When I started my oncology career many years ago my research focus was on the immunology and immunotherapy of cancer. Our goal was to solve the puzzle as to why our bodies allowed cancer to develop in the first place, and what we could do to improve our own natural response to cancer cells in an effort to help treat the disease.
The basic question that we tried to answer early on in the development of the field of cancer immunotherapy was fairly simple: If cancer cells are abnormal, why don’t our bodies recognize them as such and destroy them, much like our bodies respond to infectious agents such as viruses and bacteria?
Unfortunately, our success was limited.
Now, we may actually have a tool that helps us put theory into practice, one that may enable our bodies to recognize the cancer cell as foreign, and destroy it.
A report published today in Sciencexpress, a highly regarded medical journal, describes what appears to be the first success in using genetic engineering applied to immune based therapy, resulting in significant disease responses in two patients with recurrent melanoma.
Our tools and our knowledge were primitive when I started my research, compared to what we know today.
We used a variety of drugs such as BCG (a vaccine used to prevent tuberculosis, which also boosts the immune system and which is still in common use today to treat certain types of bladder cancer) and developed new drugs, such as interferon (which is commonly available today and used to treat a number of conditions). We even used a drug called levamisole, which was a medicine used to deworm cattle, and which in some fairly crude studies demonstrated activity as a booster of the immune system (levamisole even enjoyed a brief moment where it was used as part of clinical trials and treatment for colorectal cancer based on some modestly successful research studies).
But the goal of making the significant and durable impact on the treatment of cancer that we anticipated never materialized. Not to say that we didn’t make progress, because we did. Several treatments came out of that research, but none have been a smashing success.
Parallel to the research efforts in immunology, we made continued and substantial progress in understanding much more about cancer cells, their origin, and their internal processes.
That research has led to a much better understanding of what makes cancer cells cancerous, and I have discussed the topic many times previously in this blog and elsewhere. The targeted therapies resulting from that research have led to significant advances in cancer treatment, and the many targeted therapies in the research “pipeline” are testament to the effectiveness of those efforts.
Not to be forgotten in this discussion are the various efforts to produce an effective cancer vaccine—one that treats cancer, not one that prevents it—which have also been the topics of several blogs in the past.
Unfortunately, our vaccine efforts have not been particularly effective, although there are several promising developments that have been reported recently.
Cancer vaccines are also based on the same principle I mentioned above, namely trying to use the body’s own defense mechanisms to eradicate cancer cells by allowing our bodies to make antibodies or to “supercharge” our immune systems to recognize the cancer cells as foreign to our body, and in the process destroy the cancer.
The research reported today from the Surgery Branch at the National Cancer Institute is exciting for several reasons, which I will discuss a bit later in this blog.
The study was performed by Dr. Steven Rosenberg (who is probably the world’s expert on cancer immunology and related therapeutics and who has been working in this area for as long I can recall) and his colleagues, and is difficult to for most people to understand.
In fairly simple terms, the scientists knew that some patients with cancer had lymphocytes—which is a type of white blood cell that is the basis of our immune system—which recognized certain cancers as “foreign”, and were able to attack the cancer.
Unfortunately, for many patients with cancer, their lymphocytes do not have this capability.
What the researchers did in this study, essentially, was take some lymphocytes from patients with recurrent melanoma out of their bodies. They then took those lymphocytes to the lab, and inserted genetic code into those white blood cells which gave the lymphocytes the capability to recognize certain tumor antigens (tumor antigens are unique markers on the surface of the cancer cell). They then reinfused those genetically engineered lymphocytes back into the patients, after first treating the patients to significantly decrease the number of lymphocytes that had remained in the patients’ bodies after the first sample was drawn for the lab. (This process of decreasing the remaining lymphocytes is called lymphodepletion, which in turn gives the transfused lymphocytes a better chance of survival.)
In order for this process to work, the researchers realized that they had to devise a technique where the infused lymphocytes would last long enough to do their job of recognizing and destroying cancer cells.
Although their initial efforts were not successful at accomplishing this goal, they adjusted their approach and eventually did achieve success.
But success at having the lymphocytes survive and grow after they were given back to the patients was one thing. To have an actual clinical benefit was quite another.
And that is one of the reasons this research is so exciting.
Melanoma is a skin cancer that in fact is very treatable if found early. Unfortunately, that is not always the case. And when melanoma recurs, it is very difficult to treat effectively with most patients succumbing to their disease.
Despite many years of trying different approaches, including a variety of immunotherapy techniques, we still have poor results with most patients with metastatic melanoma.
In this project, of 15 patients treated with the more effective approach outlined above, 2 of them had significant responses. All of these patients had advanced melanoma, and all had failed prior treatments.
In the two patients who responded, one had disease in the skin and liver, and the other had disease in the lung. Both patients responded to the gene/lymphocyte therapy, and both are now free of disease at 19 and 18 months respectively.
To be certain, 2 out of 15 patients having a response to a cancer treatment is OK, but it usually isn’t something very exciting when you consider the thousands of patients who need help in treating recurrent melanoma.
And, in the past, we have had similar reports of occasional responses to a new treatment which did not materialize into the hoped-for significant impact on particular cancers.
But let’s not lose sight of what has happened here.
First, this is the first genetic engineered treatment that I am aware of that has made it from the research bench (think mice and test tubes) to the clinic and demonstrated some degree of benefit for patients with a very serious cancer.
Second, this is what I call a “proof of concept”, meaning that the treatment has shown that it can work and hopefully, with further research and further refinement, more and more patients will be helped. Not to mention that no significant side effects were noted.
Third, as the researchers note in the last sentence of their paper, “Engineering PBL (peripheral blood lymphocytes)…enables the in vitro (laboratory) recognition of tumor-associated antigens expressed on a variety of common cancers and the use of these genetically engineered cells for the treatment of patients with common epithelial cancers deserves evaluation.”
That complex sentence means that these researchers, based on their knowledge of cancer cells and the markers, or antigens, on the surface of cancer cells believe there is a real possibility that some of the common cancers we deal with--such as lung, breast, prostate and colon—may be amenable to treatment with this process as their research efforts move forward.
That is a bold statement, and I understand that these investigators are currently awaiting a green light from the FDA to move forward with their research on a broader scale.
For me, what is also exciting about this research is that it validates three decades of research effort.
It melds several lines of investigation, including (among others) our improved understanding of the immune system, new understandings of how our bodies can genetically “code” to prevent cancer, and what we have learned about the targets in the cancer cell and on the surface of the cancer cell that offer us opportunities to develop new treatments.
Each of these areas on their own is exciting enough. But to put all of them into one effort that produces results is outstanding.
We are encouraged by this report, and look forward to continued success.