PD-1 and PD-L1 inhibitors: Difference between revisions
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'''PD-1 inhibitors''' and '''PD-L1 inhibitors''' are a group of |
'''PD-1 inhibitors''' and '''PD-L1 inhibitors''' are a novel group of [[checkpoint inhibitor]]s being developed for the treatment of cancer. [[Immune checkpoint]] inhibitors such as these are emerging as a front-line treatment for several types of cancer.<ref name=FIP>{{cite journal|last1=Alsaab|first1=Hashem O.|last2=Sau|first2=Samaresh|last3=Alzhrani|first3=Rami|last4=Tatiparti|first4=Katyayani|last5=Bhise|first5=Ketki|last6=Kashaw|first6=Sushil K.|last7=Iyer|first7=Arun K.|title=PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome|journal=Frontiers in Pharmacology|date=23 August 2017|volume=8|doi=10.3389/fphar.2017.00561}}</ref> |
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PD-1 and PD-L1 inhibitors act to inhibit the association of the programmed death-ligand 1 ([[PD-L1]]) with its receptor, programmed cell death protein 1 ([[PD-1]]). The interaction of these cell surface proteins is involved in the suppression of the [[immune system]] and occurs following infection to limit the killing of bystander host cells and prevent [[autoimmune disease]].<ref name="Francisco">{{cite journal|last1=Francisco, L.M., Sage, P.T., Sharpe, A.H.|title=The PD-1 Pathway in Tolerance and Autoimmunity|pmc=2919275|journal=Immunol. Rev.|date=2010|volume=236|pages=219–242|doi=10.1111/j.1600-065X.2010.00923.x|pmid=20636820}}</ref> This immune checkpoint is also active in pregnancy,<ref name="Zhang">{{cite journal|last1=Zhang, Y.H., Tian, M. Tang, M.X., Liu, Z.Z., Liao, A.H.|title=Recent Insight into the Role of the PD-1/PD-L1 Pathway in Feto-Maternal Tolerance and Pregnancy|pmid=25640631|journal=Am. J. Reprod. Imunol.|date=2015|volume=74|issue=3|pages=201–208|doi=10.1111/aji.12365}}</ref> following tissue [[allografts]],<ref name="Tanaka">{{cite journal|last1=Tanaka, K., Albin, M., YUan, X., Yamaura, K., Habicht, A., Murayama, T., Grimm, M., Waaga, A.M., Ueno, T., Padera, R.F., Yagita, H., Azuma, M., Shin, T., Blazar, B.R., Rothstein, D.M., Sayegh, M.H., Najafian, N.|title=PDL1 Is Required for Peripheral Transplantation Tolerance and Protection from Chronic Allograft Rejection|pmc=2291549|journal=J. Immunol.|date=2007|volume=179|issue=8|pages=5204–5210|doi=10.4049/jimmunol.179.8.5204|pmid=17911605}}</ref> and in different types of [[cancer]].<ref name="Sunshine">{{cite journal|last1=Sunshine|first1=J|last2=Taube|first2=JM|title=PD-1/PD-L1 inhibitors.|journal=Current Opinion in Pharmacology|date=August 2015|volume=23|pages=32–8|doi=10.1016/j.coph.2015.05.011|pmid=26047524|pmc=4516625}}</ref> |
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== History == |
== History == |
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PD-1 and PD-L1 inhibitors are closely related to [[CTLA4]] inhibitors, such as [[ipilimumab]]. PD-1 and CTLA-4 are both expressed on activated T cells, but at different phases of immune response.<ref name=JBS>{{cite journal|last1=Iwai|first1=Yoshiko|last2=Hamanishi|first2=Junzo|last3=Chamoto|first3=Kenji|last4=Honjo|first4=Tasuku|title=Cancer immunotherapies targeting the PD-1 signaling pathway|journal=Journal of Biomedical Science|date=4 April 2017|volume=24|issue=1|doi=10.1186/s12929-017-0329-9}}</ref> |
PD-1 and PD-L1 inhibitors are closely related to [[CTLA4]] inhibitors, such as [[ipilimumab]]. PD-1 and CTLA-4 are both expressed on activated T cells, but at different phases of immune response.<ref name=JBS>{{cite journal|last1=Iwai|first1=Yoshiko|last2=Hamanishi|first2=Junzo|last3=Chamoto|first3=Kenji|last4=Honjo|first4=Tasuku|title=Cancer immunotherapies targeting the PD-1 signaling pathway|journal=Journal of Biomedical Science|date=4 April 2017|volume=24|issue=1|doi=10.1186/s12929-017-0329-9}}</ref> |
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Current clinical trials are evaluating anti-PD-1 and PD-L1 drugs in combination with other immunotherapy drugs blocking [[LAG3]], [[B7-H3]], [[KIR]], [[OX40]], [[PARP]], [[CD27]], and [[ICOS]].<ref name=JBS/> |
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==Therapeutics== |
==Therapeutics== |
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* [[BMS-936559]], by [[Bristol-Myers Squibb]] |
* [[BMS-936559]], by [[Bristol-Myers Squibb]] |
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== Adverse effects == |
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Immunotherapies as a group have off-target effects and toxicities common to them. Some of these include interstitial pneumonitis, colitis, skin reactions, immune thrombocytopenia, neutropenia, encephalopathy, Guillain-Barré syndrome, myelitis, myasthenia gravis, myocarditis and cardiac insufficiency, acute adrenal insufficiency, and nephritis.<ref name=JBS/> |
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==See also== |
==See also== |
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Revision as of 19:55, 5 January 2018
PD-1 inhibitors and PD-L1 inhibitors are a novel group of checkpoint inhibitors being developed for the treatment of cancer. Immune checkpoint inhibitors such as these are emerging as a front-line treatment for several types of cancer.[1]
PD-1 and PD-L1 inhibitors act to inhibit the association of the programmed death-ligand 1 (PD-L1) with its receptor, programmed cell death protein 1 (PD-1). The interaction of these cell surface proteins is involved in the suppression of the immune system and occurs following infection to limit the killing of bystander host cells and prevent autoimmune disease.[2] This immune checkpoint is also active in pregnancy,[3] following tissue allografts,[4] and in different types of cancer.[5]
History
The concept of blocking PD-1 and PD-L1 for the treatment of cancer was first published in 2001.[6] Pharmaceutical companies began attempting to develop drugs to block these molecules, and the first clinical trial was launched in 2006, evaluating nivolumab. As of 2017, more than 500 clinical trials involving PD-1 and PD-L1 inhibitors have been conducted in more than 20,000 patients.[7]
Cancer immunotherapy
In the cancer disease state, the interaction of PD-L1 on the tumor cells with PD-1 on a T-cell reduces T-cell function signals to prevent the immune system from attacking the tumor cells.[8] Use of an inhibitor that blocks the interaction of PD-L1 with the PD-1 receptor can prevent the cancer from evading the immune system in this way.[8] Several PD-1 and PD--L1 inhibitors are being trialled within the clinic for use in advanced melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer and Hodgkin lymphoma, amongst other cancer types.[5]
Immunotherapy with these immune checkpoint inhibitors appears to shrink tumours in a higher number of patients across a wider range of tumour types and is associated with lower toxicity levels than other immunotherapies, with durable responses.[5] However, de-novo and acquired resistance is still seen in a large proportion of patients.[8] Hence PD-L1 inhibitors are considered to be the most promising drug category for many different cancers.[5][9]
PD-1 and PD-L1 inhibitors are closely related to CTLA4 inhibitors, such as ipilimumab. PD-1 and CTLA-4 are both expressed on activated T cells, but at different phases of immune response.[7]
Current clinical trials are evaluating anti-PD-1 and PD-L1 drugs in combination with other immunotherapy drugs blocking LAG3, B7-H3, KIR, OX40, PARP, CD27, and ICOS.[7]
Therapeutics
PD-1
Pembrolizumab was developed by Merck and first approved by the FDA in 2014 for the treatment of melanoma. It was later approved for metastatic non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma. In 2017, it became the first immunotherapy drug approved for use based on the genetic mutations of the tumor rather than the site of the tumor.
Nivolumab was developed by Bristol-Myers Squibb and first approved by the FDA in 2014 for the treatment of melanoma. It was later approved for squamous cell lung cancer, renal cell carcinoma, and Hodgkin's lymphoma.
Experimental
As of 2017, four PD-1 inhibitors were under development.[7]
- pidilizumab, by Cure Tech
- AMP-224, by GlaxoSmithKlein
- AMP-514, by GlaxoSmithKlein
- PDR001, by Novartis
PD-L1
Atezolizumab (Tecentriq) is a fully humanised IgG1 antibody developed by Roche Genentech. In 2016, the FDA approved atezolizumab for urothelial carcinoma and NSCLC.
Avelumab (Bavencio) is a fully human IgG1 antibody developed by Merck Serono and Pfizer. Avelumab has been FDA approved for the treatment of metastatic Merkel-cell carcinoma. It failed phase III clinical trials for gastric cancer.[10]
Experimental
Two PD-L1 inhbitors are in the experimental phase of development.
- Durvalumab is an anti-PD-L1 antibody developed by AstraZeneca. Phase III trials for the treatment of metastatic urothelial bladder cancer in combination with an alternative immune checkpoint inhibitor have been reached.[11]
Adverse effects
Immunotherapies as a group have off-target effects and toxicities common to them. Some of these include interstitial pneumonitis, colitis, skin reactions, immune thrombocytopenia, neutropenia, encephalopathy, Guillain-Barré syndrome, myelitis, myasthenia gravis, myocarditis and cardiac insufficiency, acute adrenal insufficiency, and nephritis.[7]
See also
References
- ^ Alsaab, Hashem O.; Sau, Samaresh; Alzhrani, Rami; Tatiparti, Katyayani; Bhise, Ketki; Kashaw, Sushil K.; Iyer, Arun K. (23 August 2017). "PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome". Frontiers in Pharmacology. 8. doi:10.3389/fphar.2017.00561.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Francisco, L.M., Sage, P.T., Sharpe, A.H. (2010). "The PD-1 Pathway in Tolerance and Autoimmunity". Immunol. Rev. 236: 219–242. doi:10.1111/j.1600-065X.2010.00923.x. PMC 2919275. PMID 20636820.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Zhang, Y.H., Tian, M. Tang, M.X., Liu, Z.Z., Liao, A.H. (2015). "Recent Insight into the Role of the PD-1/PD-L1 Pathway in Feto-Maternal Tolerance and Pregnancy". Am. J. Reprod. Imunol. 74 (3): 201–208. doi:10.1111/aji.12365. PMID 25640631.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Tanaka, K., Albin, M., YUan, X., Yamaura, K., Habicht, A., Murayama, T., Grimm, M., Waaga, A.M., Ueno, T., Padera, R.F., Yagita, H., Azuma, M., Shin, T., Blazar, B.R., Rothstein, D.M., Sayegh, M.H., Najafian, N. (2007). "PDL1 Is Required for Peripheral Transplantation Tolerance and Protection from Chronic Allograft Rejection". J. Immunol. 179 (8): 5204–5210. doi:10.4049/jimmunol.179.8.5204. PMC 2291549. PMID 17911605.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ a b c d Sunshine, J; Taube, JM (August 2015). "PD-1/PD-L1 inhibitors". Current Opinion in Pharmacology. 23: 32–8. doi:10.1016/j.coph.2015.05.011. PMC 4516625. PMID 26047524.
- ^ "The Science of PD-1 and Immunotherapy | Dana-Farber Cancer Institute". Dana-Farber Cancer Institute. 13 May 2015.
- ^ a b c d e Iwai, Yoshiko; Hamanishi, Junzo; Chamoto, Kenji; Honjo, Tasuku (4 April 2017). "Cancer immunotherapies targeting the PD-1 signaling pathway". Journal of Biomedical Science. 24 (1). doi:10.1186/s12929-017-0329-9.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b c Syn, Nicholas L; Teng, Michele W L; Mok, Tony S K; Soo, Ross A. "De-novo and acquired resistance to immune checkpoint targeting". The Lancet Oncology. 18 (12): e731–e741. doi:10.1016/s1470-2045(17)30607-1.
- ^ Guha, M. (2014). "Immune checkpoint inhibitors bring new hope to cancer patients". The Pharmaceut J.
- ^ "Avelumab Falls Short in Phase III Gastric Cancer Trial". OncLive.
- ^ Curetoday (April 2016). "Durvalumab in the treatment of advanced bladder cancer".