Programmed death-1 (PD-1) and its ligand (PD-L1) inhibitors are immune sentinomib drugs, and the breadth, depth, and persistence of their responses are rare.  It is a hot spot in the research of tumor immunotherapy in recent years.  The marketed nivolumab and pembrolizumab are PD-1 inhibitors, mainly used for the treatment of melanoma and non-small cell lung cancer, for renal cell carcinoma, bladder cancer, Hodgkin's lymph. The efficacy of tumors and the like is still in large-scale clinical trials.  PD-L1 inhibitors atuzolizumab, durvalumab and avelumab have been approved for the treatment of urothelial carcinoma, and several other drugs are still in early clinical trialsstage.

Anti-tumor mechanism

PD-1 is mainly expressed in activated T cells and B cells, and its function is to inhibit cell activation, which is a normal auto-stable mechanism of the immune system, because excessive T/B cell activation causes autoimmune diseases, so PD-1 is a talisman of our body.  However, the tumor microenvironment induces infiltration of T cells with high expression of PD-1 molecules, and tumor cells highly express PD-1 ligands PD-L1 and PD-L2, resulting in continuous activation of the PD-1 pathway in the tumor microenvironment, T Cell function is inhibited and it is impossible to kill tumor cells.  PD-1 antibodies block this pathway and partially restore T cell function, allowing these cells to continue to kill tumor cells.

PD-L1 is up-regulated in a variety of tumor cells. It binds to PD-1 on T cells, inhibits T cell proliferation and activation, and inactivates T cells, eventually inducing immune escape.  Both inhibitors can block the binding of PD-1 and PD-L1, up-regulate the growth and proliferation of T cells, enhance the recognition of T cells by tumor cells, activate their attack and killing functions, and mobilize the body's own immune function.  Anti-tumor effect.

2, listed PD-1/PD-L1 inhibitors

 2.1 nifuzumab

Nivolumab is a monoclonal antibody that binds to programmed death receptor-1 (PD-1) by blocking the interaction between PD-1 and its ligands, PD-L1 and PD-L2.  This blocks the PD-1 pathway-mediated immunosuppressive response, including anti-tumor immune responses.  In 2014, it was approved by the US FDA for melanoma patients. In 2015, it was approved by the US FDA for the treatment of non-small cell lung cancer (NSCLC). It is the first lung cancer immunotherapy drug.  Dosage and Administration: 3 mg*kg, 60 min intravenous infusion, once every 2 weeks until disease progression or unacceptable toxicity.  Warnings and precautions: 1 Immune-mediated pneumonia.  2 immune mediates colitis.  3 immune-mediated hepatitis, monitoring changes in liver function.  4 immune-mediated nephritis and renal insufficiency, monitoring changes in renal function.  5 immune mediates hypothyroidism and hyperthyroidism, monitoring changes in thyroid function.  6 embryo-fetal toxicity.  Adverse reactions: the most common rash.  Special population medication: Pregnancy: Nivolumab in pregnancy can cause fetal harm, should be banned, if it is necessary to use, should weigh the pros and cons; lactation: lactating women should weigh the pros and cons, stop breastfeeding; women with reproductive potential and men: recommendations  Women with reproductive potential use effective contraception during treatment with nivolumab and at least 5 months after the last dose; children and the elderly: the safety and efficacy of nivolumab have not been fully studied; patients with liver and kidney damage: no dose adjustment recommendations.

2.2 Panglizumab

Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligand and is an IgG4 kappa immunoglobulin.  Suitable for the treatment of unresectable or metastatic melanoma.  Dosage and usage: 2 mg/kg every 3 weeks, 30 min intravenous injection.  Warnings and precautions: 1 immune mediate adverse reaction, giving corticosteroids according to the severity of the reaction.  2 immune mediates colitis.  3 immune mediates hepatitis and monitors changes in liver function.  4 immune mediates pituitary inflammation.  5 immune-mediated nephritis, monitoring changes in renal function.  6 immune mediates hyperthyroidism and hypothyroidism, monitoring changes in thyroid function.  7 embryo-fetal toxicity.

2.3 Atezolizumab

On May 18, 2016, FD A of the United States approved Genentech's Atezolizumab (trade name: Tecentriq) injection for the treatment of neoadjuvant therapy/assisted during or after platinum-containing chemotherapy.  Local advanced or metastatic urothelial carcinoma with disease progression within 12 months of therapy.  The efficacy and safety of this drug was demonstrated by a multi-center, non-blind, 2-queue trial.  Cohort 2 subjects were patients with locally advanced or metastatic urothelial carcinoma who received disease progression within 12 months of neoadjuvant therapy/adjuvant therapy with or without platinum chemotherapy.  The primary outcome was determined by objective response rate (ORR) and duration of remission (DoR).  The results of the trial showed that in cohort 2, all subjects had an ORR of 14.8% and had not reached the median duration of remission.  The most common adverse reactions of this drug are fatigue, loss of appetite, nausea, urinary tract infection, fever, and constipation.

2.4 Degree of monoclonal antibody

Duvalumab is a PD-L1 inhibitor developed by AstraZeneca. The indication is the same as acitretin, both of which are metastatic urothelial carcinoma.  Antonia et al. studied the optimal dose of tavabizumab in combination with the CTLA-4 antibody tremeli⁃mumab in patients with NSCLC.  This multicenter, non-randomized, open phase Ib clinical trial enrolled 102 patients with advanced squamous or non-squamous NSCLC.  The doses of tavacizumab were 3, 10, 15 and 20 mg/kg, respectively, once or 4 weeks; or 10 mg/kg, once or 2 weeks.  The doses of trolimumab were 1, 3, and 10 mg/kg, respectively, 6 times/4 weeks, and 3 times after 12 weeks.  Taking into account the objective response rate and the incidence of ADR, the study determined that the optimal dose for combination therapy was 20 mg/kg of valliomab, 1 time/4 weeks, and 1 mg/kg of trolimumab.  Such patients are well tolerated, and patients with different levels of PD-L1 expression can achieve better results.  The study also determined the optimal dose of tavacizumab in patients with NSCLC, and subsequent phase 3 clinical trials are ongoing.  Kelly et al. conducted Phase Ib and Phase II clinical trials to investigate the efficacy of the above two monotherapys or combination therapy for recurrent or metastatic gastric cancer and gastroesophageal junction adenocarcinoma.  The results showed that the combination therapy was better than the monotherapy treatment, and it could achieve longer progression-free survival and higher remission rate.  In addition, clinical trials have found that valvazumab has a good effect on mesothelioma, advanced solid tumors, and squamous head and neck tumors.

2.5 Avidumab

Avelumab (avelumab) is a PD-L1 inhibitor jointly developed by Merck Serono and Pfizer. In 2015, ASCO published a number of Phase I clinical trial results of the drug.  The US FDA has granted its orphan drug and breakthrough drug qualifications as well as priority approval for the treatment of Merkel cell carcinoma.  At present, the clinical trial of avizumab on NSCLC, gastric cancer, gastroesophageal junction adenocarcinoma, breast cancer, melanoma and other tumors is in progress.

3. Several issues worthy of attention

First, expand the possibility of first-line medication.  For example, Merck wants to apply Keytruda as a first-line drug for melanoma, which defeated the current standard therapy Yervoy in the Keynote-6 experiment.  Bristol-Myers is also looking for Opdivo.  The Yervoy group is an opportunity to become a first-line drug for melanoma.

Second, develop appropriate clinical biomarkers to further refine the response population of PD-1 inhibitors.  For example, Keytruda approved lung cancer indications are for PD-Ll-positive patients, while Squibb's opdivo does not have this limitation.  In addition, in a Phase 2 clinical trial involving 41 advanced cancer patients (NCTOl876511), 40%-70% of tumor patients with defects in gene mismatch repair showed tumor shrinkage, while patients with mismatch repair function were in Keytruda. The response rate is zero.

Third, PD-1 inhibitors and other therapies combined to further increase the response rate, which may be a major research direction in the pharmaceutical industry in the future.  At present, the overall response rate of PD-1 inhibitors as a single drug to real tumors is low (15%-20%), except for melanoma 50%.  Recently, Bristol-Myers Squibb bought out the global rights to the Five Prime Colony Stimulating Factor 1 Receptor (CSF1R) antibody drug for $1.74 billion. FPA008 in Phase I clinical trials is expected to be associated with opdivo.  Merck has partnered with US pharmaceutical company Incyte to advance a Phase 3 clinical trial to evaluate the efficacy of Incyte's selective IDOl inhibitor Epacadostat in combination with eytruda as a first-line therapy for advanced or metastatic melanoma.  Although the prospect of compound combination is broad, the current therapeutic window for anticancer drugs is generally narrow, and the effect of combination therapy is still difficult to predict.  Although the divo/Yervoy combination currently on the market has a therapeutic advantage in advanced melanoma, its obvious toxic side effects also limit its application.  Recently, the combination of AstraChan's T790 variant EGFR inhibitor AZD9291 and PD-LI antibody Durvalumab has also been suspended due to the discovery of pulmonary injury in clinical studies.

Fourth, PD-1 inhibitors are not yet available in China, and their high prices may become a constraint in the future, with monthly treatment costs of up to $12.5 million.  However, it is worth noting that China's innovative pharmaceutical companies are also catching up. For example, Jiangsu Hengrui sold its PD-1 antibody SHR-1210 overseas equity to Incyte for joint development with US$770 million.  We hope that such anti-tumor drugs will enter the Chinese market as soon as possible, and treat patients with cancer as soon as possible.

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