In recent years, immunotherapy aimed at reactivating weakened immune cells in cancer patients has achieved remarkable results, especially immune checkpoint inhibitors, such as programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
A series of related reports have shown the positive effects of PD-1/L1 blockers among solid tumors and hematological malignancies, but mono-therapy relying on PD-1/L1 also has worrying limitations. This paper will review and discuss this.
Overview of PD-1 immunotherapy
The discovery of PD-1 can be traced back to 1992. Ishida et al first described PD-1, a new member of the immunoglobulin gene superfamily on mouse immune cells in the EMBO journal, and reported that PD-1 can induce classical types of programmed cell death.
In 1999, researchers revealed the mechanism of PD-1 acting as an immune checkpoint through the study of lupus like autoimmune syndrome in mice.
In 2014, FDA approved the first anti-PD-1 monoclonal antibody Keytruda, followed by Opdivo for the second-line treatment of unresectable or metastatic melanoma. After that, FDA has successively approved many other anti-PD-1 antibodies for cancer treatment. Drug O (Opdivo, Nivolumab) and Drug K (Keytruda, Pembrolizumab) approved in 2014 have been well deserved star products.
Mechanism of immune checkpoint inhibitors
PD-1, a member of the CD28 family, is an inhibitory receptor expressed on activated T cells, B cells, macrophages, Regulatory cells (T-regs) and natural killer (NK) cells. It has two binding ligands PDL-1 and PDL-2 (B7 family) expressed on normal cells. The binding of PD-1 with any ligand will inhibit T cell activity, induce T cell tolerance, inhibit proliferation, reduce T cell immune response and induce cell death, so as to prevent immune cell activation and killing normal cells.
However, some malignant tumors take advantage of this mechanism. They express a large number of PDL-1/2 on the surface to reduce T cell activation and antigen-specific T cell immune response, so as to bypass immune surveillance. In addition, tumor cells also activate inherent cell signals to enhance the survival rate of cancer cells and establish a tumor barrier against substances promoting apoptosis such as IFN.
Immunosuppressive microenvironment can be seen in PDL-1/2, including squamous cell carcinoma of the head and neck (SCCHN), lung cancer, breast cancer, melanoma and endometrial carcinoma. Compared with healthy individuals, PD-L1 in patients with advanced NSCLC is significantly up-regulated, and the fact that PD-L1 is highly expressed in primary breast cancer cells suggests that this kind of cancer may benefit from immune checkpoint therapy. In addition, PD-L1 is highly expressed on circulating blood cells and can be used as a marker for checkpoint blocking.
Advantages of PD-1/L1 inhibitors
Compared with other methods for the treatment of cancer, the biggest advantage of immunotherapy is that it relies on the ability of the immune system. In addition to being safer than traditional methods such as radiotherapy, chemotherapy and surgery, it can also form adaptability and specificity to specific tumors and form a lasting memory similar to antigens, which is of great significance to prevent tumor recurrence.
Compared with mono-therapy with other immune checkpoint inhibitors, such as ipilimumab (anti-CTLA-4 monoclonal antibody) and BRAF/MEK inhibitors, mono-therapy with PD-1 inhibitors has higher overall survival and adapts to more tumor types. Like pembrolizumab, a PD-1 inhibitor, is now considered to be a front-line drug for the treatment of melanoma that ipilimumab is difficult to cure.
Moreover, the related toxicity of PD-1 inhibitors is less than that of other immunotherapies such as interleukin-2 and CTLA-4 blockers.
Disadvantages of PD-1 / L1 inhibition
- Immune-related adverse events (irAEs) induced by PD-1/L1
After repeating administration of anti PD-1/L1 antibody in the breast cancer mouse model, a fatal xeno-hypersensitivity reaction has been produced. Moreover, anti-PD-1 antibodies may cause a variety of immune side effects in various organs and systems, including pancreas, skin, liver, gastrointestinal tract, endocrine and renal system.
Some organ specific side effects (such as pneumonia) only occur under PD-1 blocking therapy. Pneumonia caused by PD-1 inhibitor treatment is more common in NSCLC patients, which 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 pembrolizumab, a PD-1 inhibitor, had caused myocarditis and acute heart failure.
- Nonspecific biomarkers
At present, the expression of PDL-1 is a validated and important predictive biomarker. However, this alone is not enough to determine which patients can receive PD-1 / L1 blocking treatment. The hypothesis that PDL-1/2 with the highest level of tumor expression can be the best response to treatment has not 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 as predictive biomarkers of anti-PD-1/L1 antibody response. However, these are not enough because they are often observed in many cancers and lack specificity.
This requires more research to identify other markers, such as the heredity and epigenetic variation of TIL, TMB and IFN- γ, circulating biomarkers and intestinal flora.
- Cost effectiveness of PD-1 inhibitors
From an economic point of view, PD-1 blocking mono-therapy is usually more expensive than other immunotherapies and conventional cancer therapies. When the imported PD-1 anticancer drugs were first-line treatment for lung cancer in China, the price was nearly 40,000 RMB/month. However, with the approval of lung cancer indications of domestic PD-1 inhibitors and access to medical insurance through medical insurance negotiations, it can be expected to benefit more than 50% of Chinese lung cancer patients in two or three years.
- Patients with primary immunodeficiency diseases (PID) and / or autoimmune disorders
Due to irAEs associated with immune checkpoint inhibitors and the occurrence of irAEs are associated with shorter survival, patients with autoimmune disorders are usually not considered to receive these types of treatment. However, recent studies have shown that patients with autoimmune disorders may benefit from immune checkpoint inhibitor treatment.
Compared with the use of anti-CTLA-4 drugs, the use of anti-PD-1/PD-L1 drugs to treat patients with autoimmune disorders may have a higher probability of disease attack.
- Anti-immune test inhibitor:
Although PD-1 signal transduction inhibition significantly enhances the antitumor response, produces a lasting clinical response, and prolongs survival in some cases, about 30%-60% of patients do not respond to PD-1 / PD-L1 inhibition.
Supplement: several mechanisms of resistance to immune checkpoint inhibitors have also been studied, such as defects in class I antigen presentation, defects in Wnt/β-Catenin pathway and IFN signal transduction, adaptive resistance to PD-1/PDL-1 receptor blockers (once the PD-1 / PDL-1 pathway is inhibited, anti-PD-1 treatment and T-cell immunoglobulin and TIM-3 overexpression occur).
Discussion on improving PD-1/L1 blocking therapy
- Identify new specific biomarkers to predict response to treatment
Predicting relative therapeutic efficacy before administration will minimize the cost and time required, reduce adverse events associated with these drugs and improve the prognosis.
Highly mutated tumors show good response to treatment, so reactive mutations at the gene level can be used as predictive biomarkers. There are also intestinal microorganisms, peripheral blood biomarkers and circulating microRNA as potential biomarkers in the study.
Based on current evidence, tumors showing high PDL-1 expression levels and TMI, MSI or dMMR have a higher response rate to PD-1 blockade. Similarly, the quantity and quality of tumor infiltrating lymphocytes (TILs) are also indicators of response to checkpoint inhibitor treatment.
- Combination therapy
In cancer treatment, combination therapy is an essential strategy. Anti-CTLA-4 drugs can improve the infiltration of T cells into the tumor microenvironment, which provides an opportunity for PD-1 blockers to play a more effective role. On May 7, 2021, AZ issued a message that the combined chemotherapy of Imfinzi and tremelimumab had been positively evaluated in the overall survival of stage IV NSCLC. It has shown the effectiveness of combination therapy.
An important weakness of PD-1 inhibitors is that they cannot penetrate the cancer microenvironment in cold tumors, which can be solved by local ablation, especially in solid tumors. For example, stereotactic body radiation therapy (SBRT), cryoablation and other methods are combined with PD-1 inhibitors.
In addition, cancer vaccines also show a synergistic effect, which change cold tumors into hot tumors by inducing effector T-cell infiltration into tumors and immune checkpoint signals, so as to improve the effectiveness of PD-1 inhibitors.
One of the mechanisms of enhancing the efficacy of the above combination therapy is by increasing T-cell infiltration in the tumor microenvironment, but it has the risk of toxicity to normal tissues expressing the same antigen as tumor cells. Therefore, it is necessary to take strategies to reduce non-tumor toxicity at the target.
Chimeric antigen receptor (CAR) T-cell immunotherapy is another effective immunotherapy. Clinical trials showed that CAR-T therapy can achieve positive results in end-stage patients with acute lymphoblastic leukemia (ALL), and its complete recovery rate was as high as 92%. The combination of CAR-T therapy with PD-1 inhibitors has also been considered to enhance the therapeutic effect, especially in hematological cancers.
- Further research
The expression of PD-L1 will be modified in the tumor microenvironment. For example, VEGF can down-regulate the expression of PD-L1, while TNF-α and IFN-γ can up-regulate the expression of PD-L1 in tumors, so immunohistochemistry examination is very necessary. At present, there is no precise standard to define the positive of PD-L1 by immunohistochemistry. Due to the heterogeneous expression between or within tumor lesions, it may cause misreading.
Genomic methods are also exciting strategies to predict immunotherapy response or drug resistance. 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, and new immunotherapies for a wider range of inhibitory receptors, such as TIM-3, LAG-3, B- and T-lymphocyte attenuator (BTLA) receptors, are also being explored.
Summary
The introduction of PD-1/L1 blocking therapy has shown obvious antitumor 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 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 attract more attention in the future. Looking for a new strategy to transform “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 combined treatment strategies. Identifying more specific biomarkers is crucial, and a lot of researches are still needed to correctly select the cancer most suitable for immunotherapy with PD-1/L-1/2 blockers.
References
1. Makuku R, Khalili N, Razi S, et al. Current and Future Perspectives of PD-1/PDL-1 Blockade in Cancer Immunotherapy[J]. Journal of Immunology Research, 2021, 2021.
2. Kuol N, Stojanovska L, Nurgali K, et al. PD-1/PD-L1 in disease[J]. Immunotherapy, 2018, 10(2): 149-160.