'Hidden Cells' May Be the Answer for Immunotherapy in Brain Cancer

To date, there are no Food and Drug Administration (FDA)-approved immunotherapy options for patients with brain cancer, as clinical trials typically have not had promising outcomes in this field.

However, research at Duke University may be on the path to change that.

CURE spoke with Peter E. Fecci, M.D., Ph.D., director of the Brain Tumor Immunotherapy Program at Duke’s Department of Neurosurgery about his latest research, which found that key parts of the immune system called T cells were being “hidden” in bone marrow for patients with brain cancer. Bringing these T cells back into the body could improve efficacy for immunotherapy.

Can you provide some background on your research, and what your findings were?

We're tumor immunologists, so our ultimate goal in our group is to build immune-based platforms for tumors, specifically for brain tumors. So, we're always trying to essentially build immunotherapies. My group often focuses on why those therapies don't work. A lot of that has to do with how cancer can actually attack the immune system and avoid it such that delivering immune-activating therapies is kind of pointless because there's not much immune system to activate.

Within glioblastoma (GBM) and brain metastasis, basically any tumor in the brain, we look to kind of understand T-cell disfunction. T cells are the main arm in the immune system that we're looking to activate. GBM in particular, which is the brain tumor that we mostly work on, turns out to be a very immunosuppressive tumor. It really attacks T-cell function. It side-steps the immune response pretty darn well. We've done a lot to highlight that over the years.

More recently, one of the big things that we found is that patients with GBM actually are really missing their T cells. For years, people have known that, but thought that it was due to things like chemotherapy and radiation, or steroids, but what we found is that even long before the patients got treated, they almost had the immune system of aged patients, where their T cells are really just not there. We looked in all kinds of places. We looked in the blood and the spleen and what we found was that not only were T cells missing from the blood, but basically all their lymphoid organs were all shrunken. That's just not something that you ever really see in any disease state.

As we kept looking, we decided to look in the bone marrow, figuring that maybe the cells weren't really being produced enough, and instead of finding diminished counts in the bone marrow, surprisingly we found that there were five times as many T cells as there should be in the marrow that were present. Essentially, the T cells that were missing from nearly everywhere else, a lot of them were hiding out in the bone marrow. We found that was true in patients and in mice with brain tumors.

What we found is that it wasn't just specific to GBM, but basically any tumor we put in the brain — lung cancer, melanoma, breast cancer – it causes spleens to shrink; it causes T cells to disappear from the blood; and it causes the T cells to collect in the bone marrow. What we eventually figured out was that the problem was with the T cell itself. The T cells were losing a receptor that they would normally need to get out of the bone marrow called S1P1, and as a result of that, they were getting trapped in the marrow.

We devised a couple of ways to genetically get those T cells out by creating a genetic alteration in mice where that receptor stuck around on the T-cell surface and didn't get lost. When we did that, we found that we could get the T cells out of the bone marrow, and when we gave those mice immunotherapies that really hadn't worked for brain tumors in the past, now some of those therapies worked very nicely because there was actually an immune system to activate.

Can you describe what is the importance of T cells when you're going to treat cancer, and why is it important to find these T cells and bring them back into the body?

In general, what people probably don't realize is that your immune system, even though people think it simply fights infection, we know that probably the immune system also helps play a role in surveilling against cancer. To beat cancer, you have to be different from the rest of the body. The immune system's job is to recognize things that are foreign -- that could be a virus or bacteria, but it could also be a mutation that isn't your cells. It's something different and foreign just like a virus is foreign.

The part of the immune system that recognizes cells as having something bad going on in them, whether it's an infection or a mutation, is the T cell. So, if you have a disease that attacks your T cells, you tend to get more cancers. Another example is AIDS. People with AIDS also have a higher frequency of cancer because the immune system isn't playing that role.

So, whenever we build an immunotherapy with the goal of fighting cancer, the part of the immune system that it really truly depends upon 95 percent of the time is T cells. If you want to deliver an immunotherapy, which is obviously a new and hot trend in cancer therapy, you really need T cells, or those therapies are not going to do much.

Can you discuss the previous lack of success of immunotherapy in brain cancer that we've seen up to date? Do your findings have potential to bring immunotherapy into this space?

There's been a number of clinical trials over the years of GBM that have had very limited success compared to some of the success you see in the news with melanoma and lung cancer where you even have immunotherapies that are FDA-approved. There are no FDA-approved immunotherapies for GBM, because most of the trials haven't had impressive results, and there have only been a limited number of trials that would support an FDA approval: big, phase 3 trials.

So, there's probably multiple reasons that these therapies fail. A big part of it is because unbeknownst to a lot of people, GBM, actually spends a pretty good amount of energy compared to other cancers suppressing the immune system and its host. That's interesting because a lot of other cancers go all over the body, but GBMs really stay in the brain, where people typically think of the immune system as having limited access. Despite that, these tumors really spend a lot of energy knocking down the immune system. People with these brain tumors have truly poor immune systems. That's probably a big part of why these trials fail.

There are other reasons, too. GBMs don't tend to have a lot of mutations, and they tend to be cold tumors, where the immune system does not have a lot of access or as much access because the tumors are in the brain.

Each of those things contributes somewhat, but the suppression of the immune system probably contributes quite a bit. So, our finding isn't true for every person with a brain tumor, but it's true in a lot of people. For those people that it is true, we think it's going to play a very substantial role in licensing immunotherapies in these people, getting these T cells out and to a point where they can actually go to the tumor is crucial if we're going to deliver a therapy whose purpose is to activate T cells.

The findings in mice indicate that this is going to be a big step forward for lifting some of the ceilings on these therapies.