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checkpoint inhibitor therapy

Indications: - treatment of melanoma, renal cell carcinoma, non-small cell lung cancer, bladder cancer, Hodgkin lymphoma, & colon cancers caused by DNA mismatch-repair deficiency [1] Procedure: - checkpoint inhibitors include: - ipilimumab (Yervoy) inhibits CTLA-4 - pembrolizumab (Keytruda) inhibits PD-1 - nivolumab (Opdivo) inhibits PD-1 Adverse effects: - may increase risk of autoimmunne disease - increased risk of endocrinopathy [2] - thyroid disease: hypothyroidism, thyroiditis - adrenal disorders - hypophysitis - central adrenal insufficiency - secondary (central) hypothyroidism - type 1 diabetes - most mild, but may be serious [2] Mechanism of action: - when T cells are activated, the activated T cells paradoxically produce 'checkpoint' proteins that then abort the T-cell attack - 2 checkpoint proteins are CTLA-4 & PD-1 - checkpoint inhibitor facilitate an uninhibited T-cell response to tumor antigens [1] Comparative biology: - in a mouse model for colon cancer, Bifidobacterium (B. pseudolongum) enhances effectiveness of checkpoint inhibitor therapy via production of inosine [3] - this results in a more permeable gut-blood barrier increasing blood inosine concentrations, leading to systemic activation of antitumor T cells [3] - Bifidobacterium species are increased in humans with colon cancer responding to checkpoint inhibitor therapy [3]

Related

checkpoint inhibitor; immune checkpoint inhibitor; PD-1/PD-L1 inhibitor

General

cancer immunotherapy

References

  1. Komaroff AL Immunotherapy to Fight Cancer Begins to Work. NEJM Journal Watch. June 16, 2015 Massachusetts Medical Society (subscription needed) http://www.jwatch.org - Sharma P and Allison JP. The future of immune checkpoint therapy. Science 2015 Apr 3; 348:56. PMID: 25838373 - Le DT et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015 May 30 PMID: 26028255
  2. Tucker ME Endocrinopathies Common With Checkpoint Immunotherapy for Cancer. American Association of Clinical Endocrinologists (AACE) 2017 Medscape. May 9, 2017 http://www.medscape.com/viewarticle/879727
  3. Mager LF et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science 2020 Sep 18; 369:1481 PMID: 32792462 https://science.sciencemag.org/content/369/6510/1481 - Shaikh FY, Sears CL. Messengers from the microbiota. Science 2020 Sep 18; 369:1427 PMID: 32943510 https://science.sciencemag.org/content/369/6510/1427