Immuno Oncology: Treatments and New Breakthroughs

A generation of immune checkpoint inhibitors rewrote the rules of cancer treatment. But they reach only one in five solid tumors — and the race is now on to unlock the other 80%.

Until recently, most cancer treatments, such as chemotherapy and radiation, were designed to block cell growth. This general mechanism is effective in targeting cancer cells, because they are typically growing more quickly and uncontrolled than normal cells, in a manner that they shouldn’t. However, general chemotherapy agents are not just toxic to cancer cells – they block growth of cells in general, leading to massive side effects and death of healthy non-cancerous cells as well.

In the last few decades, we’ve seen major breakthroughs in oncology, where treatments are specifically targeted to cancer cells (not just any growing cells, hoping the ones that will be damaged the most are cancer cells). One such breakthrough is the development of immune checkpoint inhibitors, which allow our body’s own immune system to identify and destroy cancer cells.

How Does Immuno Oncology Treatment Work

Our cells have many built-in controls to identify when something is going wrong, such as uncontrolled growth in cancer cells, and to send a signal to our immune system to destroy these cells. However, many tumor cells have identified mechanisms of evading our immune system and permitting uncontrolled growth despite our immune surveillance system. For example, many tumor cells express a protein called Programmed Cell Death Ligand (PD-L), which binds to immune cells and signals to them not to destroy the cancer cell. By blocking this mechanism of immune evasion, our immune system can identify and destroy the cancer cells. Development of checkpoint inhibitors, such as Opdivo and Keytruda, to target this pathway have opened new doors to targeting cancer cells through our own immune systems, and have been much better tolerated with lower side effects than chemotherapy and radiation. This has been game-changing for oncologists and for cancer patients.

What Are The Immuno Oncology Treatment Shortcomings?

Unfortunately, the PD-L immune checkpoint is only utilized by approximately 20% of solid tumors, which leaves 80% of tumor cells unaffected by these treatments. The next generation of immuno-oncology treatments are targeting the alternative pathways that allow cancer cells to evade the immune system, outside of PD-1. One such target, which has received much attention recently, is ENPP1 (Ectonucleotide Pyrophosphatase/ Phosphodiesterase 1), an enzyme responsible for generating phosphate for bone mineralization. Normally, this enzyme is expressed at very low levels on the cell surface and produces extracellular phosphate; however, when abnormally expressed at high levels, it can degrade a signal called cGAMP, which cells use to flag to the immune system that a cell is “not quite right” and should be destroyed. By expressing high levels of ENPP1, cancer cells can evade our immune system and continue growing.

About 50% of solid tumor cells express ENPP1 as their primary mechanism of immune evasion, according to Dr. Shoshana Shendelman, CEO of Cyana Therapeutics. Cyana Therapeutics is developing a drug to block ENPP1 activity, which could help to eradicate tumors in cancer patients. “High ENPP1 expression level on tumor cells allows the tumor to evade the body's immune system,” said Dr. Shoshana Shendelman. “We are developing CY-3132, a small molecule inhibitor of ENPP1, for the treatment of solid tumors. By blocking ENPP1 activity, CY-3132 transforms tumor cells from immune evading to immune activating. CY-3132 has been tested in many solid tumor cell lines and animal models that have traditionally been resistant to treatment, including breast cancer, colorectal cancer, pancreatic cancer and lung cancer. We believe that new treatments such as CY-3132, targeting ENPP1 activity could offer new hope to many cancer patients.”

What Are The Future Developments For Immuno Oncology Treatment?

Given how successful the PD-1 and PD-L1 checkpoint inhibitors have been across a wide range of solid tumor types, additional checkpoint inhibitors could open up opportunities for the remaining 80% of solid tumors that are not responsive to these treatments. More options for cancer patients will be very welcomed by both physicians and patients.