Today, I review, link to, and excerpt from CORE IM‘s Immune Checkpoint Inhibitors & IRAEs 101: 5 Pearls Segment.*
*Posted: May 22, 2024
By: Dr. Anuranita Gupta, Dr. Narjust Florez, Dr. Allison Betof Warner, Dr. Benjamin Schlechter and Dr. Shreya P. Trivedi
Graphic: Dr. Cathy Cichon
Audio: Daksh Bhatia
Peer Review: Dr. Hollis Viray, Dr. Tian Zhang
All that follows is from the above resource.
Play the podcast in a new window.
Time Stamps
- 01:56 Pearl 1: Mechanism of checkpoint inhibitors and their adverse events
- 07:15 Pearl 2: Organ systems affected by IRAEs
- 13:42 Pearl 3: Timeline of IRAEs
- 22:20 Pearl 4: Factors which increase susceptibility
- 26:38 Pearl 5: Complementary medicine
Sponsor: At Panacea Financial, you don’t need co-signers for personal loans and have reduced payments during training!*
*I have no relationship to CORE IM or to this sponsor. I just put in the link as a courtesy to the great folks at CORE IM.
Show Notes
Pearl 1: What are the mechanisms and adverse events of checkpoint inhibitors?
- Major Categories of Checkpoint Inhibitors
- CTLA-4 inhibitors:
- Ipilimumab
- Tremelimumab
- PD-1 inhibitors:
- Nivolumab
- Pembrolizumab
- Pidilizumab
- Cemiplimab
- PD-L1 inhibitors:
- Atezolizumab
- Durvalumab
- Avelumab
- Checkpoint inhibitors are used in the treatment of many cancers including: melanoma, lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck squamous cell carcinoma and colorectal cancer.
- Mechanism of Adverse Events:
- Background: CTLA-4 and PD-1 normally serve as “brakes” on the immune system
- Cancer cells will take advantage of these checkpoints to put “brakes” on the immune system and avoid dying!
- Mechanism of Checkpoint Inhibitors: Inhibit CTLA-4 and PD-1/PD-L1 → prevents “brakes” on the immune system → Increase immune system activation to fight against cancer!
- Other mechanisms include:
- Increasing levels of preexisting autoantibodies
- Increasing inflammatory cytokines
- Enhancing complement mediated inflammation
- Mechanism of Immune Related Adverse Events: The immune system is over-activated by the checkpoint inhibitor and attacks the body’s own cells.
Pearl 2: What organ systems are affected by immune-related adverse events (IRAE)?
- Any organ can be affected by IRAE!
- Affected organs and presentation (framework for remembering IRAEs starting with most common):
- General/Systemic: [Most common set of symptoms]
- Fatigue
- Rash (Dermatitis)
- Nausea
- Glands: [Second most common set of symptoms]
- Thyroid (Thyroiditis)
- Adrenal glands (Adrenal insufficiency)
- Pituitary (Hypophysitis)
- Pancreas (Type 1 Diabetes Mellitus)
- Solid organs: [Third most common set of symptoms]
- Lungs (Pneumonitis)
- Colon (Colitis)
- Kidney (Nephritis)
- Heart (Myocarditis)
- Certain IRAEs are more common than others!
- MORE common:
- Skin
- Gut
- Endocrine
- Lung
- Musculoskeletal
- LESS common:
- Cardiovascular
- Hematologic
- Renal
- Neurologic
- Ophthalmologic
- Certain IRAEs are more common with a specific drug class!
- CTLA-4 inhibitors:
- All grade colitis
- Hypophysitis
- Rash
- PD-1 inhibitors:
- Pneumonitis
- Hypothyroidism
- Arthralgias
- Vitiligo
- Life threatening IRAEs are:
- Severe colitis, pneumonitis
- Encephalitis
- Toxic epidermal necrolysis
- Myocarditis
- Autoimmune type I diabetes mellitus (Presenting as diabetic ketoacidosis)
Pearl 3: What is the timeline of IRAEs?
- Usually within 3 months but can occur anytime even after the checkpoint inhibitor treatment has ended!
- Timeline may vary based on CTLA-4 vs. PD-1/PDL-1 inhibitors mechanism!
- CTLA-4
- Attenuates T-cell activation at a proximal step in the immune response in the lymph nodes
- Adverse events occur on the EARLIER side
- PD-1/PDL-1
- Inhibit T cells at later stages of the immune response in peripheral tissues
- Adverse events are NOT AS EARLY CTLA-4
- Different adverse events are more likely to present at different times:
- Skin, rash and pruritus IRAEs as well as myocarditis present the earliest
- Colitis at the 4 week post exposure mark
- Endocrinopathies present later around the 6 week mark
- Delayed IRAE vs. Chronic IRAE
- Delayed IRAE
- Occurs 1 year or later after treatment starts
- Most common presentation(s)
- Colitis
- Rash
- Pneumonitis
- Note: Many of these patients have had an acute IRAE already!
- Chronic IRAEs
- Symptoms persist for >12 weeks after discontinuing checkpoint inhibitors!
Pearl 4: What factors increase susceptibility to developing IRAE? What is the impact of treating an IRAE on the cancer?
- Pre-existing autoimmune disease
- Host microbiota (i.e., GI flora) and germline factors
- There is ongoing research on the impact of germline genetic factors and composition of host microbiota (ie. GI flora) on IRAE susceptibility
- Combination therapy and CTLA-4 inhibitors
- Can cause more severe IRAE
- Checkpoint inhibitors have to be used with caution in prior organ transplant to prevent rejection
- Note: Immunosuppression to treat IRAE does not seem to decrease the anti-tumor effect of the checkpoint inhibitor!
Pearl 5: What about complementary medicine?
- It is important to create a non-judgmental space for our cancer patients to share their experiences with complementary medicine!
- Ask your patient about supplements, tea or any other products they may be using
- Elevated LFTs can prompt us to consider immune checkpoint inhibitor (ICI) hepatitis
- But other etiologies, such viral hepatitis, drug induced liver injury, alcohol use and infiltration from malignancy must be ruled out!
- Learning more about CAM (Complementary and Alternative Medicine) from At the Bedside episode:
- Online Resources: NCCIH, MSKCC – “About Herbs”
- Articles: Cochrane Reviews
- Books: Ernst, “Alternative Medicine: A Critical Assessment of 150 Modalities”
