Checkpoint inhibitor

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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]

Contents

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
NameBrand NameMarketing rightsTargetApprovedIndications (May 2023) [8]
Ipilimumab YervoyBristol-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 OpdivoBristol-Myers Squibb (North America)

+ Ono Pharmaceutical (other countries)

 PD-1 2014metastatic 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 KeytrudaMerck Sharp & Dohme PD-1 2014metastatic 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 TecentriqGenentech/Roche PD-L1 2016 bladder cancer, non-small cell lung cancer, breast cancer, small cell lung cancer, hepatocellular carcinoma, metastatic melanoma
Avelumab BavencioMerck KGaA and Pfizer PD-L1 2017Merkel cell carcinoma, urothelial carcinoma, renal cell carcinoma
Durvalumab ImfinziMedimmune/AstraZeneca PD-L1 2017non-small cell lung cancer, small cell lung cancer, biliary tract cancer
Cemiplimab LibtayoRegeneron PD-1 2018squamous cell carcinoma, basal cell carcinoma, non-small cell lung cancer
Dostarlimab JemperliTesaro PD-1 2021endometrial cancer
Relatlimab

Nivolumab

OpdualagBristol-Myers SquibbLAG-3 and PD-12022For people aged 12 or older with previously untreated melanoma that cannot be removed surgically or has metastasized within the body

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]

LAG-3 Inhibitors

In 2022, the FDA approved a combination of relatlimab and nivolumab (Opdivo) to be marketed under the name Opdualag for people aged 12 or older with previously untreated melanoma that cannot be removed surgically or has spread (metastasized) within the body. Relatlimab blocks a protein on immune cells called LAG-3. [22]

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. [23] 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. [24] [23] [25]

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. [26] Thyroiditis with resulting hypothyroidism is a common Immune-related adverse event especially with use of combinations of different ICIs. [27] The underlying mechanism of ICI induced thyroiditis may differ from other forms of thyroiditis. [28] Hypophysitis seems to be more specific to CTLA-4 inhibitors. [27] Infusion of checkpoint inhibitors has also been associated with acute seronegative myasthenia gravis. [29] 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. [30] 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 [31] 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. [32]

See also

Related Research Articles

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology (immuno-oncology) and a growing subspecialty of oncology.

<span class="mw-page-title-main">Targeted therapy</span> Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

A blocking antibody is an antibody that does not have a reaction when combined with an antigen, but prevents other antibodies from combining with that antigen. This function of blocking antibodies has had a variety of clinical and experimental uses.

<span class="mw-page-title-main">Ipilimumab</span> Pharmaceutical drug

Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

<span class="mw-page-title-main">Tremelimumab</span> Monoclonal antibody

Tremelimumab, sold under the brand name Imjudo, is a fully human monoclonal antibody used for the treatment of hepatocellular carcinoma. Tremelimumab is designed to attach to and block CTLA-4, a protein that controls the activity of T cells, which are part of the immune system.

Medarex was an American biopharmaceutical company based in Princeton, New Jersey, with manufacturing facilities in Bloomsbury and Annandale, New Jersey, and research facilities in Milpitas and Sunnyvale, California. In 2009, Medarex was purchased by Bristol Myers Squibb.

Chemoimmunotherapy is chemotherapy combined with immunotherapy. Chemotherapy uses different drugs to kill or slow the growth of cancer cells; immunotherapy uses treatments to stimulate or restore the ability of the immune system to fight cancer. A common chemoimmunotherapy regimen is CHOP combined with rituximab (CHOP-R) for B-cell non-Hodgkin lymphomas.

<span class="mw-page-title-main">Programmed cell death protein 1</span> Mammalian protein found in humans

Programmed cell death protein 1(PD-1),. PD-1 is a protein encoded in humans by the PDCD1 gene. PD-1 is a cell surface receptor on T cells and B cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.

<span class="mw-page-title-main">Nivolumab</span> Anticancer medication

Nivolumab, sold under the brand name Opdivo, is an anti-cancer medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, colon cancer, esophageal squamous cell carcinoma, liver cancer, gastric cancer, and esophageal or gastroesophageal junction cancer. It is administered intravenously.

<span class="mw-page-title-main">Pembrolizumab</span> Pharmaceutical drug used in cancer treatment

Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody, more specifically a PD-1 inhibitor, used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. It is administered by slow intravenous injection.

<span class="mw-page-title-main">Atezolizumab</span> Monoclonal anti-PD-L1 antibody

Atezolizumab, sold under the brand name Tecentriq among others, is a monoclonal antibody medication used to treat urothelial carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma and alveolar soft part sarcoma, but discontinued for use in triple-negative breast cancer (TNBC). It is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).

<span class="mw-page-title-main">Immune checkpoint</span> Regulators of the immune system

Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulating immune checkpoint targets.

An immune checkpoint regulator is a modulator of the immune system, that allows initiation of a productive immune response and prevents the onset of autoimmunity. Examples of such a molecule are cytotoxic T-lymphocyte antigen 4, which is an inhibitory receptor found on immune cells and programmed cell death 1 (CD279), which has an important role in down-regulating the immune system by preventing the activation of T-cells.

Avelumab, sold under the brand name Bavencio, is a fully human monoclonal antibody medication for the treatment of Merkel cell carcinoma, urothelial carcinoma, and renal cell carcinoma.

<span class="mw-page-title-main">PD-1 and PD-L1 inhibitors</span> Class of anticancer drugs

PD-1 inhibitors and PD-L1 inhibitors are a group of checkpoint inhibitor anticancer drugs that block the activity of PD-1 and PDL1 immune checkpoint proteins present on the surface of cells. Immune checkpoint inhibitors are emerging as a front-line treatment for several types of cancer.

<span class="mw-page-title-main">VISTA (protein)</span> Protein-coding gene in the species Homo sapiens

V-domain Ig suppressor of T cell activation (VISTA) is a type I transmembrane protein that functions as an immune checkpoint and is encoded by the VSIR gene.

<span class="mw-page-title-main">Tislelizumab</span> Monoclonal antibody

Tislelizumab, sold under the brand name Tevimbra among others, is an anti-cancer medication used for the treatment of various forms of cancer. It is a humanized monoclonal antibody directed against programmed death receptor-1. It is being developed by BeiGene.

Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody used as an anti-cancer medication for the treatment of endometrial cancer. Dostarlimab is a programmed death receptor-1 (PD-1)–blocking monoclonal antibody.

Oligoclonal antibodies are an emerging immunological treatment relying on the combinatory use of several monoclonal antibodies (mAb) in one single drug. The composition can be made of mAb targeting different epitopes of a same protein (homo-combination) or mAb targeting different proteins (hetero-combination). It mimicks the natural polyclonal humoral immunological response to get better efficiency of the treatment. This strategy is most efficient in infections and in cancer treatment as it allow to overcome acquired resistance by pathogens and the plasticity of cancers.

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. ↑ "Opdualag Approved to Treat Advanced Melanoma - NCI". www.cancer.gov. 2022-04-06. Retrieved 2025-01-19.
  23. 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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.
  27. 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.
  28. ↑ 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.
  29. ↑ Butterworth JF (2018). Morgan and Mikhail's clinical anaesthesiology 6th edition. United States: McGraw-Hill Education. p. 638. ISBN   978-1-260-28843-8.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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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