Immuno – oncology

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In the recent years, immunotherapy has become a potential strategy against various types of cancers. In light of this trend, two important components of the immune response signaling pathways – PD-1 (programmed cell death 1) and PD-L1 (programmed cell death ligand 1), are often mentioned. PD-1 is a cell membrane protein that has a role in limiting immune-induced tissue destruction at sites of active inflammation. This receptor is detected on the surface of immune cells, including on the surface of T cells. The PD-1 receptor may bind to two other molecules called its ligands – PD-L1 and PD-L2, this interaction is reducing the ability of activated T cells to generate an effective immune response. Thus, cells expressing PD-L1 or PD-L2 on their surface are “hidden” by the immune system and can not be destroyed. Studies have shown that the expression of PD-L1 on the surface of tumor cells is one of their methods of “masking” and avoiding an immune response against them.

Currently, several therapies based on antibodies directed to PD-L1 or PD-1 have already been developed. The goal is to block the interaction between the PD-1 receptor and its ligand PD-L1, which allows T-cells to attack tumor cells and improve antitumor immune response. It has been shown that PD-L1 is expressed in a number of tumors – melnoma, glioblastoma, lung cancer, kidney, head and neck, stomach, colon, pancreas, and others. There is a potential also in hematological diseases such as multiple melanoma, lymphoma and leukemia. In Europe is approved an immunotherapy for melanoma and non-small cell lung cancer.

Some of the biggest pharmaceutical and biotech companies are testing or have approved products in this area. Some of the developed antibodies are nivolumab, pembrolizumab, atezolizumab. These immunotherapies prolong patients’ lives for months, in some cases and years for others. Clinical trials for different therapeutic indications of these antibodies are also active.

In order to have a positive effect from the therapy, it is necessary to establish whether  the tumor cells have high levels of PD-L1 on their surface. This expression is dynamic and can vary even in tumor cells of the same patient. There is a standardized method for determining the level of expression of the molecule and, accordingly, the population of patients where the therapy would be most successful. Currently, analyzes are performed in pathoatomic laboratories using the immunohistochemistry method, and several companies have already developed and validated antibodies for diagnostic purposes. The used material is formalin fixed   paraffin embedded tumor tissue from patients. The percentage of tumor cells expressing the targeted molecule from the total tumor cell count was determined by staining. There are no clear criteria for patients selection. In some clinical trials, patients with more than 1% expression are considered to be possitive, in others –

those with more than 5% and in the majority – with over 50% expression. The  decision remains for the oncologist responsible for choosing the best therapy.

Since the beginning of 2017, in Bulgaria there is an active program for testing patients with non-small cell lung carcinoma. They can have their PD-L1 expression status analyzed on tissue samples from their tumor. If high levels of PD-L1 are оbserved , they may be offered immunotherapy as an alternative to conventional chemotherapy.

References:

  1. Lieping Chen and Xue Han, Anti–PD-1/PD-L1 therapy of human cancer: past, present, and future, 2015, J Clin Invest
  2. Festino L, Botti G, Lorigan P, Masucci GV, Hipp JD, Horak CE, Melero I, Ascierto PA., Cancer Treatment with Anti-PD-1/PD-L1 Agents: Is PD-L1 Expression a Biomarker for Patient Selection?, 2016, Drugs.
  3. Shailender Bhatia, MD; John A. Thompson, MD, PD-1 Blockade in Melanoma A Promising Start, but a LongWay to Go
  4. Sara Gandinia, Daniela Massib, Mario Mandalàc, PD-L1 expression in cancer patients receiving anti PD-1/PD-L1antibodies: A systematic review and meta-analysiс, 2016, Critical Reviews in Oncology/Hematology
  5. Suzanne L. Topalian1, Janis M. Taube2–4, Robert A. Anders4 and Drew M. Pardoll3, Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy, 2016, NATURE REVIEWS | CANCER
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