Until recently, a diagnosis of cancer meant surgery to cut out what could be cut out and chemotherapy to kill whatever was left. Both of these treatments are hard on patients. Surgery means the risk of anesthesia and complications, such as infections or bleeding. And, chemotherapy means exposing the whole body to potent toxins that unfortunately often kill more than just the cancer cells.
But now a new class of drugs, called immunotherapies, is changing the way we think about and treat cancer. Immunotherapeutics are specifically designed to help the body’s immune system recognize and destroy cancer cells.
I recently had a chance to visit Genentech, one of the companies on the leading edge of developing these new drugs. Here is some of what I learned about this exciting new approach.
The Cancer-Immunity Cycle
In 2013, Ira Mellman, Ph.D. and Dan Chen MD, Ph.D., two Genentech researchers, mapped out seven key steps in the interaction of a person’s immune system with cancer cells, a process that is referred to as the Cancer-Immunity Cycle. Briefly, the seven steps are as follows:
- Cancer cells have mutations that cause the release of substances called “antigens.” These antigens differentiate cancer cells from normal cells. This allows the immune system to recognize them.
- Immune cells that specialize in finding antigens capture the released antigens and take them to T cells, located in the lymph nodes.
- T cells become ‘primed’ or ‘activated’ by these foreign antigens and that begins the immune response against cancer cells
- Activated T cells then travel through blood vessels towards the location of the tumor
- When the T cells reach the cancer cells, they “infiltrate” the tumor in order to attack it.
- T cells recognize foreign cancer cells based on the antigens they released earlier.
- T cells destroy cancer cells by activating a series of steps that lead to cell death.
With immunotherapy, the aim is to trigger the Cancer-Immunity Cycle—without harming healthy cells. Companies, like Genentech, are developing medicines that can support the immune system at various stages of the cycle. Currently, eight such drugs are being evaluated in clinical trials.
The most advanced medicines in development are called checkpoint inhibitors, which are believed to help the body’s immune system identify and attack cancer cells (Steps 6 and 7 above). To learn more about this category of drug, I met with Dr. Alan Sandler, Group Medical Director for Lung at Genentech and the leader of clinical development of Genentech’s investigational drug, atezolizumab (pronounced ah-teh-zo-liz-oo-mab) or atezo, for short.
Atezo is believed to work by blocking a cancer cell membrane protein called PD-L1 (for programmed cell death ligand 1). It appears that this protein may help cancer cells evade the immune system. Blocking this protein helps the immune system detect the cancer cells, in turn activating T-Cells to attack the cancer (atezo is the MPDL3280A denoted in the graphic at the top of this post).
There are currently 36 clinical trials (search terms include MPDL3280A; anti-PDL1), across certain kinds of lung, kidney, breast, bladder cancer, skin, brain and blood cancers, including 11 ongoing Phase III studies. Earlier this year, Genentech presented pivotal results for atezolizumab in advanced bladder cancer and non-small cell lung cancer. Based on these studies, atezo has received Breakthrough Designation Status for those conditions. That means the FDA will expedite the development and review of the drug. In addition, early but encouraging results have been found in metastatic triple-negative breast cancer.
Side effects so far appear to be more tolerable than those accompanying traditional chemotherapy; the most common being fatigue and flu-like symptoms. Some other immune-modulated adverse events were also reported in a small number of patients participating in studies of the drug. For example, an increase of enzyme levels in the blood (aspartate and alanine aminotransferase; 4% each), inflammation in the lining of the colon (colitis; 1%), and inflammation of the liver (hepatitis; 1%) and lung tissue (pneumonitis; 2%) were observed.
Television advertisements for a PD-1 inhibitor that is already on the market, nivolumab (brand name Opdivo) include warnings about use of the drug in people with autoimmune diseases and, theoretically based on their mechanism of action, these drugs could be harmful to fetuses, Genentech tells me atezo “has not been studied in patients with certain autoimmune conditions or in those who are pregnant.”
When will it be on the market?
A big question for people with cancer and their loved ones is when is this drug going to be available to them. Although there are many steps and some unknowns in the process of bringing an investigational drug to market, there is some hopeful news about atezo. As I mentioned above, atezolizumab has received Breakthrough Designation Status for advanced bladder cancer and non-small cell lung cancer. Genentech plans to submit results from the bladder and lung cancer studies to the FDA in early 2016 to bring this investigational medicine to people as soon as possible.