PD-1 and PD-L1 inhibitors

Last updated
Micrograph showing a PD-L1 positive lung adenocarcinoma. Positive immunostaining can predict response to the treatment. PD-L1 positive lung adenocarcinoma -- high mag.jpg
Micrograph showing a PD-L1 positive lung adenocarcinoma. Positive immunostaining can predict response to the treatment.

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. [1]

Contents

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
NameTargetApproved
Nivolumab PD-1 2014
Pembrolizumab PD-1 2014
Atezolizumab PD-L1 2016
Avelumab PD-L1 2017
Durvalumab PD-L1 2017
Cemiplimab PD-1 2018
Dostarlimab PD-1 2021
Retifanlimab PD-1 2023
Toripalimab PD-1 2023

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

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. [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] [10]

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] [11]

Not all patients respond to PD-1/PD-L1 inhibitors. The FDA has approved several assays to measure the level of PD-L1 expressed by tumor cells, in order to predict the likelihood of response to an inhibitor. PD-L1 levels have been found to be highly predictive of response. Higher mutation burden is also predictive of response to anti-PD-1/PD-L1 agents. [8] . However, these markers are far from perfect, and there is a clinical interest in the search for new biomarkers predictive of the benefit of these therapies beyond PD-L1 and TMB levels. [12] [13] [14]

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

PD-1

Pembrolizumab (Keytruda, formerly MK-3475 and lambrolizumab) 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. [15]

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.

Cemiplimab (Libtayo) was developed by Regeneron Pharmaceuticals and first approved by the FDA in 2018 for the treatment of cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation.

Dostarlimab (Jemperli) – was developed by GlaxoSmithKline and was first approved for the treatment of mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer by the FDA in April of 2021. [16] On August 17, 2021, the FDA granted accelerated approval for the treatment of mismatch repair deficient (dMMR) recurrent or advanced solid tumors. [17]

Retifanlimab (Zynyz) was developed by Incyte and first granted accelerated approval by the FDA in March 2023 for the treatment of Merkel cell carcinoma (MCC).

Toripalimab (Loqtorzi) is a humanized IgG4 monoclonal antibody against PD-1 approved in China in 2018 and in the United States in 2023. [18] [19] [20]

Experimental

Currently, many PD-1 inhibitors are under development: [7]

  • Vopratelimab (JTX-4014) by Jounce Therapeutics [21] As of 2020 entered Phase I trial [22]
  • Spartalizumab (PDR001) is a PD-1 inhibitor developed by Novartis to treat both solid tumors and lymphomas, which as of 2018 has entered Phase III trials. [23] [24] [25]
  • Camrelizumab (SHR1210) is an anti-PD-1 monoclonal antibody introduced by Jiangsu HengRui Medicine Co., Ltd. that recently received conditional approval in China for the treatment of relapsed or refractory classical Hodgkin lymphoma. [26]
  • Sintilimab (IBI308), a human anti-PD-1 antibody developed by Innovent and Eli Lilly for patients with non-small cell lung cancer (NSCLC). [27]
  • Tislelizumab (BGB-A317) is a humanized IgG4 anti–PD-1 monoclonal antibody in pivotal Phase 3 and Phase 2 clinical trials in solid tumors and hematologic cancers. [28]
  • INCMGA00012 (MGA012) is a humanized IgG4 monoclonal antibody developed by Incyte and MacroGenics. [29]
  • AMP-224 by AstraZeneca/MedImmune and GlaxoSmithKline [30]
  • AMP-514 (MEDI0680) by AstraZeneca [31]
  • Acrixolimab (YBL-006) by Y-Biologics [32]

PD-L1

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. [33]

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. [34]

Experimental

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

  • KN035 is the only PD-L1 antibody with subcutaneous formulation currently under clinical evaluations in the US, China, and Japan [35]
  • Cosibelimab (CK-301) by Checkpoint Therapeutics is a PD-L1 inhibitor developed by Dana Farber, and is currently in Phase 3 trials for NSCLC [36]
  • AUNP12 is a 29-mer peptide as the first peptic PD-1/PD-L1 inhibitor developed by Aurigene and Laboratoires Pierre Fabre that is being evaluated in clinical trial, following promising invitro results. [37]
  • CA-170, discovered by Aurigene/Curis as the PD-L1 and VISTA antagonist, was indicted as a potent small molecule inhibitor in vitro. Thus, the compound is currently under phase I clinical trial over mesothelioma patients. [38]
  • BMS-986189 is a macrocyclic peptide discovered by Bristol-Myers Squibb of which the pharmacokinetics, safety and tolerability is currently being studied on healthy subjects. [39]

Combinational therapy

Combination with type I Interferons

PD-1/PD-L1 blockade therapy is not effective for all patients, as some may exhibit resistance. To overcome resistance, a strategy involving the combination of PD-1/PD-L1 inhibitors with type I interferons has emerged. The combination of PD-1/PD-L1 inhibitors and type I interferons has shown promise in preclinical and clinical studies (phases I and II). This combination therapy leads to increased infiltration and activation of T cells within tumors, the generation of memory T cells, and improved overall survival in both animal models and patients. Notably, this approach has demonstrated efficacy in melanoma and renal carcinoma patients. [40]

Adverse effects

Immunotherapies as a group have off-target effects and toxicities common to them. Some of these include interstitial pneumonitis [41] , colitis, hepatitis, thyroiditis, skin reactions, low levels of platelets and white blood cells, inflammation of the brain or spinal cord, neuromuscular adverse events [42] including myositis, Guillain-Barré syndrome, myasthenia gravis; myocarditis and cardiac insufficiency, acute adrenal insufficiency, and nephritis. [7] The most common kidney related changes are acute interstitial nephritis, followed by glomerular diseases and then tubular damage. [43] The detailed mechanism of these adverse effects are not fully elucidated; [44] however, they are clearly different from known autoimmune diseases. [45] Immune-mediated adverse reactions are usually attributed to generalised dysregulation of T cells [46] or development of autoantibodies, [47] although memory T cell responses against occult viral infections might also play a role in some patients with advanced melanoma following combined PD-1/CTLA-4 blockade. [48]

When compared with standard chemotherapeutic agents, PD-1/PD-L1 inhibitors had a lower reported incidence of fatigue, sensory neuropathy, diarrhea, bone marrow suppression, loss of appetite, nausea, and constipation. [8]

See also

Related Research Articles

<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 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.

<span class="mw-page-title-main">Non-small-cell lung cancer</span> Any type of epithelial lung cancer other than small-cell lung carcinoma

Non-small-cell lung cancer (NSCLC), or non-small-cell lung carcinoma, is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to small-cell carcinoma. When possible, they are primarily treated by surgical resection with curative intent, although chemotherapy has been used increasingly both preoperatively and postoperatively.

<span class="mw-page-title-main">Monoclonal antibody therapy</span> Form of immunotherapy

Monoclonal antibodies (mAbs) have varied therapeutic uses. It is possible to create a mAb that binds specifically to almost any extracellular target, such as cell surface proteins and cytokines. They can be used to render their target ineffective, to induce a specific cell signal, to cause the immune system to attack specific cells, or to bring a drug to a specific cell type.

<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.

<span class="mw-page-title-main">PD-L1</span> Mammalian protein found in humans

Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.

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

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.

Treatment of lung cancer refers to the use of medical therapies, such as surgery, radiation, chemotherapy, immunotherapy, percutaneous ablation, and palliative care, alone or in combination, in an attempt to cure or lessen the adverse impact of malignant neoplasms originating in lung tissue.

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

TIGIT is an immune receptor present on some T cells and natural killer cells (NK). It is also identified as WUCAM and Vstm3. TIGIT could bind to CD155 (PVR) on dendritic cells (DCs), macrophages, etc. with high affinity, and also to CD112 (PVRL2) with lower affinity.

<span class="mw-page-title-main">Nivolumab</span> Cancer drug

Nivolumab, sold under the brand name Opdivo, is a 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 (GEJ) 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 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, 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).

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">Tislelizumab</span> Monoclonal antibody

Tislelizumab, sold under the brand name Tevimbra among others, is a humanized monoclonal antibody directed against PD-1. It prevents PD-1 from binding to the ligands PD-L1 and PD-L2. It is designed to bind less to Fc gamma receptors. It is being developed by BeiGene.

<span class="mw-page-title-main">Galunisertib</span> Chemical compound

Galunisertib (LY2157299) is a small molecular experimental cancer drug previously in development by Eli Lilly. It is a TGF-b inhibitor. Development of galunisertib by Eli Lilly was discontinued in January 2020.

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. The first anti-cancer drug targeting an immune checkpoint was ipilimumab, a CTLA4 blocker approved in the United States in 2011.

Cemiplimab, sold under the brand name Libtayo, is a monoclonal antibody medication for the treatment of squamous cell skin cancer. Cemiplimab belongs to a class of drugs that binds to the programmed death receptor-1 (PD-1), blocking the PD-1/PD-L1 pathway.

<span class="mw-page-title-main">CKLF like MARVEL transmembrane domain containing 6</span> Transmembrane protein

CKLF like MARVEL transmembrane domain-containing 6, previously termed chemokine-like factor superfamily 6, is a transmembrane protein encoded in humans by the CMTM6 gene. This gene is located in band 22.3 on the short arm of chromosome 3. CMTM6 protein belongs to the CKLF-like MARVEL transmembrane domain-containing family of proteins. This family consist of 9 member proteins: CKLF and CMTM1 through CMTM8. The CMTM family proteins are involved in autoimmune diseases, cardiovascular diseases, the male reproductive system, haematopoiesis, and cancer development. CMTM6 protein regulates immune responses to normal and abnormal cells.

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.

References

  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 . PMC   5572324 . 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. S2CID   206987352.
  4. ↑ Tanaka K, Albin MJ, Yuan X, Yamaura K, Habicht A, Murayama T, et al. (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. 1 2 3 4 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. 1 2 3 4 5 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 . PMC   5381059 . PMID   28376884.
  8. 1 2 3 Gong J, Chehrazi-Raffle A, Reddi S, Salgia R (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 (1): 8. doi: 10.1186/s40425-018-0316-z . PMC   5778665 . PMID   29357948.
  9. 1 2 3 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. ↑ Goldkuhle M, Dimaki M, Gartlehner G, Monsef I, Dahm P, Glossmann JP, et al. (July 2018). Cochrane Haematological Malignancies Group (ed.). "Nivolumab for adults with Hodgkin's lymphoma (a rapid review using the software RobotReviewer)". The Cochrane Database of Systematic Reviews. 2018 (7): CD012556. doi:10.1002/14651858.CD012556.pub2. PMC   6513229 . PMID   30001476.
  11. ↑ Guha M (2014). "Immune checkpoint inhibitors bring new hope to cancer patients". The Pharmaceutical Journal.
  12. ↑ Casarrubios, Marta; Cruz-Bermúdez, Alberto; Nadal, Ernest; Insa, Amelia; García Campelo, María del Rosario; Lázaro, Martín; Dómine, Manuel; Majem, Margarita; Rodríguez-Abreu, Delvys; Martínez-Martí, Alex; de Castro-Carpeño, Javier; Cobo, Manuel; López-Vivanco, Guillermo; Del Barco, Edel; Bernabé Caro, Reyes; Viñolas, Nuria; Barneto Aranda, Isidoro; Viteri, Santiago; Massuti, Bartomeu; Barquín, Miguel; Laza-Briviesca, Raquel; Sierra-Rodero, Belén; Parra, Edwin R.; Sanchez-Espiridion, Beatriz; Rocha, Pedro; Kadara, Humam; Wistuba, Ignacio I.; Romero, Atocha; Calvo, Virginia; Provencio, Mariano (1 November 2021). "Pretreatment Tissue TCR Repertoire Evenness Is Associated with Complete Pathologic Response in Patients with NSCLC Receiving Neoadjuvant Chemoimmunotherapy". Clinical Cancer Research. 27 (21): 5878–5890. doi:10.1158/1078-0432.CCR-21-1200.
  13. ↑ Casarrubios, Marta; Provencio, Mariano; Nadal, Ernest; Insa, Amelia; del Rosario García-Campelo, María; Lázaro-Quintela, Martín; Dómine, Manuel; Majem, Margarita; Rodriguez-Abreu, Delvys; Martinez-Marti, Alex; De Castro Carpeño, Javier; Cobo, Manuel; López Vivanco, Guillermo; Del Barco, Edel; Bernabé, Reyes; Viñolas, Nuria; Barneto Aranda, Isidoro; Massuti, Bartomeu; Sierra-Rodero, Belén; Martinez-Toledo, Cristina; Fernández-Miranda, Ismael; Serna-Blanco, Roberto; Romero, Atocha; Calvo, Virginia; Cruz-Bermúdez, Alberto (September 2022). "Tumor microenvironment gene expression profiles associated to complete pathological response and disease progression in resectable NSCLC patients treated with neoadjuvant chemoimmunotherapy". Journal for ImmunoTherapy of Cancer. 10 (9): e005320. doi:10.1136/jitc-2022-005320.
  14. ↑ Laza‐Briviesca, Raquel; Cruz‐Bermúdez, Alberto; Nadal, Ernest; Insa, Amelia; García‐Campelo, María del Rosario; Huidobro, Gerardo; Dómine, Manuel; Majem, Margarita; Rodríguez‐Abreu, Delvys; Martínez‐Martí, Alex; De Castro Carpeño, Javier; Cobo, Manuel; López Vivanco, Guillermo; Del Barco, Edel; Bernabé Caro, Reyes; Viñolas, Nuria; Barneto Aranda, Isidoro; Viteri, Santiago; Massuti, Bartomeu; Casarrubios, Marta; Sierra‐Rodero, Belén; Tarín, Carlos; García‐Grande, Aránzazu; Haymaker, Cara; Wistuba, Ignacio I.; Romero, Atocha; Franco, Fernando; Provencio, Mariano (July 2021). "Blood biomarkers associated to complete pathological response on NSCLC patients treated with neoadjuvant chemoimmunotherapy included in NADIM clinical trial". Clinical and Translational Medicine. 11 (7). doi:10.1002/ctm2.491.
  15. ↑ 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): 124–8. doi:10.1126/science.aaa1348. PMC   4993154 . PMID   25765070.
  16. ↑ "FDA grants accelerated approval to dostarlimab-gxly for DMMR endometrial cancer". FDA. 11 June 2021.
  17. ↑ "FDA grants accelerated approval to dostarlimab-gxly for DMMR advanced solid tumors". FDA. February 2022.
  18. ↑ "Toripalimab - Shanghai Junshi Biosciences - AdisInsight". adisinsight.springer.com. Retrieved 2019-08-25.
  19. ↑ Keam, S.J. (2019). "Toripalimab: First Global Approval". Drugs. 79 (5): 573–578. doi: 10.1007/s40265-019-01076-2 . PMID   30805896.
  20. ↑ "FDA approves toripalimab-tpzi for nasopharyngeal carcinoma". US Food and Drug Administration. October 27, 2023.
  21. ↑ "Our Pipeline | Jounce Therapeutics" . Retrieved 2020-09-19.
  22. ↑ Jounce Therapeutics, Inc. (2020-09-02). "Phase 1 First in Human Study of Programmed Cell Death Receptor-1 (PD-1) Inhibitor Monoclonal Antibody (mAb) JTX-4014 in Adult Subjects With Advanced Refractory Solid Tumor Malignancies".{{cite journal}}: Cite journal requires |journal= (help)
  23. ↑ Kopp-Kubel S (1978-04-01). "International Nonproprietary Names (INN) for pharmaceutical substances". Bulletin of the World Health Organization. 73 (3): 275–9. doi:10.1093/ajhp/35.4.477a. PMC   2486664 . PMID   7614659.
  24. ↑ "PDR001". Immuno-Oncology News. 2017-10-25. Retrieved 2019-08-24.
  25. ↑ "NCI Drug Dictionary". National Cancer Institute. 2011-02-02. Retrieved 2019-08-24.
  26. ↑ Markham A, Keam SJ (August 2019). "Camrelizumab: First Global Approval". Drugs. 79 (12): 1355–1361. doi:10.1007/s40265-019-01167-0. PMID   31313098. S2CID   197422122.
  27. ↑ "Sintilimab - Eli Lilly/Innovent Biologics - AdisInsight". adisinsight.springer.com. Retrieved 2019-08-25.
  28. ↑ "Library Association-Annual Meeting". The Library. s1-1 (1): 215. 1889-01-01. doi:10.1093/library/s1-1.1.215-b. ISSN   0024-2160.
  29. ↑ "Incyte Press Release". investor.incyte.com. Retrieved 2020-04-20.
  30. ↑ "Study to Assess the Safety, Tolerability, and Pharmacokinetics of AMP-224 in Patients With Advanced Cancer". www.clinicaltrials.gov. Retrieved 2020-04-24.
  31. ↑ "AstraZeneca stops monotherapy study at centerpiece of $500M buyout". www.fiercebiotech.com. 2 February 2018. Retrieved 2020-04-24.
  32. ↑ kgi-admin (2023-02-24). "Acrixolimab by Y-Biologics for Solid Tumor: Likelihood of Approval". Pharmaceutical Technology. Retrieved 2023-03-07.
  33. ↑ Broderick JM (28 November 2017). "Avelumab Falls Short in Phase III Gastric Cancer Trial". OncLive.
  34. ↑ AstraZeneca press release, 19 February 2018
  35. ↑ Zhang F, Wei H, Wang X, Bai Y, Wang P, Wu J, et al. (December 2017). "Structural basis of a novel PD-L1 nanobody for immune checkpoint blockade". Cell Discovery. 3 (1): 17004. doi:10.1038/celldisc.2017.4. PMC   5341541 . PMID   28280600.
  36. ↑ "Checkpoint Therapeutics to Participate in Two Upcoming Investor Conferences". finance.yahoo.com. 9 September 2021. Retrieved 2021-09-20.
  37. ↑ Juneja VR, McGuire KA, Manguso RT, LaFleur MW, Collins N, Haining WN, et al. (April 2017). "PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity". The Journal of Experimental Medicine. 214 (4): 895–904. doi:10.1084/jem.20160801. PMC   5379970 . PMID   28302645.
  38. ↑ Okazaki T, Honjo T (April 2006). "The PD-1-PD-L pathway in immunological tolerance". Trends in Immunology. 27 (4): 195–201. doi:10.1016/j.it.2006.02.001. PMID   16500147.
  39. ↑ "Pharmacokinetics, Safety, Tolerability and Pharmacodynamics of BMS-986189 in Healthy Subjects - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. 5 February 2018. Retrieved 2019-08-24.
  40. ↑ Razaghi, Ali; Durand-Dubief, Mickaël; Brusselaers, Nele; Björnstedt, Mikael (2023). "Combining PD-1/PD-L1 blockade with type I interferon in cancer therapy". Frontiers in Immunology. 14. doi: 10.3389/fimmu.2023.1249330 . ISSN   1664-3224. PMC   10484344 . PMID   37691915.
  41. ↑ Sierra-Rodero, Belén; Cruz-Bermúdez, Alberto; Nadal, Ernest; Garitaonaindía, Yago; Insa, Amelia; Mosquera, Joaquín; Casal-Rubio, Joaquín; Dómine, Manuel; Majem, Margarita; Rodriguez-Abreu, Delvys; Martinez-Marti, Alex; De Castro Carpeño, Javier; Cobo, Manuel; López Vivanco, Guillermo; Del Barco, Edel; Bernabé Caro, Reyes; Viñolas, Nuria; Barneto Aranda, Isidoro; Viteri, Santiago; Massuti, Bartomeu; Laza-Briviesca, Raquel; Casarrubios, Marta; García-Grande, Aránzazu; Romero, Atocha; Franco, Fernando; Provencio, Mariano (August 2021). "Clinical and molecular parameters associated to pneumonitis development in non-small-cell lung cancer patients receiving chemoimmunotherapy from NADIM trial". Journal for Immunotherapy of Cancer. 9 (8): e002804. PMID   34446577.
  42. ↑ Johansen A, Christensen SJ, Scheie D, Højgaard JL, Kondziella D (April 2019). "Neuromuscular adverse events associated with anti-PD-1 monoclonal antibodies: Systematic review". Neurology. 92 (14): 663–674. doi:10.1212/WNL.0000000000007235. PMID   30850443. S2CID   73496636.
  43. ↑ Wanchoo R, Karam S, Uppal NN, Barta VS, Deray G, Devoe C, et al. (2017). "Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review". American Journal of Nephrology. 45 (2): 160–169. doi: 10.1159/000455014 . PMID   28076863.
  44. ↑ 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.
  45. ↑ Johnson DB, Sullivan RJ, Ott PA, Carlino MS, Khushalani NI, Ye F, et al. (February 2016). "Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders". JAMA Oncology. 2 (2): 234–40. doi: 10.1001/jamaoncol.2015.4368 . PMID   26633184.
  46. ↑ Oh DY, Cham J, Zhang L, Fong G, Kwek SS, Klinger M, et al. (March 2017). "Immune Toxicities Elicted by CTLA-4 Blockade in Cancer Patients Are Associated with Early Diversification of the T-cell Repertoire". Cancer Research. 77 (6): 1322–1330. doi:10.1158/0008-5472.CAN-16-2324. PMC   5398199 . PMID   28031229.
  47. ↑ Young A, Quandt Z, Bluestone JA (December 2018). "The Balancing Act between Cancer Immunity and Autoimmunity in Response to Immunotherapy". Cancer Immunology Research. 6 (12): 1445–1452. doi:10.1158/2326-6066.CIR-18-0487. PMC   6281171 . PMID   30510057.
  48. ↑ Hutchinson JA, Kronenberg K, Riquelme P, Wenzel JJ, Glehr G, Schilling HL, et al. (March 2021). "Virus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis". Nature Communications. 12 (1): 1439. Bibcode:2021NatCo..12.1439H. doi: 10.1038/s41467-021-21572-y . PMC   7933278 . PMID   33664251.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.