In the previous write-ups, I have explained the basics of Small Cell Lung Cancer and the diverse genetic markers that are directly involved in diagnosis and treatment of the disease. This blog is a dive-in article that will dig into the details of checkpoint inhibitors and their mechanism.
So, read on…..
Programmed cell death
The basic concept of checkpoint immunotherapy is that immune system identifies malignant cells and destroys them through a series of chemical reactions. In a cancer patient, the immune system fails to recognize the tumour cell leading to uncontrolled proliferation of tumour cells. The type I transmembrane glycoprotein PD-1 (programmed death-1) is predominantly found on the surface of the T-cells. PD-L1 acts as the vital receptor that binds with PD-1 and interacts with each other to determine the destruction of malignant cells. But during extensive growth of tumours, the cancer cells inhibit PD-1/PD-L1 signal and gradually build up large number of tumour antigen expressing T cells.
Nivolumab is a human-derived IgG4 monoclonal antibody against PD-1. Nivolumab individually or in combination with ipilimumab have been administered to patients who had relapse after a first line systemic chemotherapy. They exhibited appreciable results in SCLC patients after failed platinum chemotherapy. Nivolumab monotherapy and nivolumab plus ipilimumab renders a promising activity, safety and efficacious profile for patients with limited-stage or extensive-stage SCLC. In the open-labelled clinical trial CheckMate 032, nivolumab alone and its combination with ipilimumab showed good overall prognosis, substantial objective response and tolerable safety in second line SCLC patients.
Ipilimumab is a monoclonal IgG1 kappa antibody acting against the surface receptor CTLA-4. This monoclonal antibody actively involves in the enhancement of T cells and in turn activates the immune system. Previous clinical trials that were conducted expressed that ipilimumab had better response to different kind of tumours. Ipilimumab shows satisfactory results in inhibiting the growth of SCLC cells with better prognosis.
Monoclonal antibody drugs
CTLA-4 is present on the surface of the cytotoxic T lymphocytes (CTLs) and remains as the prime checkpoint receptor. This receptor actively involves in mediating specific anti-tumour complex and therefore it regulates the immune response negatively. The T-cell reaction is activated after two sequential signals. The B7-mediated activation occurs after the formation of an antigen-antibody complex and the second signal after the B7-mediated activation signal. CTLA-4 present on the T-cell surface inhibits the B7 family molecules to bind on CD28, and the T- cell activation gets totally disrupted. Following the anti-CTLA-4 monoclonal antibody blockage, the CTLA-4 can prevent its inhibitory function with CD80/CD86 and enhance the anti-tumor immune response of the body.