Tumor immunotherapy refers to a therapy that kills tumor cells by activating the body’s immune system. The basic idea is to relieve immunosuppression of the tumor microenvironment, improve the antigen presentation function of antigen-presenting cells, and promote the production of T lymphocytes by the body so as to activate the body’s own immune system and achieve the purpose of identifying and killing cancer cells.
In the past decade, new tumor treatment programs such as immunomodulator PD-1 and CAR-T cell therapy have completed the transformation from scientific research results to clinical applications. Since 2014, a total of 9 PD-1 / PD-L1 drugs have been approved for marketing worldwide. According to Evaluate Pharma data, the global tumor immunotherapy market size reached USD 61.9 billion in 2016 and is expected to grow to USD 120 billion by 2021.
Finding and rationally setting biomarker of tumor immunodiagnosis is the key to accurate tumor diagnosis. At this stage, genetic testing service providers mainly provide detection products around popular biomarkers such as PD-L1 expression level (TPS / CPS), MMR / MSI detection, and TMB. They will build different sequencing combinations according to indications, specimen types, clinical evidence, etc.
PD-L1 expression
PD-L1 expression is one of the three major predictors predicting the suitability of PD-1 / PD-L1 inhibitors for patients with multiple solid tumors. The main clinical detection method is immunohistochemistry (IHC). The higher the expression of PD-L1, the more likely it is that tumors will escape through the PD-1 / PD-L1 signaling pathway rather than other signaling pathways. Early studies have shown that with the increase of PD-L1 expression, the efficacy of PD-1 / PD-L1 inhibitors increases, the time for disease control is prolonged, and the prognosis of patients improves. Currently, there are five types of PD-L1 immunohistochemical detection reagents: 22C3, 28–8, SP263, SP142 and 73–10.
However, while the clinical evidence endorses the expression of PD-L1, it also provides the opposite evidence. There are also cases where patients with different cancer types do not express PD-L1 but are still effective with immune checkpoint inhibitors. For example, PD-L1 expression has no predictive effect in renal cancer.
MMR, also known as mismatch repair, is a repair mechanism after DNA replication, which can maintain the accuracy of DNA replication and control gene mutations; MSI, which means microsatellite instability, represents tumor genome mutation levels and indirectly reflects tumor immunogenicity.
In 2015, a study published in the New England Journal of Medicine showed that patients with dMMR had relatively long progression-free survival (PFS) and overall survival (OS) compared to patients with pMMR colorectal cancer, and had a higher response rate to treatment. And based on data analysis of 100,000 tumor patients, the vast majority of patients with MSI-H (83%) fall in the TMB-H area, that is, there are many patients with microsatellite stability, and the use of immune drugs is also very effective, so single use of this biomarker will miss many people who are suitable for medication.
Tumor mutation load (TMB) refers to the number of genetic mutations detected per million bases. The number of somatic mutations in different cancers ranges from 0.01 mutations / Mb to more than 400 mutations / Mb. Some of these mutations will transcribe and express polypeptide epitopes or tumor neonatal antigens.
Theoretically, cancer patients who carry more genetic mutations have more neo-antigens produced by cancer cells, which is different from normal cells. They are more likely to be recognized by immune cells and are more likely to benefit from them. In 2014, scientists analyzed the whole exon sequencing (WES) data of CTLA-4 antibody-treated patients and found the relationship between TMB and treatment effect. This is the first time TMB has been used in immunotherapy. In 2015, scientists again analyzed lung cancer patients treated with PD-1 antibodies through WES and found that high TMB was positively correlated with clinical effects. In 2016, a retrospective analysis of the WES data of the CheckMate026 clinical trial found that patients with high TMB who received PD-1 inhibitors had significantly better clinical benefits than chemotherapy. As a result, TMB began to attract worldwide attention.
In fact, TMB is an indicator in the research, and no corresponding industry standards and consensus have yet been issued. There is no standard for panel design, algorithms, and cut-off values for judging the level of TMB. Different clinical trials use TMB test results provided by different testing agencies. Clinical applications must be based on data from clinical performance validation and prospective studies.

Author's Bio: 

BOC Sciences provides a comprehensive collection of immune checkpoint inhibitors as well as other types of impurities, metabolites, and small molecule inhibitors.