My New Year’s Vision of a Colorectal Cancer Immunotherapy Future
To start off year #2 of my blog and to kick off the New Year, instead of looking back (I did that with my recent post “World in My Eyes (Favorite Posts of 2015”) – I decided to look forward. And look forward in a positive but also provocative and perhaps controversial way.
Making bold predictions in science is often considered a fool’s errand. Science is all about exploring the unknown, attempting to do what has never been done before. Those two key aspects of science are why I love it! But those two key aspects are also what often makes predictions very difficult. With one key successful experiment – previously assumed impossibilities can become instantly possible. With one key failed experiment – previously assumed paths forward can become instantly impossible. That is both the excitement and the frustration inherent in science – and what makes accurate predictions so difficult.
But I decided to kick off this New Year by doing exactly that. Making predictions. Making science predictions. If that weren’t bold enough, I decided to do it in one of the fastest moving & least predictable fields of science: Cancer Immunotherapies. Unlike Nostradamus I won’t be writing in abstruse quatrains where everyone reading can choose to find truth if they so choose. Instead I’ll be reasonably specific.
My goal is to lay out where I personally predict & believe the current scientific & translational research of colorectal cancer (CRC) immunotherapies will lead within the next 5- and 10-year time-frames. Keeping in mind that “within” phrasing, I believe some of them may occur sooner than 5 or 10 years.
The rest of the post are my sincere, personal beliefs but… they are just that: MY sincere, personal beliefs. I do not speak for anyone else (either literally or implied). In fact there is a huge spectrum of opinion in the scientific world so I don’t even necessarily speak for a majority of scientists – I am on the optimistic end of the spectrum. I also (once again unlike Nostradamus claimed) do not have a crystal ball in order to guarantee anything. Since there are so many unknowns in science, you may choose to look at these predictions not as predictions per se but instead as simply my personal hopeful vision of the next decade in experimental CRC immunotherapies. That is your choice but I follow the world of CRC very immunotherapies closely & I honestly do personally believe in these predictions. I am comfortable writing them in public, history will be the judge of their accuracy.
With that said, here I go…
First Some Background
One reason why I and much of the oncology drug discovery field are currently focused on attempts to successfully use the immune system as the “anchor” of the next generation of cancer treatments is because tumors are living organisms. Tumors evolve naturally and evolve in response to treatment through natural selection. So they are a moving and actively evasive target – which is a real problem for traditional drugs which can’t change or adapt as their target changes.
That is one reason why most current Stage IV cancer treatments can initially work but eventually fail due to eventual resistance. In contrast to traditional drugs, the immune system is adaptable with multiple parallel components. With immunotherapies activating the immune system, a complex movable tumor target can have a complex movable “drug” i.e. the immune system itself. Tumors can still evolve immune resistance mechanisms (why we have so many cases of cancer even in the presence of immune systems!!) but once an immune system is successfully activated against a cancer, it is hoped that these therapies will not be as prone to resistance generation as traditional drug strategies, at least in some patients.
Of course, the potential power of the immune system against cancer has been conceptually known for over a hundred years. In isolated cases over history, there was noted the correlation between infection (which causes an activated immune system) and cancer regression. Much more completely and famously, this was closely studied by Dr. William Coley who is considered to be the first true pioneer in cancer immunotherapy. In the late 1800’s Dr. Coley pioneered the study of intentionally injecting immune activating bacteria into cancer patients to cause an immune response, with the aim to treat cancer. There is an interesting very recent NPR story on the early days of immunotherapy here. At the time (and until recently) there was a significant lack of understanding of the details of the very complicated immune system, although the general concept appears correct. Conception does not automatically equal successful complicated science & therapeutics however. In terms of cancer immunotherapies, I believe the required complicated science & technology is now finally catching up to its >100 year old idea conception. Much of that basic scientific research was thankfully partially funded by the Cancer Research Institute (CRI), which was founded by Dr. Coley’s daughter Helen Coley Nauts.
My Prediction: CRC Immunotherapy Progress in the Next <5 Years
My MSI-high CRC <5-year prediction (data still pending!): anti-PD-1 Immunotherapies are already showing preliminary signs of clinical activity in MSI-high CRC patients as I wrote about here. Within <5-years, my prediction is that PD-1 pathway inhibition and the current & impending next round of combination immunotherapy regimens will be confirmed to effectively control disease in many patients (but not all), for a clinically significant amount of time. I predict that the clinical efficacy achieved could be similar to the amazing results currently seen in melanoma patients. I believe this will transform the treatment of MSI-high CRC patients in the relatively near-term. I’m intentionally avoiding any mention of “cure” predictions – I’ll leave that impossible prediction for the history books to write about, but that aside, I think we would all cheer for an immune system “controlled disease” without traditional chemo side effects for any amount of time!
My non-MSI-high CRC <5-year prediction (data still pending!): non-MSI CRC is much tougher to treat with immunotherapies. Within <5-years however, I predict tricks will be discovered to achieve immunotherapy response rates in “some” double-digit percentage (XX%) of patients. “Response” being defined as clinically meaningful disease control for a clinically significant amount of time. This is probably the boldest of my predictions but I honestly believe it. This scientific & medical advance is desperately needed by the non-MSI CRC patient population and if it were eventually FDA-approved, it would transform current treatment protocols.
My Prediction: CRC Immunotherapy Progress in the Next <10 Years
My CRC (both MSI-high and non-MSI-high) <10 year prediction: Within a 10 year time-frame, experimental therapies like personalized therapeutic cancer vaccines (whether manufactured or released via something like oncolytic viruses) and personalized T-Cell therapies (similar to the pioneering NCI trial NCT01174121) will steadily become more & more widespread in clinical trials (both via cancer centers and biotech/pharma), opening access to these experimental therapies to an ever larger numbers of patients. Therapeutic cancer vaccines are already showing significant activity in pre-clinical animal models of CRC although it must be stated that activity in animal models often does not necessarily translate into human activity – only clinical trials can prove/disprove that.
The beginning signs of these experimental personalized therapies expanding to more & more patients in clinical trials is already being seen beyond the already mentioned NCI personalized T-Cell trial that I tried to get into (written about here) with e.g. the announcement of a CRC personalized vaccine trial at MD Anderson (NCT02600949). Personalized experimental therapy clinical trials are also beginning to expand into the biotech/pharma world with the (at least initially) non-CRC personalized vaccine trials by BioNTech and also by Neon Therapeutics as well as the (at least initially) non-CRC personalized T-cell therapy strategy announcements of Neon Therapeutics. I believe they are just the first of a larger number of companies/cancer centers to announce clinical trial testing of these personalized strategies in the relatively near future, including for CRC.
Within a <10-year time-frame, I predict the combination of these personalized therapies + modern immunotherapy drugs could significantly boost the % response rate & duration of action in patients. The theory: The vaccine teaches the immune system that the tumors are dangerous & should be removed (or the T-Cell therapy jumps directly into active T-cells) and then modern immunotherapy drug(s) remove the major immunosuppression tricks the tumor tries to use in order to hide from the immune system. If the tumor is hit hard/fast enough – it would hopefully have a lot of trouble trying to mutate a new major trick to evade the immune system in time.
Current bottlenecks are: knowing which tricks an individual patient’s tumors are using to evade the immune system, the genetic analysis (e.g. whole exome sequencing) of tumors to determine their personalized mutations and then determining which of these mutations are recognized by the immune system. These bottlenecks are being actively studied by scientists right now, which is where my “<10 year time-frame” is coming from.
The personalized aspect is also currently limited by engineering. You need to roll out sequencing & personalized therapy manufacture to multiple locations, you can’t have thousands of cancer patients flying to the NIH for a personalized trial! But the required engineering has gone through technological leaps & bounds the past few years – the problem, like most things engineering, is I believe solvable in a <10-year time-frame, bringing the possibility of personalized therapy (at least in the clinical trial stage) to multiple locations nationwide.
As I mentioned, history will be the judge of my accuracy. Although bold & optimistic – as a scientist I am comfortable making these predictions as just that, current predictions (not promises) – as a patient & an advocate I am filled with Hope that they will come true. Hopeful for my CRC friends, hopeful for the entire CRC community & hopeful for myself.
We need this cavalry to arrive and I honestly believe I hear hoofs stomping not too far in the distance.