Using the Immune System to Fight Cancer
Results from two clinical trials released last week show promise for a new therapy using the immune system to fight cancer. Published in the New England Journal of Medicine and presented at the American Society for Clinical Oncology 2012 Annual Meeting, new data shows early promise for cancer treatment aimed at restoring the immune system’s ability to detect and eliminate cancer.
The immune system is constantly at work looking for “non-self,” such as invading bacteria and viruses or abnormal cells. An immune response can be very powerful, and there are a number of diseases caused by an out-of-control immune system that starts attacking “self” (autoimmune diseases). To prevent that from happening, normal cells in the body express certain proteins that tell the immune system to stop attacking. However, cancer also can use those proteins to trick the immune system into ignoring growing tumors. By preventing tumors from tricking the immune system with “stop” signals (blocking inhibition), we hope to jumpstart an immune response to attack and kill tumor cells.
We have one approved immunotherapy that uses this strategy of blocking immune system inhibition. Ipilimumab (Yervoy) blocks a protein called CTLA-4, expressed on immune cells as an inhibitor of immune responses. Ipilumumab blocks CTLA-4, which prevents inhibition of an immune response – resulting inincreased immune function against tumor cells. Ipilumumab was recently approved for patients with melanoma, but can be accompanied by negative side effects due to an overactive immune system.
Researchers have honed in on another negative regulator of the immune system: PD-1 (expressed on immune cells) and PD-L1 (expressed on tumor cells). They conducted two Phase 1 Clinical Trials (NCT00730639 andNCT00729664) of antibody therapies against PD-1 and PD-L1, enrolling patients with advanced non-small cell lung cancer (NSCLC), melanoma, prostate cancer or renal cell or colorectal cancers. These large trials showed positive and lasting responses in all three cancers, including non-small cell lung cancer. This is very exciting, as NSCLC hasn’t responded well to other immunotherapies. In addition to an immediate immune response, these drugs also have potential to trigger the immune system’s memory. Once we can prime the immune system to recognize cancer, it can remember and build an army of immune cells ready to fight the cancer again.
Interestingly, the data also showed some correlation between positive responses and patients who have tumors with increased expression of PD-L1, meaning we could also have a biomarker to identify patients most likely to respond to treatment. Phase 2 trials involving biomarkers (NCT01354431 and NCT01358721 for renal cell carcinoma) are under way, and phase 3 studies of the anti–PD-1 antibody for the treatment of non–small-cell lung cancer, melanoma, and renal-cell cancer are being planned.
There is tremendous potential in harnessing the immune system, the body’s most powerful defense mechanism. These upcoming trials show great promise in making immunotherapy a potent weapon against lung cancers.
Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. New England Journal of Medicine, 2012. DOI: 10.1056/NEJMoa1200694.
Ribas, A. Tumor Immunotherapy Directed at PD-1. New England Journal of Medicine, 2012. DOI: 10.1056/NEJMe1205943
Topalian SL, et al. Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer. New England Journal of Medicine, 2012 DOI: 10.1056/NEJMoa1200690