As we step into the era of personalized medicine, we need to characterize and validate novel cancer targets precisely – not just for therapeutic purpose but as diagnostic biomarkers. The tumor is no longer just diagnosed by morphology but by immunohistochemistry and other molecular patterns – in a multiplex and high-throughput technology platform. Cancer biomarkers are of different kinds ranging from DNA, RNA, RNAi, and protein. Amongst the protein markers, there are immune molecules (ligands or surface receptors) that are expressed specifically in a cancer context, either in pre-cancerous cells or cancerous cells or in combative immune cells (1).
Immune checkpoints are a class of regulatory molecules (stimulatory or inhibitory) that are significant in maintaining balanced immune homeostasis (2). An optimal immune response to pathogens and aberrant self-antigens is imperative to the survival of the host. The inhibitory immune checkpoints have been – in recent years - seen as promising molecular candidates for oncotherapy and as potential biomarkers for cancer.
One such biomarker is PD-1 (in concert with PD-L1) - an immunosuppressive checkpoint (late immune response mainly in peripheral tissues). It is expressed on all immune-centric cells (activated T cells, B cells, NK cells). It associates with corresponding ligands PD-L1 and PD-L2 – these ligands are generally expressed on tumor cells in the tumor microenvironment - to inhibit T cell proliferation through distinct signaling pathways, to dampen cytokine release and reduce expression of survival proteins. Thus, the PD-1/PDL-1 interaction axis – in the tumor microenvironment - helps in evading anti-tumor responses and promotes cancer-associated immune suppression.
Expression of PD-L1 on tumor cells is one specific parameter that can be clinically tested. A range of solid and hematological malignancies express PD-L1, co-opting the PD-1/PD-L1 immune response checkpoint to evade the immune attack (6). Induction of PD-L1 can be due to oncogenic gene amplification event. However, in most cases, it is due to an immune resistance mechanism wherein PD-1 expressing T cells engage with PD-L1 tumor cells leading to IFNɣ release. IFNɣ receptor signaling in tumor cell eventually dampens this activated T cell response (6).
Expression levels of PD-L1 have been clinically monitored and found to be correlated with PD-1/PD-L1 therapeutic inhibition. Pertinent points to be noted are:
- PD-L1 immunohistochemistry has identified a subset of patients that would respond more to anti-PD-1/PD-L1 blockade treatment in melanoma, non-small cell lung cancer, and bladder cancer.
- Pembrolizumab was the first checkpoint inhibitor to be approved with the requirement for a companion diagnostic test to measure tumor PD-L1 expression for non-small cell lung cancer treatment. Nivolumab was approved with the first complementary diagnostic test to assay tumor PD-L1 expression in order to stratify patients with improved survival.
- PD-L1-negative tumor staining is thought to be due to constraints in IHC assay and inherent variability in tumor samples. Four IHC tests have been approved by the US Food and Drug
Administration (FDA) as either companion or complementary diagnostics for anti-PD-1/PD-L1 therapies (13).
There is a substantial unmet need in diagnostic biomarkers: the large pipeline of immune checkpoint therapy will dictate the patenting of new diagnostic biomarkers. As of now, the efficacy of tumor PD-L1 biomarker as pre-dosing or diagnostic and prognostic marker looks promising.
BioGenex is pleased to announce the launch of Anti-PD-1 mouse monoclonal antibody and Anti-PD-L1 rabbit monoclonal antibody for the screening of PD-1 and PD-L1 biomarkers respectively. BioGenex is offering these new antibodies in different formats: - ready-to-use (RTU) vials for manual staining and bar-coded vials for the i6000® and Xmatrx® family of automated staining systems. They are also available in concentrated format along with the antibody diluent and are also compatible with third-party detection systems. With our Super Sensitive Detection System, our IHC solution offers the widest portfolio with over 400 primary antibodies, reagents, consumables, and ancillaries.
“Introduction of these antibodies for cancer diagnostics demonstrates our commitment towards ‘Accelerating the Pace of Precision Medicine’. We are determined and will continue to bring quality products to our customers,” said Krishan Kalra Ph.D. CEO of BioGenex.
- Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol. 2012 Sep; 23(Suppl 8): viii6–viii9.
- Ribas A., Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 2018:Vol. 359, Issue 6382, pp. 1350-1355.
- Patel SP, Kurzrock R. PD-L1 Expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 2015;14(4):847-856.
- Hansen AR, Siu LL. PD-L1 testing in cancer: challenges in companion diagnostic development. JAMA Oncol. 2016;2(1):15–6.