checkpoint inhibitor therapy
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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]
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]
Procedure
- checkpoint inhibitors include:
- ipilimumab (Yervoy) inhibits CTLA-4
- pembrolizumab (Keytruda) inhibits PD-1
- nivolumab (Opdivo) inhibits PD-1
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]
More general terms
Additional terms
References
- ↑ 1.0 1.1 1.2 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: https://www.ncbi.nlm.nih.gov/pubmed/25838373
Le DT et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015 May 30 PMID: https://www.ncbi.nlm.nih.gov/pubmed/26028255 - ↑ 2.0 2.1 2.2 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
- ↑ 3.0 3.1 3.2 3.3 Mager LF et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science 2020 Sep 18; 369:1481 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32792462 https://science.sciencemag.org/content/369/6510/1481
Shaikh FY, Sears CL. Messengers from the microbiota. Science 2020 Sep 18; 369:1427 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32943510 https://science.sciencemag.org/content/369/6510/1427