Checkpoint inhibitor therapy is a form of cancer immunotherapy. The therapy targets immune checkpoints, key regulators of the immune system that when stimulated can dampen the immune response to an immunologic stimulus. Some cancers can protect themselves from attack by stimulating immune checkpoint targets. Checkpoint therapy can block inhibitory checkpoints, restoring immune system function.[1] The first anti-cancer drug targeting an immune checkpoint was ipilimumab, a CTLA4 blocker approved in the United States in 2011.[2]

Currently approved checkpoint inhibitors target the molecules CTLA4, PD-1, and PD-L1. PD-1 is the transmembrane programmed cell death 1 protein (also called PDCD1 and CD279), which interacts with PD-L1 (PD-1 ligand 1, or CD274). PD-L1 on the cell surface binds to PD-1 on an immune cell surface, which inhibits immune cell activity. Among PD-L1 functions is a key regulatory role on T cell activities.[3][4] It appears that (cancer-mediated) upregulation of PD-L1 on the cell surface may inhibit T cells that might otherwise attack. Antibodies that bind to either PD-1 or PD-L1 and therefore block the interaction may allow the T-cells to attack the tumor.[5]

The discoveries in basic science allowing checkpoint inhibitor therapies led to James P. Allison and Tasuku Honjo winning the Tang Prize in Biopharmaceutical Science and the Nobel Prize in Physiology or Medicine in 2018.[6][7]

Types

Approved checkpoint inhibitors
Name Brand Name Marketing rights Target Approved Indications (May 2023) [8]
Ipilimumab Yervoy Bristol-Myers Squibb CTLA-4 2011 metastatic melanoma, renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer, malignant pleural mesothelioma, esophageal squamous carcinoma (in combination with Nivolumab)[9]
Tremelimumab Imjudo AstraZeneca CTLA-4 2022 hepatocellular carcinoma (in combination with Durvalumab),[10] non-small-cell lung cancer (in combination with Durvalumab and platinum-based chemotherapy)[11]
Nivolumab Opdivo Bristol-Myers Squibb (North America)

+ Ono Pharmaceutical (other countries)

 PD-1 2014 metastatic melanoma, non-small cell lung cancer, renal cell carcinoma, Hodgkin's lymphoma, head and neck cancer, urothelial carcinoma, colorectal cancer, hepatocellular carcinoma, small cell lung cancer, esophageal carcinoma, malignant pleural mesothelioma, gastric cancer (or gastroesophageal junction cancer)
Pembrolizumab Keytruda Merck Sharp & Dohme PD-1 2014 metastatic melanoma, non-small cell lung cancer, head and neck cancer, Hodgkin's lymphoma, urothelial carcinoma, gastric cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, small cell lung cancer, esophageal carcinoma, endometrial cancer, squamous cell carcinoma, biliary tract cancer
Atezolizumab Tecentriq Genentech/Roche PD-L1 2016 bladder cancer, non-small cell lung cancer, breast cancer, small cell lung cancer, hepatocellular carcinoma, metastatic melanoma
Avelumab Bavencio Merck KGaA and Pfizer PD-L1 2017 Merkel cell carcinoma, urothelial carcinoma, renal cell carcinoma
Durvalumab Imfinzi Medimmune/AstraZeneca PD-L1 2017 non-small cell lung cancer, small cell lung cancer, biliary tract cancer
Cemiplimab Libtayo Regeneron PD-1 2018 squamous cell carcinoma, basal cell carcinoma, non-small cell lung cancer

Cell surface checkpoint inhibitors

CTLA-4 inhibitors

The first checkpoint antibody approved by the FDA was ipilimumab, approved in 2011 for treatment of melanoma.[2] It blocks the immune checkpoint molecule CTLA-4. Clinical trials have also shown some benefits of anti-CTLA-4 therapy on lung cancer or pancreatic cancer, specifically in combination with other drugs.[12][13]

However, patients treated with check-point blockade (specifically CTLA-4 blocking antibodies), or a combination of check-point blocking antibodies, are at high risk of suffering from immune-related adverse events such as dermatologic, gastrointestinal, endocrine, or hepatic autoimmune reactions.[14] These are most likely due to the breadth of the induced T-cell activation when anti-CTLA-4 antibodies are administered by injection in the blood stream.

Using a mouse model of bladder cancer, researchers have found that a local injection of a low dose anti-CTLA-4 in the tumour area had the same tumour inhibiting capacity as when the antibody was delivered in the blood.[15] At the same time the levels of circulating antibodies were lower, suggesting that local administration of the anti-CTLA-4 therapy might result in fewer adverse events.[15]

PD-1 inhibitors

Initial clinical trial results with IgG4 PD-1 antibody nivolumab (under the brand name Opdivo and developed by Bristol-Myers Squibb) were published in 2010.[1] It was approved in 2014. Nivolumab is approved to treat melanoma, lung cancer, kidney cancer, bladder cancer, head and neck cancer, and Hodgkin's lymphoma.[16]

  • Pembrolizumab (brand name Keytruda) is another PD-1 inhibitor that was approved by the FDA in 2014 and was the second checkpoint inhibitor approved in the United States.[17] Keytruda is approved to treat melanoma and lung cancer and is produced by Merck.[16]
  • Spartalizumab (PDR001) is a PD-1 inhibitor being developed by Novartis to treat both solid tumors and lymphomas.[18][19][20]

PD-L1 inhibitors

In May 2016, PD-L1 inhibitor atezolizumab was approved for treating bladder cancer.[21]

Intracellular checkpoint inhibitors

Other modes of enhancing [adoptive] immunotherapy include targeting so-called intrinsic checkpoint blockades. Many of these intrinsic regulators include molecules with ubiquitin ligase activity, including CBLB, and CISH.

CISH

More recently, CISH (cytokine-inducible SH2-containing protein), another molecule with ubiquitin ligase activity, was found to be induced by T cell receptor ligation (TCR) and negatively regulate it by targeting the critical signaling intermediate PLC-gamma-1 for degradation.[22] The deletion of CISH in effector T cells has been shown to dramatically augment TCR signaling and subsequent effector cytokine release, proliferation and survival. The adoptive transfer of tumor-specific effector T cells knocked out or knocked down for CISH resulted in a significant increase in functional avidity and long-term tumor immunity. Surprisingly there was no changes in activity of Cish's purported target, STAT5. CISH knock out in T cells increased PD-1 expression and the adoptive transfer of CISH knock out T cells synergistically combined with PD-1 antibody blockade resulting in durable tumor regression and survival in a preclinical animal model. Thus, Cish represents a new class of T-cell intrinsic immunologic checkpoints with the potential to radically enhance adoptive immunotherapies for cancer.[23][22][24]

Adverse effects

Immune-related adverse events may be caused by checkpoint inhibitors. Altering checkpoint inhibition can have diverse effects on most organ systems of the body. Colitis (inflammation of the colon) occurs commonly. The precise mechanism is unknown, but differs in some respects based on the molecule targeted.[25] Thyroiditis with resulting hypothyroidism is a common Immune-related adverse event especially with use of combinations of different ICIs.[26] The underlying mechanism of ICI induced thyroiditis may differ from other forms of thyroiditis.[27] Hypophysitis seems to be more specific to CTLA-4 inhibitors.[26] Infusion of checkpoint inhibitors has also been associated with acute seronegative myasthenia gravis.[28] A lower incidence of hypothyroidism was observed in a trial of combined B cell depletion and immune checkpoint inhibitor treatment compared with studies of immune checkpoint inhibitor monotherapy.[29] This holds promise for combining check point inhibitor therapy with immunosuppressive drugs to achieve anti-cancer effects with less toxicity.

Studies are beginning to show that intrinsic factors, such as species of the genus Bacteroides that inhabit the gut microbiome [30] prospectively modify risk of developing immune related adverse events. Further evidence of this can be found in patients that saw reversal of immune toxicity following fecal microbiome transplant from healthy donors.[31]

See also

References

  1. 1 2 Pardoll DM (March 2012). "The blockade of immune checkpoints in cancer immunotherapy". Nature Reviews. Cancer. 12 (4): 252–64. doi:10.1038/nrc3239. PMC 4856023. PMID 22437870.
  2. 1 2 Cameron F, Whiteside G, Perry C (May 2011). "Ipilimumab: first global approval". Drugs. 71 (8): 1093–104. doi:10.2165/11594010-000000000-00000. PMID 21668044.
  3. ↑ Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ (July 2007). "Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses". Immunity. 27 (1): 111–22. doi:10.1016/j.immuni.2007.05.016. PMC 2707944. PMID 17629517.
  4. ↑ Karwacz K, Bricogne C, MacDonald D, Arce F, Bennett CL, Collins M, Escors D (October 2011). "PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells". EMBO Molecular Medicine. 3 (10): 581–92. doi:10.1002/emmm.201100165. PMC 3191120. PMID 21739608.
  5. ↑ Syn NL, Teng MW, Mok TS, Soo RA (December 2017). "De-novo and acquired resistance to immune checkpoint targeting". The Lancet. Oncology. 18 (12): e731–e741. doi:10.1016/s1470-2045(17)30607-1. PMID 29208439.
  6. ↑ "2014 Tang Prize in Biopharmaceutical Science". Archived from the original on 2017-10-20. Retrieved 2016-06-18.
  7. ↑ Devlin H (2018-10-01). "James P Allison and Tasuku Honjo win Nobel prize for medicine". The Guardian. Retrieved 2018-10-01.
  8. ↑ "FDA Approval History". Drugs.com. Retrieved 2021-04-26.
  9. ↑ "FDA approves Opdivo in combination with chemotherapy and Opdivo in combination with Yervoy for first-line esophageal squamous cell carcinoma indications". Food and Drug Administration. Retrieved 2023-05-22. FDA : Drugs (May 31, 2022)
  10. ↑ "FDA approves tremelimumab in combination with durvalumab for unresectable hepatocellular carcinoma". Food and Drug Administration. Retrieved 2023-05-22. FDA : Drugs (October 24, 2022)
  11. ↑ "FDA approval of tremelimumab in combination with durvalumab and platinum-based chemotherapy for metastatic non-small cell lung cancer". Food and Drug Administration. Retrieved 2023-05-22. FDA : Drugs (November 18, 2022)
  12. ↑ Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. (June 2012). "Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study". Journal of Clinical Oncology. 30 (17): 2046–54. doi:10.1200/JCO.2011.38.4032. PMID 22547592.
  13. ↑ Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, et al. (September 2013). "Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer". Journal of Immunotherapy. 36 (7): 382–9. doi:10.1097/CJI.0b013e31829fb7a2. PMC 3779664. PMID 23924790.
  14. ↑ Postow MA, Callahan MK, Wolchok JD (June 2015). "Immune Checkpoint Blockade in Cancer Therapy". Journal of Clinical Oncology. 33 (17): 1974–82. doi:10.1200/JCO.2014.59.4358. PMC 4980573. PMID 25605845.
  15. 1 2 van Hooren L, Sandin LC, Moskalev I, Ellmark P, Dimberg A, Black P, et al. (February 2017). "Local checkpoint inhibition of CTLA-4 as a monotherapy or in combination with anti-PD1 prevents the growth of murine bladder cancer". European Journal of Immunology. 47 (2): 385–393. doi:10.1002/eji.201646583. PMID 27873300. S2CID 2463514.
  16. 1 2 Pollack A (2016-05-18). "F.D.A. Approves an Immunotherapy Drug for Bladder Cancer". The New York Times. ISSN 0362-4331. Retrieved 2016-05-21.
  17. ↑ "Enrolling the immune system in the fight against cancer". The Economist. Retrieved 2017-10-01.
  18. ↑ World Health Organization (2017). "International Nonproprietary Names for Pharmaceutical Substances (INN)" (PDF). WHO Drug Information. 31 (2).
  19. ↑ "PDR001". Immuno-Oncology News.
  20. ↑ "Spartalizumab". NCI Drug Dictionary, National Cancer Institute.
  21. ↑ Heimes AS, Schmidt M (January 2019). "Atezolizumab for the treatment of triple-negative breast cancer". Expert Opinion on Investigational Drugs. 28 (1): 1–5. doi:10.1080/13543784.2019.1552255. PMID 30474425. S2CID 53788304.
  22. 1 2 Palmer, Douglas C.; Guittard, Geoffrey C.; Franco, Zulmarie; Crompton, Joseph G.; Eil, Robert L.; Patel, Shashank J.; Ji, Yun; Van Panhuys, Nicholas; Klebanoff, Christopher A.; Sukumar, Madhusudhanan; Clever, David (2015-11-16). "Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance". Journal of Experimental Medicine. 212 (12): 2095–2113. doi:10.1084/jem.20150304. ISSN 0022-1007. PMC 4647263. PMID 26527801.
  23. ↑ Guittard, Geoffrey; Dios-Esponera, Ana; Palmer, Douglas C.; Akpan, Itoro; Barr, Valarie A.; Manna, Asit; Restifo, Nicholas P.; Samelson, Lawrence E. (December 2018). "The Cish SH2 domain is essential for PLC-γ1 regulation in TCR stimulated CD8+ T cells". Scientific Reports. 8 (1): 5336. Bibcode:2018NatSR...8.5336G. doi:10.1038/s41598-018-23549-2. ISSN 2045-2322. PMC 5871872. PMID 29593227.
  24. ↑ Palmer, Douglas C.; Webber, Beau R.; Patel, Yogin; Johnson, Matthew J.; Kariya, Christine M.; Lahr, Walker S.; Parkhurst, Maria R.; Gartner, Jared J.; Prickett, Todd D.; Lowery, Frank J.; Kishton, Rigel J. (2020-09-25). "Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade". bioRxiv: 2020.09.24.306571. doi:10.1101/2020.09.24.306571. S2CID 222069725.
  25. ↑ Postow MA, Sidlow R, Hellmann MD (January 2018). "Immune-Related Adverse Events Associated with Immune Checkpoint Blockade". The New England Journal of Medicine. 378 (2): 158–168. doi:10.1056/nejmra1703481. PMID 29320654. S2CID 5211582.
  26. 1 2 Barroso-Sousa, Romualdo; Barry, William T.; Garrido-Castro, Ana C.; Hodi, F. Stephen; Min, Le; Krop, Ian E.; Tolaney, Sara M. (2018). "Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens". JAMA Oncology. 4 (2): 173–182. doi:10.1001/jamaoncol.2017.3064. PMC 5838579. PMID 28973656. Retrieved 2023-06-25.
  27. ↑ Pollack, Rena; Stokar, Joshua; Lishinsky, Natan; Gurt, Irina; Kaisar-Iluz, Naomi; Shaul, Merav E.; Fridlender, Zvi G.; Dresner-Pollak, Rivka (January 2023). "RNA Sequencing Reveals Unique Transcriptomic Signatures of the Thyroid in a Murine Lung Cancer Model Treated with PD-1 and PD-L1 Antibodies". International Journal of Molecular Sciences. 24 (13): 10526. doi:10.3390/ijms241310526. ISSN 1422-0067. PMC 10341615. PMID 37445704.
  28. ↑ Butterworth JF (2018). Morgan and Mikhail's clinical anaesthesiology 6th edition. United States: McGraw-Hill Education. p. 638. ISBN 978-1-260-28843-8.
  29. ↑ Risbjerg RS, Hansen MV, Sørensen AS, Kragstrup TW (2020-05-25). "The effects of B cell depletion on immune related adverse events associated with immune checkpoint inhibition". Experimental Hematology & Oncology. 9 (1): 9. doi:10.1186/s40164-020-00167-1. PMC 7249386. PMID 32509417.
  30. ↑ Usyk, Mykhaylo; Pandey, Abhishek; Hayes, Richard B.; Moran, Una; Pavlick, Anna; Osman, Iman; Weber, Jeffrey S.; Ahn, Jiyoung (2021-10-13). "Bacteroides vulgatus and Bacteroides dorei predict immune-related adverse events in immune checkpoint blockade treatment of metastatic melanoma". Genome Medicine. 13 (1): 160. doi:10.1186/s13073-021-00974-z. ISSN 1756-994X. PMC 8513370. PMID 34641962.
  31. ↑ Baruch, Erez N.; Youngster, Ilan; Ben-Betzalel, Guy; Ortenberg, Rona; Lahat, Adi; Katz, Lior; Adler, Katerina; Dick-Necula, Daniela; Raskin, Stephen; Bloch, Naamah; Rotin, Daniil (2021-02-05). "Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients". Science. 371 (6529): 602–609. Bibcode:2021Sci...371..602B. doi:10.1126/science.abb5920. ISSN 0036-8075. PMID 33303685. S2CID 228101416.
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