PD-1 and PD-L1 inhibitors

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PD-1 inhibitors and PD-L1 inhibitors are a novel group of checkpoint inhibitors being developed for the treatment of cancer. PD-1 and PD-L1 are both proteins present on the surface of cells. 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]

Approved PD-1/PD-L1 inhibitors
Name Target Approved
Nivolumab PD-1 2014
Pembrolizumab PD-1 2014
Atezolizumab PD-L1 2016
Avelumab PD-L1 2017
Durvalumab PD-L1 2017

History[edit]

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] By the end of 2017, PD-1/PD-L1 inhibitors had been approved for the treatment of nine forms of cancer.[8]

Cancer immunotherapy[edit]

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.[9] 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.[9] 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.[9] Hence PD-L1 inhibitors are considered to be the most promising drug category for many different cancers.[5][10]

PD-1 and PD-L1 inhibitors are closely related to CTLA4 (cytotoxic T-lymphocyte-associated protein 4) 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[edit]

PD-1[edit]

Pembrolizumab (formerly MK-3475 or lambrolizumab, Keytruda) was developed by Merck and first approved by the Food and Drug Administration in 2014 for the treatment of melanoma. It was later approved for metastatic non-small cell lung cancer 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. It was shown, that patients with higher non-synonymous mutation burden in their tumors respond better to the treatment. Both their objective response rate and progression-free survival was shown to be higher than in patients with low non-synonymous mutation burden.[11] This suggests that tobacco smoking, due to its high carcinogenicity,[12] not only causes promotion of cancer (in case of non-small-cell lung carcinoma), but also increases chances of the immune system to recognize and attack to the tumor.

Nivolumab (Opdivo) 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[edit]

As of 2017, at least five PD-1 inhibitors were under development.[7]

PD-L1[edit]

Atezolizumab (Tecentriq) is a fully humanised IgG1 (immunoglobulin 1 antibody developed by Roche Genentech. In 2016, the FDA approved atezolizumab for urothelial carcinoma and non-small cell lung cancer.

Avelumab (Bavencio) is a fully human IgG1 antibody developed by Merck Serono and Pfizer. Avelumab is FDA approved for the treatment of metastatic merkel-cell carcinoma. It failed phase III clinical trials for gastric cancer.[14]

Durvalumab (Imfinzi) is a fully human IgG1 antibody developed by AstraZeneca. Durvalumab is FDA approved for the treatment of urothelial carcinoma and unresectable non-small cell lung cancer after chemoradiation.[15]

Experimental[edit]

At least two PD-L1 inhibitors are in the experimental phase of development.

Adverse effects[edit]

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[edit]

References[edit]

  1. ^ Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw SK, Iyer AK (23 August 2017). "PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome". Frontiers in Pharmacology. 8: 561. doi:10.3389/fphar.2017.00561. PMID 28878676.
  2. ^ Francisco LM, Sage PT, Sharpe AH (July 2010). "The PD-1 pathway in tolerance and autoimmunity". Immunological Reviews. 236: 219–42. doi:10.1111/j.1600-065X.2010.00923.x. PMC 2919275. PMID 20636820.
  3. ^ Zhang YH, Tian M, Tang MX, Liu ZZ, Liao AH (September 2015). "Recent Insight into the Role of the PD-1/PD-L1 Pathway in Feto-Maternal Tolerance and Pregnancy". American Journal of Reproductive Immunology. 74 (3): 201–8. doi:10.1111/aji.12365. PMID 25640631.
  4. ^ Tanaka K, Albin MJ, Yuan X, Yamaura K, Habicht A, Murayama T, Grimm M, Waaga AM, Ueno T, Padera RF, Yagita H, Azuma M, Shin T, Blazar BR, Rothstein DM, Sayegh MH, Najafian N (October 2007). "PDL1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection". Journal of Immunology. 179 (8): 5204–10. doi:10.4049/jimmunol.179.8.5204. PMC 2291549. PMID 17911605.
  5. ^ 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.
  6. ^ "The Science of PD-1 and Immunotherapy". Dana-Farber Cancer Institute. 13 May 2015.
  7. ^ a b c d e Iwai Y, Hamanishi J, Chamoto K, Honjo T (April 2017). "Cancer immunotherapies targeting the PD-1 signaling pathway". Journal of Biomedical Science. 24 (1): 26. doi:10.1186/s12929-017-0329-9. PMID 28376884.
  8. ^ Gong, Jun; Chehrazi-Raffle, Alexander; Reddi, Srikanth; Salgia, Ravi (23 January 2018). "Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations". Journal for Immunotherapy of Cancer. 6. doi:10.1186/s40425-018-0316-z. ISSN 2051-1426. PMC 5778665.
  9. ^ a b c 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.
  10. ^ Guha M (2014). "Immune checkpoint inhibitors bring new hope to cancer patients". The Pharmaceutical Journal.
  11. ^ Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. (April 2015). "Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer". Science. 348 (6230): 124–128. doi:10.1126/science.aaa1348. PMC 4993154. PMID 25765070.
  12. ^ Pfeifer GP, Denissenko MF, Olivier M, Tretyakova N, Hecht SS, Hainaut P (October 2002). "Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers". Oncogene. 21 (48): 7435–51. doi:10.1038/sj.onc.1205803. PMID 12379884.
  13. ^ Regeneron press release, 8 September 2017
  14. ^ Broderick JM (28 November 2017). "Avelumab Falls Short in Phase III Gastric Cancer Trial". OncLive.
  15. ^ AstraZeneca press release, 19 February 2018
  16. ^ Checkpoint Therapeutics press release, 21 March 2018