Engineered NK Cells for Cancer; Surprise Bills: It's TTHealthWatch!

— This week's topics also include CMV vaccine in bone marrow transplant recipients and insights on how smoking causes cancer



This week's topics include natural killer cells and cancer, CMV vaccine in bone marrow transplant recipients, surprise medical bills, and mutations in bronchial epithelium in smokers and nonsmokers

Program notes:

0:47 CAR-transduced natural killer cells

1:45 Majority responded without major toxicity

2:46 Manage with a kill switch

3:17 Bone marrow transplant and CMV infection

4:18 Reduced CMV by half

5:06 Mutations in bronchial epithelium in smokers

6:07 Driver mutations increased in smokers

7:07 Telomere length assessed

8:08 Smoking cessation benefits

8:25 Surprise medical bills

9:25 After common elective procedures

10:25 For in hospital network

12:01 End


Elizabeth Tracey: Use of natural killer cells to fight cancer.

Rick Lange, MD: Surprise billing in surgery.

Elizabeth: Tobacco use and mutations in cells in the lung.

Rick: And a vaccine to prevent viral infections in people that received a bone marrow transplant.



Elizabeth: Rick, I'd like to turn first to this one that we were talking about before we started recording about how to frame it up. This is in the New England Journal of Medicine and the title of the paper is, "Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors." Wow! This is a mouthful. I'm interested in it because, of course, CAR-T therapy -- which has been around now for a couple years -- turns out to be really helpful in B-cell cancers and certain types of cancers. However, a large number of those folks really have pretty terrible toxic effects, and some of them die as a result of the use of this particular therapy.

In this case, what they did is, instead of this T subset, they used natural killer cells. They were able to really have an impact on folks who had really advanced cancers and had had previous treatment. They did not see that whole syndrome of neurotoxicity, cytokine release, graft-versus-host, and no increase in levels of inflammatory cytokines. This was only 11 patients with relapsed or refractory CD19-positive cancers, the majority of whom had a response to this treatment without development of major toxic effects. I am so encouraged. The other thing I like about this is that you can create these natural killer cells and they can be off-the-shelf instead of having to be specifically tailored for folks when they have CAR-T therapy, and CAR-T therapy is unbelievably expensive. I think there's two really great things about this study.

Rick: The current CAR therapy -- that is chimeric antigen receptor therapy -- it's used to redirect the specificity of T cells against a number of different hematologic cancers. As you alluded to, they're produced on an individual patient basis. Therefore, it's very complex. It's very expensive. It's associated with significant toxicity. These patients oftentimes end up in the intensive care unit, but it's very effective when it works.

This new way of addressing this uses off-the-shelf T cells. They don't have to be matched with regard to what's called HLA antigens. Furthermore, they manage these cells so if they, in fact, do become an issue, they can administer a medication that causes these cells to die on their own. Now, it appears to be safe. It's a small number of patients. It seemed to be effective. Eight patients responded and seven patients had complete remission. Our listeners should be aware they combined this with chemotherapy, because even after successful CAR therapy, about a third or fourth of patients develop recurrence of a cancer within the following year.

Elizabeth: Good news! Let's turn to one of yours. Which do you choose?

Rick: Elizabeth, since we're talking about cancer patients, let's talk about those that received a bone marrow transplant to treat their cancer. One of the complications associated with that later is to develop what's called a "cytomegalovirus infection," CMV infection. Most of us sometime in our life have had a CMV infection, and it usually causes low-grade symptoms. It doesn't become an issue unless we become immunosuppressed. Then the virus can recur and it can cause significant problems. Individuals that are extremely immunosuppressed are those that have had bone marrow transplant therapy.

We treat those CMV infections in those patients with antiviral drugs, but those drugs also have toxicities. What these authors did was they developed a vaccine that they would give to individuals that are already known to have CMV in the past. These are patients that have had a bone marrow transplant, and at 28 and 56 days after the transplant, they received this particular vaccine. It's called a triplex vaccine because it targets three different antigens. The patients that did not get the vaccine, their rate of developing a CMV infection was about 20%. Those that received the vaccine, it cut it in half. There were no serious adverse effects associated with the vaccine. For proof of concept, it looks very promising.

Elizabeth: That's in Annals of Internal Medicine. I think this is potentially interesting, of course, in neonates and in other people who are susceptible to CMV infection that sometimes can be quite dire and life threatening.

Rick: Right. What we don't know, again, are these patients received the vaccine a month and two months after they received the bone marrow transplant because you have to have an active immune system to be able to respond to the vaccine. We don't know whether giving it earlier would be beneficial. There was some measurable immune response even 12 months after the vaccine was given.

Elizabeth: Potentially good news. To Nature, this was a study that you didn't particularly like, but I got really excited by. This is looking at tobacco smoking and somatic mutations in human bronchial epithelium -- the cells that are inside the bronchi -- and they retrieved these cells from people who had bronchoscopy, sometimes for other reasons. They sequenced whole genomes of 632 colonies derived from single bronchial epithelial cells from 16 subjects. Some of those subjects were current smokers. Some were former smokers, and some of them were actually children. As I said, they were a part of this study. It was ethical to do this because they were having this exam for another reason.

They were looking for a number of mutational changes in all of these colonies of these cells, and not surprisingly, of course, they found more of those kinds of mutations in folks who were current smokers. They also found more what are called "driver mutations," which are those that could predispose or ultimately lead to cancer. They did note that those also increased in frequency with the age of the subject. Some of those cells even had two or three drivers in them.

What I thought was really fascinating about this study was that in former smokers these were not persistent changes that then lent to a lifetime of increased risk for lung cancer. They actually showed that these driver mutations decreased. They speculate that there's a population of stem cells that are resident in this area that nobody has ever identified before that may start to divide, and then the other cells that do have the mutations are no longer there, which is really great news.

They also looked at one other thing that, of course, is super popular right now and that's telomere length. They found sort of that same situation. There's an inverse relationship, of course, between telomere length and mutation burden independent of whether they have a driver mutation or not. Almost near-normal mutational burden in ex-smokers who also had considerably longer telomeres, and this lends more to their hypothesis that it's this stem cell population that's repopulating that whole area when somebody stops smoking.

Rick: They called it a two-compartment model. It's interesting that this hasn't been done before. We've looked at cell lines and how tobacco affects cancer cells, but how this affects normal epithelium and in smokers and in ex-smokers really is paucity of data. For those patients that had mutations in the cells, it was very heterogenous. Some had a thousand mutations per cell. Some had 10,000 mutations per cell. There's not a single driver. There are multiple drivers, so it's not just activating one gene, but multiple genes in a sequence. You want to create a niche where there may have been previous cells with mutations and/or inflammation and surround it with normal cells that create a more healthy environment. Again, a very interesting study. Our listeners should be aware that the health benefits of smoking cessation start immediately, but they continue on, and this may be a part of that, and that is the proliferation of normal stem cells.

Elizabeth: Let's go from the nerdish to, again, something with tremendous public health importance in the Journal of the American Medical Association. What about those awful, unfortunate, surprise medical bills?

Rick: When we talk about surprise billing, we're referring to what happens when a patient that has health insurance receives care from either a clinician or a facility that's included in their insurance network, but the patient, nevertheless, unexpectedly receives surprise bills from clinicians who are involved in their care that are out-of-network. Now you say, "That just doesn't seem right." Is it something that happens frequently or infrequently and what's the impact on the patient?

Those are the questions that these investigators attempted to address. They looked at privately insured patients who received care from their in-network physicians and asked, "How often do they also receive surprise bills?" To do that, they looked at claims data from a large U.S. commercial insurer from almost 350,000 patients who had undergone 1 of 7 common elective operations. I say common because all of our listeners will know either someone that's had one or may have had one of these themselves. We're talking about elective joint arthroscopy, laparoscopic cholecystectomy, a hysterectomy, a knee replacement, breast lumpectomy, a colectomy, and even coronary artery bypass surgery. All of those done by an in-network primary surgeon at an in-network facility between 2012 and 2017.

What they discovered is despite the fact that these were in-network physicians or facilities, about 20.5% of the episodes had an out-of-network bill. By the way, that out-of-network bill was billed to the patient at the cost of an additional $2,011. When did this most commonly happen? There were surgical assistants in 37% of the cases. That contributed over $3,600 to the bill. Out-of-network bills were also associated with anesthesiologists in 37% of the episodes, and that was about $1,200 additional cost. Elizabeth, that's a significant addition. Now that's for in-hospital network, but even among 83,000 procedures performed in an ambulatory surgery center for in-network primary surgeons, there was still an out-of-network facility bill in 7% and out-of-network professional bill for another 17%.

Elizabeth: These things, I think, are absolutely untenable, and certainly we're seeing a lot more in the popular press relative to people who get some staggering bills when they are forced to go out-of-network, especially in emergent situations. Any suggestion on the part of these authors on what needs to be done about this?

Rick: This is a pernicious problem because people are unaware of these things. As a consumer of health care, you should ask your physician who's performing the procedure or the facility that's performing the procedure, "Are there any out-of-network costs associated with that?" Direct your care to avoid those, or at least if you can't avoid them, at least be aware of what they are. In that case, they're no longer surprise bills and that's what we're trying to avoid. Finally, there's legislation that's been going on in many states, by the way, to either avoid surprise billing or to limit it. For example, a patient shouldn't pay more than, I'm going to pick some number, $250 or $500 per episode for surprise billing. We will need to address this legislatively.

