency of BM’s
  • Dark tarry stools
  • Blood in stools
26
Q

What irAE can be seen with the hepatic system?

A
  • Inflammation (hepatitis) can lead to liver failure, which S&S including:
  • Elevated LFT’s
  • Fever
  • Jaundice
  • n/v
  • Dark urine
  • Increased bruising
  • Pain R upper stomach
27
Q

What irAE can be seen with the neurologic system?

A
  • Neuropathy may develop, causing:
  • Numbness/tingling to hands and feet
  • Weakness to extremities and face
  • Guillain-Barre system (immune system attacks part of the peripheral NS)
  • Myasthenia gravis (autoimmune neuromuscular disease)
  • Meningitis
28
Q

What irAE can be seen with the endocrine system?

A
  • Tend to affect the pituitary, thyroid and adrenal glands
  • HA’s
  • Fatigue
  • Nausea
  • Vision changes
  • Weight gain
  • Dizziness
  • Fainting
  • Changes in mood/behaviour
  • Monitor for adrenal insufficiency (causes hypotension, dehydration and electrolyte imbalances)
29
Q

What irAE can be seen with the renal system?

A
  • Decreased urine
  • Sang in urine
  • Edema
  • anorexia
30
Q

What irAE can be seen with the ocular system?

A
  • Blurry vision
  • Double vision
  • Eye reddness/pain
  • Dryness
  • Sensitivity
31
Q

What irAE can be seen with the pulmonary system?

A
  • Pneumonitis (PD-1 inhibitors particularly) can cause:
  • New or worse cough
  • SOB
  • Chest pain
32
Q

Which group of patients may not be suitable for checkpoint inhibitor therapy?

A
  • Concurrent autoimmune conditions
  • Inability or unwillingness to report symptoms in a timely manner
  • Far away from health care services