PD-1 and PD-L1 inhibitors

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immunostaining
can predict response to the treatment.

PD-1 inhibitors and PD-L1 inhibitors are a group 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]

PD-1 and PD-L1 inhibitors act to inhibit the association of the programmed death-ligand 1 (

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
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

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

ICOS.[7]

Therapeutics

PD-1

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]

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.

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]

PD-L1

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]

non-small cell lung cancer after chemoradiation.[34]

Experimental

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

Combinational therapy

Combination with type I Interferons

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

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

sensory neuropathy, diarrhea, bone marrow suppression, loss of appetite, nausea, and constipation.[8]

See also

References

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  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)
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  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
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