I wanted to spend my first scientific post on the hottest current topic in oncology research: immunotherapies. First of all: believe the hype.

I have been doing oncology research for more than 20 years. The recent emergence of immunotherapies acting against multiple advanced-stage cancer types (the long-strived for “Holy Grail” of oncology research) has truly caused a paradigm-shift. There is now immense research being done at all levels of private companies, cancer centers, research universities, research institutes and government labs to extend this first round of success into more patients and tumor types – and I firmly believe that these efforts will succeed!

Understanding Checkpoint Inhibitors

To understand immunotherapy, you need to understand “checkpoint inhibitors.” Hundreds of articles have been written about the truly paradigm-shifting “checkpoint inhibitors” such as the recently FDA-approved PD-1 and CTLA-4 inhibitors. At the very basic level, a checkpoint inhibitor is a treatment that helps the immune system see and go after cancer cells that are “pretending to be healthy” in order to avoid immune system detection. Clinical trials with checkpoint inhibitors are demonstrating great effect against multiple tumor types – including recently significant activity in a preliminary clinical trial of PD-1 inhibition in MMR-deficient (MSI) colorectal cancer (CRC). (Preliminary results were just released at ASCO 2015. They look exciting and a next phase trial (NCT02460198) is about to start.)

BUT… What about the rest our CRC community -- the approximately 80-85% who are not MMR deficient? Why have checkpoint inhibitors for the most part failed the majority of CRC patients in trials and how are immunotherapy researchers responding to this with newly designed therapies?

What makes a tumor “hot” and why are most CRC cases “cold”?

First, it’s important to understand the difference between “hot” and “cold” tumors in CRC.

Hot CRC Tumors

A tumor’s “hotness” is defined by how well it can be recognized by the immune system as dangerous and subsequently how well the immune system tries to attack it. For a number of cancers, a significant proportion of the tumors are considered to be “hot” – e.g. MSI-CRC, melanoma, renal cancer and lung cancer to name a few. These tumors tend to have a lot of mutations (“high mutational load”) which may give the immune system “more shots on goal” to recognize the tumor as dangerous. These tumors also tend to exist in neighborhoods (i.e. “tumor microenvironments”) that allow for successful immune system attacks after checkpoint inhibition.

Cold CRC Tumors

Non-MSI CRC tumors are a unique and different case. These are often referred to as “cold” tumors. In terms of the number of tumor genetic mutations, non-MSI CRC is one of the most highly mutated tumor types. In general non-MSI tumors do not respond to checkpoint inhibitors even though cancers with fewer genetic mutations, such as cancers of the stomach and head & neck, have shown responses.

Why?

It comes down to the tumor microenvironment (TME). Non-MSI tumors often exist in an environment that suppresses the immune system. So… simple checkpoint inhibition is not enough to remove the “Nothing to see here immune system, keep moving along!” shield (almost ”Romulanesque cloaking device”) surrounding the tumors.

Now that we’ve discussed “hot” and “cold” tumors, stay tuned for PART 2 of this series tomorrow where we will try to answer the question: What is being done by scientists to try to help those patients with “cold” tumors?

Dr. Tom Marsilje is a >20 year oncology research scientist with “currently incurable” stage IV colon cancer and also a Colon Club 2016 Colondar 2.0 model. He is a Ph.D. scientist and not an M.D., he exclusively gives his opinions on the “science” of experimental therapies – nothing written should be misinterpreted as implying medical advice.

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