Cancer remains a severe and challenging health problem. It remains the number two killer in developed nations, after heart disease. It is also a complex category of diseases that are very difficult to treat. Despite that, progress has been steady, with cancer survival increasing by about 1% per year over the last few decades. This adds up – with cancer survival increasing by 32% from its peak in 1991 to 2019. There is no single reason for this increase, it is the cumulative effect of multiple new treatments and advances.
This is important to keep in mind when interpreting news reports of new cancer treatments. There will likely never be (at least not anytime in the foreseeable future) a “cure for cancer”. Rather, there will be a series of incremental treatments. New treatments always sound incredibly promising, and sound as if, in theory, they should eradicate all cancers. Then in clinical trials it turns out they are an effective treatment, but far from a cure. Yet they add to the total set of tools we have to fight cancer, chipping away at the problem and contributing to the increase in survival.
We also have to recognize the time it takes to develop these ideas into safe and effective treatments. Often there is a 20-30 year delay from original concept to making a significant impact in the clinic. At the beginning of my career in the 1990s I remember hearing about monoclonal antibodies and how powerful they were. Already they were an important tool for research. But it is really only in the last decade that monoclonal antibody therapies have taken off, and now it appears there is a monoclonal therapy for almost everything.
The use of viruses as a tool for treatment also has a long history. The first virus was discovered in 1892, and soon after it was observed that viral infections could be associated with tumor regression. Deliberate viral infections were used to treat cancer, but they did not work very well and the viruses also causes significant morbidity in healthy tissues. There was a resurgence of research in the 1950s and 1960s, but ultimately this went nowhere. Now we are in the middle of another resurgence of anti-tumor (“oncolytic”) viral therapy spawned by increasing technology in genetic manipulation, where we can engineer viruses to be more specific and more deadly to cancer cells.
The new study
A recent study illustrates where the research is. The researchers are using an enhanced herpes simplex virus (the virus that causes cold sores) called RP2 which they have modified in two ways. The first is to add a GM-CSF (granulocyte macrophage colony-stimulating factor), a fusogenic protein. Fusogenic proteins allow cells to fuse together. They also have effects on immune activity, and may both stimulate and repress tumor growth. So the effects are complex, but in this study the researchers were hoping that this protein would help target cancer cells, activate the immune system against them, and be directly oncolytic – killing cancer cells by causing them to fuse with neighboring cells.
They also added anti-CTLA-4 antibody-like molecules, which are a type of checkpoint inhibitor. This is another relatively new cancer treatment. Checkpoints (discovered in 1995) are proteins that keep immune T-cells from killing other cells, as a way of protecting host cells from auto-immune damage. Cancers often evolve these checkpoint proteins in order to protect themselves from the immune system. Checkpoint inhibitors are designed to inactivate these proteins selectively on cancer cells, allowing T-cells to target and kill them.
The RP2 virus, therefore, should target cancer cells, directly killing them and activating the immune system against them. Sounds promising. For some patients they also combined this therapy with a proven monoclonal antibody therapy – nivolumab (nivo), to see if there is a synergistic effect. Here are the results:
Objective responses with RP2 monotherapy were observed in 3 out of 9 pts including 1 CR for ≥15 months in mucoepidermoid carcinoma, 1 PR for ≥18 months in esophageal cancer with liver metastases, 1 PR in uveal melanoma with liver metastases that progressed at 15 months. Objective responses with RP2 + nivo treatment were 44.4% in cutaneous melanoma (4/9), 25% in uveal melanoma (2/8), and 33% in SCCHN (1/3) pts. All seven responding patients had previously failed anti-PD-1 therapy, with all but one response durable to date for >425 days.
Again, not a total cure, but these are promising results for such an early-stage study mostly designed to evaluate safety. Anti-PD-1 therapy is another checkpoint inhibitor. So these patients have already failed standard therapy, including similar advanced therapies. Any response is therefore likely incremental, meaning it can contribute to overall cancer survival.
Obviously a lot more research has to be done, and it may be another 10-15 years before these treatments become standard. So far it seems that the RP2 virus is well tolerated, but there is a lot of concern with safety when deliberately infecting patients with viruses. In this case the virus is directly injected into tumors, which does help with targeting, but viruses reproduce and spread so there is always concern they can cause harm to the host beyond the targeted tumor.
Conclusion: The hope and the hype of cancer treatments
Advances like this need to be looked at in two ways simultaneously. First, we need to be realistic about how long it takes to develop such treatments, and the ultimate impact they will have on cancer survival. They take a long time and generally have incremental effects. On the other hand, we are living in a science-fiction future from the perspective of just a few decades ago. We are using advanced genetic engineering and monoclonal antibodies to target proteins we didn’t even know existed in previous decades, and enhancing immune function in highly specific ways. It is imperfect and messy, but powerful. Improvements in cancer survival times are not only steadily increasing, they are accelerating.
This is what real science looks like, and it is far better then chasing our tails looking for magical or “alternative” therapies.