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Cancers considered "hot tumors", such as melanoma, contain antitumor T cells and may respond to checkpoint inhibitor antibodies<ref name="Schlom2018">Schlom J, Gulley JL. Vaccines as an Integral Component of Cancer Immunotherapy. JAMA. Published online November 08, 2018. {{doi|10.1001/jama.2018.9511}}</ref>.


==Immune checkpoint inhibitors==


==Immune checkpoint inhibitors==
[[Monoclonal antibody|Monoclonal antibodies]] are a type of [[cancer immunotherapy]] that have been developed to target immune checkpoints. These checkpoints ''down''-regulate programmed cell death 1 or apoptosis. [[Cancer immunotherapy]] to block these checkpoints may encourage apoptosis of cancer cells.
 
Drug toxicities include<ref name="pmid27809739">{{cite journal| author=Bourke JM, O'Sullivan M, Khattak MA| title=Management of adverse events related to new cancer immunotherapy (immune checkpoint inhibitors). | journal=Med J Aust | year= 2016 | volume= 205 | issue= 9 | pages= 418-424 | pmid=27809739 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27809739  }} </ref><ref name="pmid28973656">{{cite journal| author=Barroso-Sousa R, Barry WT, Garrido-Castro AC, Hodi FS, Min L, Krop IE et al.| title=Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis. | journal=JAMA Oncol | year= 2017 | volume=  | issue=  | pages=  | pmid=28973656 | doi=10.1001/jamaoncol.2017.3064 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28973656  }} </ref><ref>Postow et al. http://www.nejm.org/doi/full/10.1056/NEJMra1703481 NEJM 2018</ref>:
* Gastrointestinal
* Dermatologic
* Endocrine
* Exacerbation of pre-existing autoimmune disease<ref name="pmid29297009">{{cite journal| author=Abdel-Wahab N, Shah M, Lopez-Olivo MA, Suarez-Almazor ME| title=Use of Immune Checkpoint Inhibitors in the Treatment of Patients With Cancer and Preexisting Autoimmune Disease: A Systematic Review. | journal=Ann Intern Med | year= 2018 | volume=  | issue=  | pages=  | pmid=29297009 | doi=10.7326/M17-2073 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29297009  }} </ref>.


[[Monoclonal antibody|Monoclonal antibodies]] have been developed to target immune checkpoints.
===PD-1 inhibitors===
===PD-1 inhibitors===
These antibodies target the [[Programmed Cell Death 1 Receptor]] (PD-1 Receptor). Programmed Cell Death Type I is also known as [[apoptosis]]. The PD-1 Receptor is "an inhibitory T-lymphocyte receptor that has specificity for [[CD274 antigen]] and [[Programmed Cell Death 1 Ligand 2 Protein]]."<ref>{{MeSH|Programmed Cell Death 1 Receptor}}</ref><ref name="pmid27806234">{{cite journal| author=Boussiotis VA| title=Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway. | journal=N Engl J Med | year= 2016 | volume= 375 | issue= 18 | pages= 1767-1778 | pmid=27806234 | doi=10.1056/NEJMra1514296 | pmc=5575761 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27806234  }} </ref>
These antibodies can activate the immune system to attack cancers. These antibodies target the [[Programmed Cell Death 1 Receptor]] (PD-1 Receptor or CD279). Programmed Cell Death Type I is also known as [[apoptosis]]. The PD-1 Receptor is "an inhibitory T-lymphocyte receptor that has specificity for [[CD274 antigen]] and [[Programmed Cell Death 1 Ligand 2 Protein]]."<ref>{{MeSH|Programmed Cell Death 1 Receptor}}</ref><ref name="pmid27806234">{{cite journal| author=Boussiotis VA| title=Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway. | journal=N Engl J Med | year= 2016 | volume= 375 | issue= 18 | pages= 1767-1778 | pmid=27806234 | doi=10.1056/NEJMra1514296 | pmc=5575761 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27806234  }} </ref>  
 
[[Image:Pembrolizumab for overall survival.png|400px]]
 
[[Pembrolizumab]] is a 'humanized monoclonal IgG<sub>4</sub> kappa isotype antibody against PD-1'.<ref name="pmid25891174">{{cite journal| author=Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP et al.| title=Pembrolizumab for the treatment of non-small-cell lung cancer. | journal=N Engl J Med | year= 2015 | volume= 372 | issue= 21 | pages= 2018-28 | pmid=25891174 | doi=10.1056/NEJMoa1501824 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25891174  }} </ref> Pembrolizumab was approved by the [[FDA]] for “patients with unresectable or metastatic, microsatellite-instability–high (MSI-H) or mismatch-repair–deficient (dMMR) solid tumors, regardless of tumor site or histology”. <ref name="pmid29020592">{{cite journal| author=Lemery S, Keegan P, Pazdur R| title=First FDA Approval Agnostic of Cancer Site - When a Biomarker Defines the Indication. | journal=N Engl J Med | year= 2017 | volume= 377 | issue= 15 | pages= 1409-1412 | pmid=29020592 | doi=10.1056/NEJMp1709968 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29020592  }} </ref> Pembrolizumab creates more objective tumor response among tumors in which at least 50% of its cells express PD-L1<ref name="pmid25891174">{{cite journal| author=Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP et al.| title=Pembrolizumab for the treatment of non-small-cell lung cancer. | journal=N Engl J Med | year= 2015 | volume= 372 | issue= 21 | pages= 2018-28 | pmid=25891174 | doi=10.1056/NEJMoa1501824 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25891174  }} </ref>.
 
[[Nivolumab]] may case drug toxicity in about 40% of patients - rash and diarrhea are the most common effects<ref name="pmid22658127">{{cite journal| author=Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al.| title=Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. | journal=N Engl J Med | year= 2012 | volume= 366 | issue= 26 | pages= 2443-54 | pmid=22658127 | doi=10.1056/NEJMoa1200690 | pmc=3544539 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22658127  }} </ref>.
 
Examples:
* [[Pembrolizumab]] (Keytruda)
* [[Pembrolizumab]] (Keytruda)
* [[Nivolumab]] (Opdivo)
* [[Nivolumab]] (Opdivo)


===PD-L1 inhibitors===
===PD-L1 inhibitors===
These antibodies can activate the immune system to attack cancers. These antibodies target PD-L1, or cluster of differentiation 274 (CD274) which is the transmembrane protein ligand to PD-1.
* [[Atezolizumab]] (Tecentriq)
* [[Atezolizumab]] (Tecentriq)
* [[Avelumab]] (Bavencio)
* [[Avelumab]] (Bavencio)
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The CTLA-4 Antigen is "an inhibitory [[T cell]] receptor that is closely related to [[CD28 antigen]]. It has specificity for [[CD80 antigen]] and [[CD86 antigen]] and acts as a negative regulator of peripheral T cell function. CTLA-4 antigen is believed to play role in inducing [[peripheral tolerance]]."<ref>{{MeSH|CTLA-4 Antigen}}</ref>
The CTLA-4 Antigen is "an inhibitory [[T cell]] receptor that is closely related to [[CD28 antigen]]. It has specificity for [[CD80 antigen]] and [[CD86 antigen]] and acts as a negative regulator of peripheral T cell function. CTLA-4 antigen is believed to play role in inducing [[peripheral tolerance]]."<ref>{{MeSH|CTLA-4 Antigen}}</ref>


[[Ipilimumab]] may cause autoimmune pituitary disease<ref name="pmid23471977">{{cite journal| author=Corsello SM, Barnabei A, Marchetti P, De Vecchis L, Salvatori R, Torino F| title=Endocrine side effects induced by immune checkpoint inhibitors. | journal=J Clin Endocrinol Metab | year= 2013 | volume= 98 | issue= 4 | pages= 1361-75 | pmid=23471977 | doi=10.1210/jc.2012-4075 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23471977  }} </ref> and exacerbate autoimmune disease in recipients with pre-existing autoimmune disease<ref name="pmid26633184">{{cite journal| author=Johnson DB, Sullivan RJ, Ott PA, Carlino MS, Khushalani NI, Ye F et al.| title=Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders. | journal=JAMA Oncol | year= 2016 | volume= 2 | issue= 2 | pages= 234-40 | pmid=26633184 | doi=10.1001/jamaoncol.2015.4368 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26633184  }} </ref>. The U.S. FDA has issued guidance on managing side effects.<ref>https://www.fda.gov/downloads/Drugs/DrugSafety/PostMarketDrugsafetyInformationforPatientsandProviders/UCM249435.pdf</ref><ref>https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=ipilimumab</ref>
Examples:
* [[Ipilimumab]] (Yervoy)
* [[Ipilimumab]] (Yervoy)
===Raf protein kinase inhibitors===
Raf inhibitors are "a family of closely-related serine-threonine kinases that were originally identified as the cellular homologs of the retrovirus-derived [[V-RAF kinases]]. They are MAP kinase kinase kinases that play important roles in [[signal transduction]]."<ref>{{Mesh|Raf inhibitors}}</ref>
Examples:
* [[Vemurafenib]]
==Vaccines==
Vaccines may provide immunotherapy of cancers<ref name="Schlom2018">Schlom J, Gulley JL. Vaccines as an Integral Component of Cancer Immunotherapy. JAMA. Published online November 08, 2018. {{doi|10.1001/jama.2018.9511}}</ref>.


==See also==
==See also==

Latest revision as of 03:03, 9 November 2018

Cancers considered "hot tumors", such as melanoma, contain antitumor T cells and may respond to checkpoint inhibitor antibodies[1].

Immune checkpoint inhibitors

Monoclonal antibodies are a type of cancer immunotherapy that have been developed to target immune checkpoints. These checkpoints down-regulate programmed cell death 1 or apoptosis. Cancer immunotherapy to block these checkpoints may encourage apoptosis of cancer cells.

Drug toxicities include[2][3][4]:

  • Gastrointestinal
  • Dermatologic
  • Endocrine
  • Exacerbation of pre-existing autoimmune disease[5].

PD-1 inhibitors

These antibodies can activate the immune system to attack cancers. These antibodies target the Programmed Cell Death 1 Receptor (PD-1 Receptor or CD279). Programmed Cell Death Type I is also known as apoptosis. The PD-1 Receptor is "an inhibitory T-lymphocyte receptor that has specificity for CD274 antigen and Programmed Cell Death 1 Ligand 2 Protein."[6][7]

Pembrolizumab is a 'humanized monoclonal IgG4 kappa isotype antibody against PD-1'.[8] Pembrolizumab was approved by the FDA for “patients with unresectable or metastatic, microsatellite-instability–high (MSI-H) or mismatch-repair–deficient (dMMR) solid tumors, regardless of tumor site or histology”. [9] Pembrolizumab creates more objective tumor response among tumors in which at least 50% of its cells express PD-L1[8].

Nivolumab may case drug toxicity in about 40% of patients - rash and diarrhea are the most common effects[10].

Examples:

PD-L1 inhibitors

These antibodies can activate the immune system to attack cancers. These antibodies target PD-L1, or cluster of differentiation 274 (CD274) which is the transmembrane protein ligand to PD-1.

CTLA-4 blockade

The CTLA-4 Antigen is "an inhibitory T cell receptor that is closely related to CD28 antigen. It has specificity for CD80 antigen and CD86 antigen and acts as a negative regulator of peripheral T cell function. CTLA-4 antigen is believed to play role in inducing peripheral tolerance."[11]

Ipilimumab may cause autoimmune pituitary disease[12] and exacerbate autoimmune disease in recipients with pre-existing autoimmune disease[13]. The U.S. FDA has issued guidance on managing side effects.[14][15]

Examples:

Raf protein kinase inhibitors

Raf inhibitors are "a family of closely-related serine-threonine kinases that were originally identified as the cellular homologs of the retrovirus-derived V-RAF kinases. They are MAP kinase kinase kinases that play important roles in signal transduction."[16]

Examples:

Vaccines

Vaccines may provide immunotherapy of cancers[1].

See also

References

  1. ↑ 1.0 1.1 Schlom J, Gulley JL. Vaccines as an Integral Component of Cancer Immunotherapy. JAMA. Published online November 08, 2018. doi:10.1001/jama.2018.9511
  2. ↑ Bourke JM, O'Sullivan M, Khattak MA (2016). "Management of adverse events related to new cancer immunotherapy (immune checkpoint inhibitors)". Med J Aust. 205 (9): 418–424. PMID 27809739.
  3. ↑ Barroso-Sousa R, Barry WT, Garrido-Castro AC, Hodi FS, Min L, Krop IE; et al. (2017). "Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis". JAMA Oncol. doi:10.1001/jamaoncol.2017.3064. PMID 28973656.
  4. ↑ Postow et al. http://www.nejm.org/doi/full/10.1056/NEJMra1703481 NEJM 2018
  5. ↑ Abdel-Wahab N, Shah M, Lopez-Olivo MA, Suarez-Almazor ME (2018). "Use of Immune Checkpoint Inhibitors in the Treatment of Patients With Cancer and Preexisting Autoimmune Disease: A Systematic Review". Ann Intern Med. doi:10.7326/M17-2073. PMID 29297009.
  6. ↑ Anonymous (2024), Programmed Cell Death 1 Receptor (English). Medical Subject Headings. U.S. National Library of Medicine.
  7. ↑ Boussiotis VA (2016). "Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway". N Engl J Med. 375 (18): 1767–1778. doi:10.1056/NEJMra1514296. PMC 5575761. PMID 27806234.
  8. ↑ 8.0 8.1 Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP; et al. (2015). "Pembrolizumab for the treatment of non-small-cell lung cancer". N Engl J Med. 372 (21): 2018–28. doi:10.1056/NEJMoa1501824. PMID 25891174.
  9. ↑ Lemery S, Keegan P, Pazdur R (2017). "First FDA Approval Agnostic of Cancer Site - When a Biomarker Defines the Indication". N Engl J Med. 377 (15): 1409–1412. doi:10.1056/NEJMp1709968. PMID 29020592.
  10. ↑ Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF; et al. (2012). "Safety, activity, and immune correlates of anti-PD-1 antibody in cancer". N Engl J Med. 366 (26): 2443–54. doi:10.1056/NEJMoa1200690. PMC 3544539. PMID 22658127.
  11. ↑ Anonymous (2024), CTLA-4 Antigen (English). Medical Subject Headings. U.S. National Library of Medicine.
  12. ↑ Corsello SM, Barnabei A, Marchetti P, De Vecchis L, Salvatori R, Torino F (2013). "Endocrine side effects induced by immune checkpoint inhibitors". J Clin Endocrinol Metab. 98 (4): 1361–75. doi:10.1210/jc.2012-4075. PMID 23471977.
  13. ↑ Johnson DB, Sullivan RJ, Ott PA, Carlino MS, Khushalani NI, Ye F; et al. (2016). "Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders". JAMA Oncol. 2 (2): 234–40. doi:10.1001/jamaoncol.2015.4368. PMID 26633184.
  14. ↑ https://www.fda.gov/downloads/Drugs/DrugSafety/PostMarketDrugsafetyInformationforPatientsandProviders/UCM249435.pdf
  15. ↑ https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=ipilimumab
  16. ↑ Template:Mesh
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