by Christian Hyde, MD
In the World War 2 movie, "Saving Private Ryan," a small town
held by Allied foot soldiers is being over-run by Nazi tanks. At the crucial moment in the battle, when all
hope seems lost, a friendly Allied airplane turns the tide by bombing an
armored tank and rallying the exhausted defenders.
Similarly, with cancer, the main primary tumor and bulky metastases represent hard targets which have withstood immune destruction for months if not years. The tumor creates a ring of defense that make it difficult if not impossible for immune cells to infiltrate the enemy. Radiation therapy is the laser-guided smart-bomb that can be dropped on a tank hatch or down the chimney of a concrete bunker, forcing the tumor cells inside to surrender to the body’s re-invigorated immune soldiers.
It has been found in animals as well as humans, that once
the tumor becomes too large and established, that immunotherapy simply becomes
ineffective when confronted with overwhelming tumor bulk. What is needed then may be a combined effort
using a force multiplier.
A “force multiplier” of 10 allows 5 soldiers to fight like
50. Air support is a force multiplier,
technology is a force multiplier, good communication and good morale are all
force multipliers. In cancer, radiation
and immunotherapy are force multipliers for each other. These combined benefits can be “local,” meaning
where the radiation is aimed, or “abscopal,” where the radiation “scope” has
not been aimed.
This is a relatively new frontier, but early results offer
room for encouragement and hope, even of cure. Some major uncertainties remain, but at least the following questions
have some answers:
We also know from the PACIFIC Trial, which gave durvalumab
(Imfinzi) immunotherapy after chemo-radiation to stage IIIB non-small cell lung
cancer patients, that safety is similar between those who did or did not
receive radiation and immunotherapy. Notably,
the median time to death or distant metastases was 59% longer with
chemo-radiation plus immunotherapy (23.2 months) than with chemo-radiation
alone (14.6 months). (Antonia SJ, Villegas A, Daniel D, et al; NEJM, 2017)
Short answer: probably safe. We know from melanoma, where not just one but two immune checkpoint
drugs are given together (ipilimumab+nivolumab) that adding radiation does not
significantly increase local immune side effects. For example, radiating the abdomen does not necessarily
increase the risk of autoimmune colitis or hepatitis. This comes from the work of Dr. Jonathan Schoenfeld,
Dr. F. Stephen Hodi, and others in Boston who looked at side effects among patients who
received PD-1 blockade, anti-CTLA-4, or both within 2 weeks of radiation
therapy. The highest risk of any immune side
effect was seen among those receiving both PD-1 and CTLA-4 inhibitors, which is
well known from studies without radiation. (Bang A, Whilhite TJ, Pike LRG, et
al; Int J Rad Oncol Biol Phys, 2017).
The question of how to combine immunotherapy and radiation has
also been evaluated in a prospective randomized trial at MD Anderson that gave
high-dose radiation (radiosurgery) to lung or liver metastases during
ipilimumab immunotherapy. This study was
recently presented at the American Society for Radiation Oncology (ASTRO)
meeting in 2017, by James Welsh, MD. His
group showed combination ipilimumab plus radiosurgery to the liver or lung was safe
and well tolerated with no severe (grade 4 or 5) toxicity.
3. Is it effective to combine radiation and immunotherapy at the same time?
Short answer: Yes, but expect only local synergy for now. How does local synergy work? Like the military
force multiplier: 10x5=50. An airplane
alone against a bunker = damage that gets repaired later. Foot soldiers alone =
siege but not victory. Air power plus soldiers = liberation.
Focused radiation damages a tumor mass and lowers its
barriers, making it easier for the immune system to recognize and
infiltrate. Damaged cancer cells are
smart though, and react to X-ray damage by showing a signal on their cell
surface, like hoisting a friendly flag, that makes them safe from follow-up
immune destruction. The “friendly flag”
is a protein called PD-L1, but the current generation of checkpoint drugs help the
patient’s immune system to ignore this friendly PD-L1 flag, like not seeing it
or not trusting it. Damaged tumor cells
hiding behind this false flag can then be permanently cleared by the enhanced
immune system.
In the MD Anderson trial by Dr. Welsh and others, both local
and maybe even distant synergy were seen in a patient with anaplastic thyroid
cancer, a very serious type of cancer. The patient had a lung metastasis that was irradiated, and was
controlled locally as expected, but there was also shrinkage in the primary
tumor in the neck resulting in disease control for more than 13 months (ASTRO 2017
Meeting press release, www.astro.org).
In conclusion, as new immune combinations become more
effective, we can expect to see greater tumor control. However, auto-immune side effects, like
friendly fire on the body’s own cells, are a limiting factor. Sometimes the immunotherapy needs reinforcement,
too. By focusing the immune system on
the targets that matter most, the tumors, and setting up those tumors for
successful control, local radiation can help turn the tide in favor of the good
guys: you.
Was with Dr Welsh yesterday 8 -3-18 I feel very lucky that he is working with me. I'm stage 4 since Nov 17 On Taf-Mek combo, and results not good. In ICU now at Hines VA Getting the best care possible. Thankyou Dr Welsh for looking into by case and caring. Joe Tallman US Navy 79-83
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