A Plethora of Promises
There's lots of new papers being published in the junction of the fields of cancer and immunology. To get a numerical grasp of the extent of the goings on, I did a Google scholar search for articles with the words "cancer" AND "immunity" anywhere in their text, limiting the output to papers published in 2019. I entered the two search terms on Jan 12 at 2PM and turned up 1,750 hits! If you're conting, that's just 12 days including weekends! The evident breakneck pace at which research is proceeding has implications that are both positive and negative. On the plus side is the obvious supposition that the chances of making progress in understanding both the basic biology of tumorigenesis and the prospects for finding an effective therapy go up the more research is done studying the subject. The negative implications are more subtle. What's an oncologist or cancer researcher to do under the weight of these papers? How can they possibly keep up? Added to their burden is the possibility, even the probability, that many of the conclusions reached in these publications will surely be incorrect or irrelevant or misleading. Or the therapy that they suggest may be appropriate for one patient and harmful to another. After all, we've seen that cancer is a heterogeneous disease. And then there's the issue of whether the few findings that show promise can be adequately tested in human subjects. Clinical trials are expensive. With so many studies ongoing, it will be a task to figure out which ones have the highest probabilities of panning out. Some may work best in combination with others, thereby multiplying the possibilities even further.
Not withstanding these challenges, I thought it would be worthwhile to occasionally alert readers to some recent publications that have aroused my interest and seem to me indications of future directions in which the field of immunotherapy may go. Keep in mind that many promising indications have lead to cul-de-sacs and even ingenious approaches often don't succeed. You've been warned.
The paper that I'm going to discuss is by Daniel-Adriano Silva and 24 other authors and is entitled "De novo design of potent and selective mimics of IL-2 and IL-15" (Nature 565: 186 - 191 (2019)). Silva is from the University of Washington in Seattle, and his fellow collaborators come from universities located all over the world, including Portugal, Spain, the United Kingdom, California, and Maryland. I imagine that coordinating their project must have been a nightmare. Briefly, what they've done is to devise a new method of designing proteins and to use it to build an improved version of the protein interleukin-2 (IL-2) that may be useful for immumotherapy.
Before getting into the meat of the paper, it might be useful to review some information about IL-2. It's a cytokine, specifically a member of the interleukin family that consists of some 40 odd signalling proteins. Interleukins are secreted proteins that bind to receptors on white blood cells (leukocytes) thereby changing their behavior. IL-2, in particular, was discovered more than 35 years ago, and was, according to Stephen Rosenberg (J Immunol 192: 5451-5458(2014)), "the first effective immunotherapy for cancer". In the lead paragraph of his paper, Rosenberg writes:
"In November 1984, a 33-year-old woman with metastatic melanoma who had progressed through multiple prior treatments received the aggressive infusion of rIL-2. Within one month after treatment, biopsy of one of her tumors showed extensive necrosis, after two months, all tumor deposits were shrinking, and a few months later, all evidence of cancer was gone. This patient has remained disease-free for the past 29 years. She was the first cancer patient to respond to the administration of IL-2 and, thus, the first to demonstrate that a purely immunologic maneuver that stimulated T lymphocytes could mediate complete destruction of large, invasive, vascularized cancers in humans." (the rIL-2 in the first sentence refers to IL-2 produced in bacteria via recombinant DNA technology).
Since that initial treatment, many other patients with metastasized melanomas and kidney tumors, cancers that have not responded to other treatments, have been treated with IL-2. About 5 to 10% of these patients showed complete and lasting remission of their disease. About double that number achieved partial remission. On the basis of these findings, in 1992 the FDA approved IL-2 therapy for the treatment of metastatic kidney disease. Six years later, IL-2 was approved for treatment of metastatic melanoma. That's the good news. The bad news is that it takes massive, near toxic, doses of IL-2 to achieve these results.
A New IL-2
Silva and his 24 collaborators set out to limit the toxicity of IL-2. They knew that IL-2 binds tightly to a consisting of three protein chains: alpha, beta, and gamma (see the figure at the right and the iCn3D derived molecular model below). It also can bind to just the gamma and beta proteins, albeit less tightly. When bound to only two proteins it exhibits less toxicity, at least in animals. Armed with this information, they took on the challenging task of creating a brand new protein that mimicked the structure and activity of IL-2 but would only bind to the gamma and beta protein components of its receptor. Because native IL-2 is an unstable protein, they also sought to build a version that had a longer life span. Creating a modified IL-2 by changing a few amino acids here and there is not a difficult task for genetic engineers. But designing a totally new protein, one that is more stable and capable of selectively binding to a specific receptor, is a task of herculean proportion. Other researchers have succeeded in similar efforts, but only with small proteins of much less complexity.
I'm afraid that the way that they carried out this feat is beyond the scope of this blog (and largely beyond my understanding). In their own words, "We developed a computational protein design method in which the structural elements that interact with the desired receptor subunits(s) are fixed in space..., and an idealized de novo globular protein structure is built to support these elements." The result? A protein of 100 amino acids (called Neo-2/15) whose sequence is quite distinct from the IL-2 of mice or humans. Neo-2/15 is so different that antibodies against it don't cross react with native IL-2.
Of course, the key issue is how well it works. Silva et al tested Neo-2/15 in mice with melanoma or colon cancer. Both kinds of tumors grew less well when treated with the Neo-2/15 protein as compared with native IL-2. And what of the future? The authors write: "De novo design of protein mimetics has the potential to transform the field of protein-based therapeutics, enabling the development of molecules that improve on biology by enhancing therapeutic properties and reducing side effects, not only for cytokines, but for almost any biologically active molecule..." Six of the scientists involved in this work have founded a company based on the inventions described in their paper.