A phase 1b immunotherapy trial, conducted by Mario Sznol, a clinical research leader at Yale Cancer Center, originally shows encouraging results – long-lasting with high survival rates — in the long-term follow-up study. This study was published in the New England journal of Medicine and presented at ASCO in 2013.
The trial estimated the safety and efficacy of the combination regimen of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4; Yervoy), given either concurrently or sequentially, to patients with advanced melanoma whose disease progressed after prior treatment. The one-year overall survival rate was 94% and the two-year rate was 88%.
Currently, scientists are detecting that when PD-1 blockers and CTLA4 blockers are used together, they have a much greater impact than either alone: knocking out CTLA4 allows the body to create an army of anti-cancer T-cells, and knocking out PD-1 or PD-L1 allows this army to attack.
Uncover the handshake of cancer cells with T cells
Cancer cells would develop a “secret handshake” to trick the body’s T-cells. Understanding what roles some inside molecules(such as PA-1) play is vital to unleashing the immune system’s lines of attack, and getting better results for patients. There are some significant strides in decoding the interaction of PD-1 and PD-L1 listed as follows.
In 1992, Japanese researchers found a molecule on the surface of T-cells they named “programmed death 1″, or PD-1, which subsequently turned out to be a key part of their molecular handshake.
In 1999, a lab in Minnesota isolated a molecule, which they called PD-L1 (for “programmed death ligand 1″). Researchers then discovered that cancers often produced large amounts of PD-L1 – this was one of the key ways in which they were tricking the body’s defenses. This fired the starting gun on a race to develop drugs to disrupt the handshake by targeting either PD-1 and PD-L1 and pretty much every major pharma company joined in.
By 2006, a lab in Atlanta, Georgia, had proved in mice, that disrupting the PD-1-PD-L1 handshake could cure chronic viral lung infections – blocking this process could be relevant for a wide range of other diseases. The pressure to bring these drugs through trials began to build.
Not yet ready for prime time
This combination regimen is hugely promising in treating metastatic cancer, while it can also cause some pretty fearsome side-effects – particularly a nasty inflammatory bowel condition called colitis, which leads to diarrhoea and stomach cramps.
“The treatment of advanced melanoma has changed dramatically in the last few years, but there continues to be a need to increase the number of patients who experience a long-term survival benefit,” Sznol said. “While these are phase 1b data, the duration of response and one- and two-year survival rates observed with the combination regimen of nivolumab and ipilimumab are very encouraging and support the rationale for the ongoing, late-stage trials of this combination regimen.”
As a concept, targeting the subtle molecular interactions between our immune system and cancer looks like a breakthrough that’s here to stay. In fact, some experts even think that the idea will eventually replace ‘traditional’ chemotherapy and radiotherapy, and become a new paradigm for treating the disease.
Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33.