First, there is no knife involved. It’s just a machine designed to give radiation extremely accurately in the brain. I wish the name would not have included the word ‘knife,’ because that scares our patients.
I absolutely love the Gamma Knife. A Gamma Knife can get us to less than a tenth of a millimeter of error in our targeting, and we can leave the rest of the normal brain alone.
When we’re talking about using radiation on the brain, accuracy is literally everything because we’re using it to kill tumor cells.
Can you target very small tumors with the ‘knife’-- gamma knife?
Yes, the smaller the better. We love small. We can give 192 beams to one little tiny area, it’s so precise.
For larger areas, there’s no hard limit, but the larger the tumor, the greater the volume of normal brain around it that gets hit by some degree of radiation. We have ways to deal with that by adjusting our dose or maybe having the patient come back for a couple of treatments instead of doing it all in one day. But practically speaking, there’s no real limit.
Does this technology deliver higher doses of radiation than standard radiation?
That’s basically true, but it is targeted. There’s a difference between giving radiation all in one big dose versus a bunch of small doses. Because Gamma Knife is so accurate, we can really hit just the target hard, once, compared to previously when there was only radiation treatment of the entire brain.
What effect does whole brain radiation have on the patient? Are there fewer side effects with the Gamma Knife?
Sure—absolutely. The brain doesn’t want to get exposed to a large dose of radiation. That can affect short-term memory and overall energy levels. So, if we can avoid it, we should and we can. That’s not to say there isn’t a time and place for whole-brain radiation; we just have to pick and choose our battles.
After Gamma Knife treatment is patient hospitalized? What should they expect?
It’s remarkably well-tolerated. Almost all of our patients go home the very same day. They’re a little tired for a couple of days, and there might be some soreness, but that’s about it. That is a huge benefit because it’s so much faster than other forms of radiation. We can get them on to the next phase of treatment—chemotherapy or a targeted therapy or clinical trial without a delay.
We’re talking about cancers that start in the brain, primary brain tumors and brain cancer that spread to the brain from elsewhere in the body, right?
By far and away, the most common brain tumors that we are treating today are cancers that have spread to the brain, things called brain metastases.
I think that’s in large part credit to oncologists who are getting better and better at treating disease everywhere else in the body with all the advances that have been made with the new inhibitor drugs and immunotherapies. But unfortunately, because of the blood-brain barrier, those new therapies are not as effective getting into the brain.
While we’re doing better at controlling disease outside the brain, we still need better ways to control disease inside the brain.
When would you give whole-brain radiation?
It’s very much dependent on the individual patient and the situation. If we don’t have a good targeted therapy to back us up, and we have many, many cancerous spots to go after—30, 40, 50—then it makes more sense to treat with whole-brain radiation.
Certain types of disease, for example small-cell lung cancer, commonly spread to the brain, so we tend to have a lower threshold for using whole-brain radiation in that scenario. But even then, we’re trying to back off.
I’m particularly excited about what we’re seeing with these new antibody drug conjugates like HER2-targeted therapies, which are really helping us delay that need for whole-brain treatment. We can use Gamma Knife to target just the most important tumors, and the drugs can perhaps take care of smaller ones. That’s a big change from just a few years ago.
Are those kinds of decisions why medicine has moved to multidisciplinary teams to address diseases?
Absolutely. We would have nowhere near the confidence to do what we do if we didn’t know we had the backup of people like Dr. Veronica Chiang, one of our neurosurgeons who can operate when needed or use laser technology if there’s any radiation treatment effect we need to address.
I also need someone to call to see whether we have a targeted therapy that will take care of the smaller spots, so I can just go after the biggest or most symptomatic ones. You can’t do this by any one specialty anymore, if you ever could.
What about patients who have primary brain tumors—cancers like glioblastoma—do you use the Gamma Knife there or on cancers elsewhere in the body?
That’s very rare. For example, glioblastoma is infiltrative by nature, and it tends to require covering a larger volume to get all the microscopic extensions. It’s usually better to go with that fractionated course of radiation in combination with chemotherapy.
And the Gamma Knife was built for brain cancers, so it’s not used elsewhere in the body. But the concept of stereotactic radiosurgery—treating something super accurately with a high dose of radiation in a few fractions—absolutely applies elsewhere in the body. We just call it something else: stereotactic body radiotherapy (SBRT).
For example, it might be used for pancreatic cancers or lung cancers. The field of radiation has exploded with new, faster, better ways to treat cancer.
Let’s move on to some of your own research, which focuses on a very different area—lupus-related antibodies—in the treatment of glioblastomas.
Glioblastoma is one of the most aggressive primary brain tumors that we encounter. One reason it’s so tough to beat is it has figured out ways to cloak itself so that our own immune system can’t see it or fight it off. We try to be aggressive with surgery and radiation and chemotherapy, but we really need backup from the immune system. Yet the T-cells just don’t tend to find the tumor. That’s why glioblastoma is often called immunologically “cold.” If there was a way to heat up those tumors, we could get better outcomes.
How do lupus antibodies figure in here?
Where would we look to find a hyperactive immune system? In lupus, a patient’s immune system heats up and starts attacking its own cells and tissues. If we figure out the mechanisms driving that and isolate a few, maybe we can use them to awaken the immune system in glioblastoma. That’s what my lab focuses on—understanding mechanisms of autoimmunity to use them against cancer.
Lupus sometimes involves the brain itself, correct?
Absolutely. Patients with lupus sometimes experience antibodies attacking the brain. But how is that happening, if antibodies aren’t supposed to cross the blood-brain barrier or penetrate live cells?
Typical antibody therapy focuses on binding things outside cells or on the cell surface. Once an antibody is taken up by a cell via the usual endosomal route, it’s destroyed. But a subset of lupus antibodies is “anti-DNA,” which is a hallmark of lupus. Our idea was that tumor cells release a lot of DNA as they grow and die—like an exhaust trail. Maybe these anti-DNA antibodies can track that exhaust back to the tumor. And indeed, they do.
Even more remarkable, once they bind DNA outside the tumor, the tumor’s nucleoside salvage pathway pulls those nucleosides (and thus the attached antibody) inside. That means these lupus antibodies skip the usual destruction route in lysosomes and gain free rein inside the cell. Some go to the nucleus, others to the cytoplasm. We recently published in Science Signaling that one of these antibodies, once in the cytoplasm, binds RNA and triggers a pattern-recognition receptor. That receptor says, “Something bad is happening,” recruits T-cells, and engages the immune response.
In other words, the antibody is heating up that cold tumor. By itself, it improves outcomes, and combining it with a checkpoint inhibitor works even better. So we’re really thrilled about this and want to move toward clinical trials as soon as possible.
Research is really pushing treatment forward. It’s led to a revolution in cancer therapeutics over the last 20 or so years. We’re excited to be part of that.