Checkpoint inhibitor explained

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.

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.[2] [3] 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.[4]

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.[5] [6]

Types

Approved checkpoint inhibitors!Name!Brand Name!Marketing rights !Target!Approved!Indications (May 2023) [7]
IpilimumabYervoyBristol-Myers SquibbCTLA-42011metastatic melanoma, renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer, malignant pleural mesothelioma, esophageal squamous carcinoma (in combination with Nivolumab)[8]
TremelimumabImjudoAstraZenecaCTLA-42022hepatocellular carcinoma (in combination with Durvalumab),[9] non-small-cell lung cancer (in combination with Durvalumab and platinum-based chemotherapy)[10]
NivolumabOpdivoBristol-Myers Squibb (North America)

+ Ono Pharmaceutical (other countries)

PD-12014metastatic 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)
PembrolizumabKeytrudaMerck Sharp & DohmePD-12014metastatic 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
AtezolizumabTecentriqGenentech/RochePD-L12016bladder cancer, non-small cell lung cancer, breast cancer, small cell lung cancer, hepatocellular carcinoma, metastatic melanoma
AvelumabBavencioMerck KGaA and PfizerPD-L12017Merkel cell carcinoma, urothelial carcinoma, renal cell carcinoma
DurvalumabImfinziMedimmune/AstraZenecaPD-L12017non-small cell lung cancer, small cell lung cancer, biliary tract cancer
CemiplimabLibtayoRegeneronPD-12018squamous cell carcinoma, basal cell carcinoma, non-small cell lung cancer
DostarlimabJemperliTesaroPD-12021endometrial 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.[11] 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.

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. 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]

PD-L1 inhibitors

See main article: PD-L1 inhibitor. 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] [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. 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

Notes and References

  1. Pardoll DM . The blockade of immune checkpoints in cancer immunotherapy . Nature Reviews. Cancer . 12 . 4 . 252–64 . March 2012 . 22437870 . 4856023 . 10.1038/nrc3239 .
  2. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ . Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses . Immunity . 27 . 1 . 111–22 . July 2007 . 17629517 . 2707944 . 10.1016/j.immuni.2007.05.016 .
  3. Karwacz K, Bricogne C, MacDonald D, Arce F, Bennett CL, Collins M, Escors D . PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells . EMBO Molecular Medicine . 3 . 10 . 581–92 . October 2011 . 21739608 . 3191120 . 10.1002/emmm.201100165 .
  4. Syn NL, Teng MW, Mok TS, Soo RA . De-novo and acquired resistance to immune checkpoint targeting . The Lancet. Oncology . 18 . 12 . e731–e741 . December 2017 . 29208439 . 10.1016/s1470-2045(17)30607-1 .
  5. Web site: 2014 Tang Prize in Biopharmaceutical Science . 2016-06-18 . 2017-10-20 . live . https://web.archive.org/web/20171020051653/http://www.tang-prize.org/en/owner.php?cat=11&y=2 .
  6. Web site: Devlin H . James P Allison and Tasuku Honjo win Nobel prize for medicine . The Guardian . 2018-10-01 . 2018-10-01.
  7. Web site: FDA Approval History. 2021-04-26. Drugs.com. en.
  8. Web site: FDA approves Opdivo in combination with chemotherapy and Opdivo in combination with Yervoy for first-line esophageal squamous cell carcinoma indications . . 2023-05-22. FDA : Drugs (May 31, 2022)
  9. Web site: FDA approves tremelimumab in combination with durvalumab for unresectable hepatocellular carcinoma . . 2023-05-22. FDA : Drugs (October 24, 2022)
  10. Web site: FDA approval of tremelimumab in combination with durvalumab and platinum-based chemotherapy for metastatic non-small cell lung cancer . . 2023-05-22. FDA : Drugs (November 18, 2022)
  11. Cameron F, Whiteside G, Perry C . Ipilimumab: first global approval . Drugs . 71 . 8 . 1093–104 . May 2011 . 21668044 . 10.2165/11594010-000000000-00000 .
  12. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M . 6 . 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 . June 2012 . 22547592 . 10.1200/JCO.2011.38.4032 . free .
  13. Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, Zheng L, Diaz LA, Donehower RC, Jaffee EM, Laheru DA . 6 . 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 . September 2013 . 23924790 . 3779664 . 10.1097/CJI.0b013e31829fb7a2 .
  14. Postow MA, Callahan MK, Wolchok JD . Immune Checkpoint Blockade in Cancer Therapy . Journal of Clinical Oncology . 33 . 17 . 1974–82 . June 2015 . 25605845 . 4980573 . 10.1200/JCO.2014.59.4358 .
  15. van Hooren L, Sandin LC, Moskalev I, Ellmark P, Dimberg A, Black P, Tötterman TH, Mangsbo SM . 6 . 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 . February 2017 . 27873300 . 10.1002/eji.201646583 . 2463514 . free .
  16. News: F.D.A. Approves an Immunotherapy Drug for Bladder Cancer. Pollack A . 2016-05-18. The New York Times. 2016-05-21. 0362-4331. vanc.
  17. News: Enrolling the immune system in the fight against cancer. The Economist. 2017-10-01. en.
  18. World Health Organization . International Nonproprietary Names for Pharmaceutical Substances (INN). WHO Drug Information . 31 . 2 . 2017 . World Health Organization.
  19. Web site: PDR001 . Immuno-Oncology News.
  20. Web site: Spartalizumab . NCI Drug Dictionary, National Cancer Institute.
  21. Heimes AS, Schmidt M . Atezolizumab for the treatment of triple-negative breast cancer . Expert Opinion on Investigational Drugs . 28 . 1 . 1–5 . January 2019 . 30474425 . 10.1080/13543784.2019.1552255 . 53788304 .
  22. 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. en. 212. 12. 2095–2113. 10.1084/jem.20150304. 0022-1007. 4647263. 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. en. 8. 1. 5336. 10.1038/s41598-018-23549-2. 2045-2322. 5871872. 29593227. 2018NatSR...8.5336G.
  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. en. 2020.09.24.306571. 10.1101/2020.09.24.306571. 222069725. free.
  25. Postow MA, Sidlow R, Hellmann MD . Immune-Related Adverse Events Associated with Immune Checkpoint Blockade . EN . The New England Journal of Medicine . 378 . 2 . 158–168 . January 2018 . 29320654 . 10.1056/nejmra1703481 . 5211582 .
  26. Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens . 2023-06-25 . JAMA Oncology . 10.1001/jamaoncol.2017.3064 . 5838579 . 28973656 . 2018 . Barroso-Sousa . Romualdo . Barry . William T. . Garrido-Castro . Ana C. . Hodi . F. Stephen . Min . Le . Krop . Ian E. . Tolaney . Sara M. . 4 . 2 . 173–182 .
  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 . en . 24 . 13 . 10526 . 10.3390/ijms241310526 . 37445704 . 10341615 . 1422-0067 . free .
  28. Book: Butterworth JF . Morgan and Mikhail's clinical anaesthesiology 6th edition. McGraw-Hill Education. 2018. 978-1-260-28843-8. United States. 638.
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  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. 10.1186/s13073-021-00974-z. 34641962. 8513370. 1756-994X . free .
  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. en. 371. 6529. 602–609. 10.1126/science.abb5920. 33303685. 2021Sci...371..602B. 228101416. 0036-8075. free.

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