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Can Immunotherapy Play a Role in Locally Advanced NSCLC?
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Dr. Nasser Hanna, Indiana University Health, discusses the possible role of immunotherapy in locally advanced NSCLC.




So where do we go from here? We certainly demonstrated some improvements in outcomes in the 80s and 90s and early 2000s, but we’ve sort of hit a little bit of a road block. We’ve tried a number of strategies to try to improve outcomes over chemotherapy and radiation alone. We’ve tried giving more chemotherapy before or after chemoradiation, that didn’t work out. We’ve tried escalating doses of radiation therapy, that didn’t work out. We’ve tried incorporating surgery after chemotherapy and radiation, and for a small subset of patients that seems to be effective, but for the larger group of patients that’s not really any more effective. We’ve tried empirically incorporating molecularly targeted therapy into chemotherapy and radiation and so far that hasn’t panned out. We’ve even tried to incorporate new classes of drugs, what we call antiangiogenics — these are drugs that we sometimes use in the metastatic setting and they help disrupt the blood vessels in tumors, but those proved to be either unsafe or ineffective in patients will stage III disease.

So we’ve really sort of hit a plateau a little bit on where we’ve gotten for the treatment of stage III disease. Now the newest strategies are to look at molecularly targeted therapies, but in targeted patient populations — but probably the more promising avenue of research is really in that of immunotherapy.

Immunotherapy is here, it’s a reality, it’s standard treatment for patients who have metastatic disease, and here’s the general idea: the general idea is that your immune system recognizes the presence of cancer in the body as being foreign — these cancer cells have on their surface certain proteins that the immune system recognizes as not belonging or abnormal. That’s a similar process in which the immune system recognizes viruses as foreign invaders where they recognize proteins on the surface of the virus for instance. So we’ve known for really a century that the immune system does respond to the presence of cancer in the body, and in some cases it can be helpful at suppressing cancer or killing cancer cells, but these cancer cells have developed in such a way that they’re able to resist the immune system by and large.

One of the ways that they’ve been able to resist the immune system has recently been discovered. It turns out that on the surface of cancer cells, and in particular on the surface of lung cancer cells, are certain proteins that interact with proteins on your immune cells, called T cells. When these proteins interact with one another, it’s basically like a running back with a football giving a stiff arm to a defender trying to tackle him — the defender is trying to get at it, just like the immune cell was trying to get after the cancer, but he just can’t get close enough to the cancer cell.

Well we now have a class of drugs of immunotherapy that sort of allow that T cell in your immune system to attack the cancer cell. And does it work? It’s great science, it sounds good, but does it actually work? The answer is yes, it actually works! In patients who have metastatic disease there are now drugs that work with the immune system in this manner that are able to cause a significant number of tumors to shrink. Amazingly sometimes these tumors remain regressed not just for months, but sometimes for years, and in randomized clinical trials so far it appears that in some cases the immunotherapy may be even more effective than the chemotherapy. 

That’s very good news and we’re beginning to further understand how to better take advantage of our knowledge and improve immunotherapy for patients with metastatic disease

So the natural question is, “can we take this information and incorporate it in the treatment of someone that has potentially curable disease?” That would be somebody with stage I, II or III by and large, and so these strategies are under way at this time. There are strategies that are going to be looking at giving immunotherapy after somebody has had surgery, and now there are a number of clinical trials that are testing the idea of giving immunotherapy after or during chemotherapy and radiation for those who have stage III disease. This is a prime time to give immunotherapy, but it may also be a risky time and I’ll explain that.

The reason why it may be a prime time is when your tumor gets radiated, cancer cells are dying and proteins are expressed and released from the dying tumor cells, there's lots of inflammation, and the immune system goes into overdrive. It’s one of the reasons why when you give chemotherapy and radiation, you can get swelling on the chest wall, you can get a sore esophagus for a while, you can actually cause some inflammation in the lungs. There’s a tremendous amount of inflammation that’s occurring during this process. It’s during that period of time we believe that breaking that barrier between that viable cancer cell and the immune cell may be optimal. There are a number of clinical trials now that that are testing the idea of giving immunotherapy to these patients.

Now there is a cautionary note: we know that these immunotherapies do carry some risks — sometimes the immune system works really well against your own body’s tissues and so you can get inflammation of normal tissues with immunotherapy. For patients with stage III disease, the thing that I worry the most about is, are we going to get excessive inflammation of the esophagus which can be very painful and debilitating, and are we going to get excessive inflammation of the lungs, what we call pneumonitis? Now these side effects can oftentimes be treated by tamping down the immune system by giving steroids and in most cases that can be safely done, but there are some cases where these side effects can be extreme and I suspect there will be some cases in which these toxicities will be irreversible.

So until we fully understand how to safely do this and whether it’s effective, this type of strategy should only be done under the auspices of a carefully conducted, closely monitored clinical trial. There are those clinical trials that are ongoing right now and I think we’re going to understand the safety side of things in the next year, and in terms of the effectiveness it’s probably going to take another two, three or more years to fully understand that. But I would say as of today probably the most promising hope that the outcomes for patients with stage III disease will be better in the upcoming years does come in this area of immunotherapy.

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