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I live in what is now known as the urban wildland interface west of Denver, the kind of area prone to the devastating fires that have been scorching California. Our firewise community efforts have taught us a lot about how a single windblown ember from miles away can destroy your house, and many of us have done a lot of mitigation. But, if the “big one” comes, our best hope is to grab the family albums and head down the hill.
Cancer can be very similar. If someone walks in with widespread disease, unless it is one of the highly treatable ones like testis cancer, flying over the patient with flame retardant (chemotherapy) may delay things for a while, but often the home is lost. The earliest realization of how to do better may have come from breast cancer. William Halstead realized in 1894 that putting out the fire effectively might include getting the surrounding “embers” (lymph nodes) at the time of removing the primary breast tumor (campfire in this analogy). A century later, it had become clear that in many instances the embers had spread too far for more radical surgical approaches, but that in some cases the embers could be extinguished (adjuvant chemotherapy) before the fire got out of control.
But what if the fire could be self-extinguishing? What if there was a boy scout at the campfire with a fire extinguisher? Better yet, what if you had smoke jumpers who could parachute in and help the boy by putting out the small fires elsewhere started by the embers? Immunotherapy offers just such hope. In the 1980’s we learned that giving high dose IL-2 to some patients with particularly sensitive tumors (kidney, melanoma) could produce cures in some cases. I liken this to sending in a group of non-specialist firemen/women in huge numbers to fight the forest fire doing the best they can.
Sending these individuals to more specialized training resulted in Provenge (sipuleucel-T), the first “vaccine” approved for treating any cancer, prostate being the target, and I was fortunate to participate in some of the first trials of this approach. But what was needed was both more effective equipment (in this case the PD-1 inhibitors that can “extinguish” the cancer’s ability to turn off the immune response) and more highly trained firefighters (potentially think of CAR-T cells) who have advanced skills, graduate degrees from a university, and can be deployed to go in search of the embers.
Now to torture this analogy just a bit further, let’s imagine that rather than sending the firefighters to universities for advanced generalized training, we could send them to CIA camps where they would receive the most specialized training possible right at the site where the fire started. In cancer, this may be the idea of using cryotherapy or irreversible electroporation to kill the local tumor, then injecting some cocktail of immune stimulatory molecules that enhance the body’s ability to create very effective T-cells that can go out as smoke jumpers looking for the embers (metastases), without the need for the university training outside the body (Sip-T or CAR-T).
Already there are clinical trials underway with this technique that show promise. Gary Onik has demonstrated some remarkable responses in metastatic prostate cancer patients. Diwakar Davar just presented similarly exciting data in high risk melanoma patients who received intratumoral CMP-001 and systemic nivolumab before resection of the primary tumors. 62% of the patients had no tumor left in their surgical specimens! So the cancer/firefighters are out there and although there will always be wildfires we simply can’t extinguish, the prospects for controlling them before or soon after they have spread have never looked better.