Current and future prospects of PD-1/PDL-1 inhibitors in cancer immunotherapy

Long press the QR code to receive In recent years, immunotherapy aimed at reactivating the weakened immune cells of cancer patients has achieved obvious results.
Of particular note are immune checkpoint inhibitors, such as targeted procedural Cell death protein-1 (PD-1), for cytotoxic T lymphocyte antigen 4 (CTLA-4), etc.

A series of related reports have shown the positive effects of PD-1/L1 blockers among solid tumors and hematological malignancies, but monotherapy relying on PD-1/L1 also has worrying limitations.
This article Review and discuss this.

01 Overview of the history of PD-1 immunotherapy: The history of PD-1 discovery can be traced back to 1992.
In The EMBO Journal, Ishida and others first described PD-, a new member of the immunoglobulin gene superfamily on mouse immune cells.
1.
It is reported that PD-1 can induce classical type of programmed cell death.

In 1999, researchers studied the lupus-like autoimmune syndrome in mice and revealed the mechanism by which PD-1 acts as an immune checkpoint.

In 2014, the FDA approved Keytruda, the first anti-PD-1 monoclonal antibody, followed by nivolumab for the second-line treatment of unresectable or metastatic melanoma.
After that, the FDA approved many other anti-PD-1 antibodies for Cancer treatment.

The O drugs and K drugs approved in 2014 are well-deserved star products.

02 Mechanism of immune checkpoint inhibitor: PD-1 is a member of the CD28 family and is expressed on activated T cells, B cells, macrophages, regulatory T cells (Tregs) and natural killer (NK) cells The inhibitory receptor.

It has two binding ligands-PDL-1 and PDL-2 (B7 family) expressed on normal cells.
The combination of PD-1 with either ligand can inhibit T cell activity, induce T cell tolerance, and inhibit Proliferate, reduce the immune response of T cells and induce cell death, thereby preventing immune cell activation and killing normal cells.

However, some malignant tumors use this mechanism.
It expresses a large amount of PDL-1/2 on the surface to reduce T cell activation and antigen-specific T cell immune response, thereby bypassing immune surveillance.
In addition, cancer cells will also activate Inherent cell signals can enhance the survival rate of cancer cells, and establish a tumor barrier against substances that promote apoptosis such as interferons.

PDL-1/2 suppresses the immune microenvironment in including but not limited to head and neck squamous cell carcinoma, lung cancer, breast cancer, melanoma and endometrial cancer.

Compared with healthy individuals, PD-L1 is significantly up-regulated in patients with advanced NSCLC, and PD-L1 is highly expressed in breast cancer primary cancer cells, and other facts indicate that this type of cancer may benefit from immune checkpoint therapy.
In addition, PD-L1 It is highly expressed on metastatic cells in the blood circulation and can be used as a marker for immune checkpoint blockade.

The purpose of PD-1/PDL-1/ 2 inhibitors is to cut off this pathway, increase the proliferation of immune cells, and enhance the body's natural anti-tumor monitoring system.

03 Advantages of PD-1 / L1 inhibitors: Compared with other methods of treating cancer, the biggest advantage of immunotherapy is that it uses the ability of the immune system.
In addition to being safer than traditional methods such as radiation, chemotherapy, and surgery, it It can also form adaptability and specificity to specific tumors, and form a durable memory similar to antigens, which is of great significance for preventing tumor recurrence.

Compared with other immune checkpoint inhibitors, such as ipilimumab (anti-CTLA-4 monoclonal antibody) and BRAF/MEK inhibitor monotherapy, PD-1 inhibitor monotherapy has a higher overall survival rate and is more adaptable Type of tumor.

Like the PD-1 inhibitor pembrolizumab, it is now considered to be the frontline drug for the treatment of melanoma that is refractory to ipilimumab.

Moreover, PD-1 inhibitors are less toxic than other immunotherapies such as interleukin-2 and CTLA-4 blockers.

04 Disadvantages of PD-1/L1 inhibition: ①PD-1/L1 induced immune-related adverse events (irAEs) in a mouse model of breast cancer, after repeated administration of anti-PD-1/L1 antibodies, resulted in fatal Xenogeneic hypersensitivity.

Moreover, anti-PD-1 antibodies may cause a variety of immune side effects in various organs and systems including the pancreas, skin, liver, gastrointestinal tract, endocrine and renal systems.

Certain organ-specific side effects (such as pneumonia) only occur under PD-1 blockade therapy.
Pneumonia caused by PD-1 inhibitor treatment is more common in NSCLC patients and is an important adverse event.
In addition, PD- 1/L1 treatment can cause systemic effects, such as meningeal radiculitis, multiple radiculitis, arrhythmia, etc.

It has been reported that the PD-1 inhibitor pembrolizumab causes myocarditis and acute heart failure.

② Non-specific biomarkers At present, the expression of PDL-1 is a validated and important predictive biomarker.

However, this alone is not enough, it is not enough to determine which patients can receive PD-1/L1 blockade therapy.

The hypothesis that the highest level of PDL-1 / 2 expressed by tumors is the best response to treatment has not yet been confirmed.

PDL-1 single nucleotide polymorphisms (SNPs), such as rs4143815 and rs2282055, have been further selected as final responders.

MSI and dMMR are considered to be predictive biomarkers of anti-PD-1/L1 antibody response.
However, this is not enough because they are often observed in many cancers and lack specificity.

This requires more research to identify other markers, such as genetic and epigenetic variations of TIL, TMB, IFN-γ, circulating biomarkers, and intestinal flora.

③ Cost-effectiveness of PD-1 inhibitors From an economic point of view, PD-1 blocking monotherapy is usually more expensive than other immunotherapies and conventional cancer therapies.

When the first imported PD-1 anti-cancer drug was obtained in China for the first-line treatment of lung cancer, the price was nearly 40,000 yuan/month.
However, with the approval of the domestic PD-1 inhibitor for lung cancer indications, and the entry of medical insurance through medical insurance negotiations, it is expected to be available in More than 50% of lung cancer patients in China will be benefited within two to three years.

④Patients with underlying primary immunodeficiency and/or autoimmunity due to irAEs related to immune checkpoint inhibitors, and the occurrence of irAEs is related to a shorter survival period, patients with autoimmune diseases are usually not considered to receive these types the treatment.

However, recent studies have shown that patients with autoimmune diseases may benefit from immune checkpoint inhibitor therapy.

Compared with the use of anti-CTLA-4 drugs, the use of anti-PD-1 / PD-L1 drugs to treat patients with autoimmune diseases will have a higher probability of disease attacks.

⑤ Anti-immune check inhibitors Although PD-1 signal conduction inhibition significantly enhances the anti-tumor response, can produce a lasting clinical response, and in some cases prolong the survival period, there are still about 30%-60% of patients There is no response to PD-1/PD-L1 inhibition.

Supplement: Several mechanisms of resistance to immunoassay inhibitors have also been studied, such as defects in class I antigen presentation, defects in Wnt/β-catenin pathway and interferon signaling, and adaptive resistance to PD-1/PDL-1 receptors.
Body blockers (Once the PD-1/PDL-1 pathway is inhibited, anti-PD-1 therapy and T cell immunoglobulin and TIM-3 overexpression will occur.

) 05 Improve the effectiveness of PD-1/L1 blocking therapy Discussion: ①Identify new specific biomarkers to predict the response to treatment and predict relative treatment efficacy before administration.
This will minimize the cost and time required, reduce adverse events associated with these drugs, and improve the prognosis.

Highly mutated tumors show a good response to treatment, and therefore reactive mutations at the gene level may be used as predictive biomarkers.

There are also intestinal microbes, peripheral blood biomarkers, circulating microRNAs, etc.
, as potential biomarkers in research. According to current evidence, tumors showing high levels of PDL-1 expression and TMI, MSI or dMMR have a higher response rate to PD-1 blockade.

Similarly, the number and quality of tumor infiltrating lymphocytes (TILs) are also indicators of response to treatment with checkpoint inhibitors.

② Combination therapy is an indispensable strategy in cancer treatment.
Anti-CTLA-4 drugs can improve the infiltration of T cells into the tumor microenvironment.
This fact makes PD-1 blockers more effective.
The effect provides an opportunity.
On May 7, 2021, AZ issued a message saying: Imfinzi and tremelimumab combined chemotherapy has been positively evaluated in terms of overall survival of stage IV non-small cell lung cancer, demonstrating the effectiveness of the combination therapy.

An important weakness of PD-1 inhibitors is that they cannot penetrate the cancer microenvironment in cold tumors.
This can be solved by local ablation, especially in solid tumors, such as stereotactic radiotherapy (SBRT) and cryoablation.
And other methods combined with PD-1 inhibitors.

In addition, cancer vaccines also show a synergistic effect, which can increase the effectiveness of PD-1 inhibitors by inducing effector T cells to infiltrate tumors and immune checkpoint signals to turn cold tumors into hot tumors.

One of the mechanisms for enhancing the efficacy of the above combination therapy is by increasing the infiltration of T cells in the tumor microenvironment, but it has the risk of toxicity to normal tissues that express the same antigen as tumor cells.
Therefore, strategies need to be taken to reduce the target site.
Non-tumor toxicity is also an aspect that must be considered.

Chimeric antigen receptor (CAR) T cell therapy is another effective immunotherapy method.

Clinical trials have shown that CAR T cell therapy can achieve positive results in end-stage acute lymphoblastic leukemia (ALL) patients, with a complete recovery rate of up to 92%.

The combination of CAR T cell therapy and PD-1 inhibitors is also considered to enhance the therapeutic effect, especially in blood system cancers.

③Further study PD-L1 expression can be modified in the tumor microenvironment.
For example, VEGF can down-regulate the expression of PD-L1, while TNF-α and IFN-γ up-regulate the expression of PD-L1 in tumors, so immunohistochemistry Testing is very necessary.

At present, there is no precise standard to define the positivity of PD-L1 through immunohistochemistry.
The heterogeneous expression between or within tumor lesions may cause misunderstandings.

Genomic methods are also exciting strategies for predicting immunotherapy response or drug resistance, and single-cell sequencing technology also contributes to the effectiveness of anti-cancer immunotherapy.

The development of radioactive tracers for activated T cells is also ongoing, with broader inhibition of receptors such as TIM-3, LAG-3, and T cell failure-related B and T lymphocyte-associated protein (BTLA) receptors And other new immunotherapies are also constantly being explored.

06 Summary: The introduction of PD-1/L1 blocking therapy has shown significant anti-tumor effects in the treatment of many different solid and hematological malignancies.

This form of immunotherapy is particularly effective in tumors showing high PDL-1/2 expression, MSI, TML and dMMR.

Compared with individual biomarkers, the use of multiple biomarkers may be more effective in predicting the response, and the development of new drugs that can block other co-inhibitory receptors (such as TIM-3, LAG-3, TIGIT, BTLA and VISTA), Should cause more attention in the future.

Looking for a new strategy for transforming "cold" tumors into "hot" tumors with high T cell infiltration in the tumor microenvironment will provide a more ideal remission rate for PD-1/L1 blocking therapy.

A deeper understanding of the cellular and molecular mechanisms of drug resistance and synergy will help improve the rational design of combination therapy strategies.

Identifying more specific biomarkers is crucial, and a lot of research is still needed to correctly select the most suitable cancers for PD-1/L-1/2 blockers as immunotherapy.

Reference content: N, Stojanovska L, Nurgali K, Apostolopoulos V.
PD-1/PD-L1 in disease.
Immunotherapy.
2018 Feb; 10(2):149-160.
doi: 10.
2217/imt-2017-0120.
PMID: 29260623.
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