Dhanya Nambiar, PhD, discusses the role of galectin-1 in the tumor microenvironment, and the potential for targeting this protein in patients with head and neck cancer.
Dhanya Nambiar, PhD
The carbohydrate-binding protein Galectin-1 (Gal-1) is secreted at a high level by cancer cells. Researchers at Stanford University examined whether targeted Gal-1 as part of a combinatorial approach would be effective in head and neck cancer.
The investigators hypothesized that inhibiting Gal-1 may synergize with radiation and/or immunotherapy, and by using the CRISPR/Cas9 deletion approach, an orthotropic model of head and neck cancers with and without Gal-1 expression was developed.
The decision to target Gal-1, explains lead study author Dhanya Nambiar, PhD, is because the presence of Gal-1 in the tumor microenvironment suppresses T cells.
“The tumor basically uses Gal-1 as kind of a barrier, and if you do not have these immune cells coming into the tumor, it is not going to get recognized or killed by our immune system. That makes it really hard for any immunotherapy targets to work on it, because for immunotherapeutic drugs that are currently in clinical trials, you usually need a pre-existing immune response for them to work.” Nambiar said.
In an interview with OncLive at the 2017 AACR Annual Meeting, Nambiar discussed the role of galectin-1 in the tumor microenvironment, and the potential for targeting this protein in patients with head and neck cancer.Nambiar: Almost 50% or more of patients that have cancer get radiation therapy, and it is limited by a lot of toxicities. Our lab is looking at how radiation affects immune response, and one of the proteins that we are interested in is Gal-1 which can affect immune cells from coming into the tumor.
We are trying a combinatorial approach where we think that if you inhibit Gal-1, bring in the T cells and use these checkpoint inhibitors to keep them active for longer. So, it is a kind of double-edged targeting that will make them more responsive. We have seen this in head and neck cancers and it is showing very good efficacy when we combine these 2 drugs together. We are now just trying to develop this into different models and look into how we can better these responses. We are also hoping that if it works in these pre-clinical models it might even make its way into a trial.This protein has been worked on in our lab for quite some time. One of the first results that came from our lab was that these tumors are very hypoxic, they usually do not get a lot of oxygen, which makes them more aggressive—they can survive in these hypoxic conditions. How they do that is by modulating certain proteins that help them do that, and Gal-1 is one of the hypoxia-responsive genes—it gets induced during hypoxia.
Then we had to understand what was causing the tumors to be more aggressive. We found that the T-cell responses in tumors are very much limited when they have higher levels of Gal-1. We also looked at patient samples. We did a trial with radiation with people who are treated with radiation and radiation can actually upregulate this protein, which is not what we want. We were thinking that if we target this, maybe will get a better immune response to work.
We’ve known for a long time that radiation causes lymphocyte depletion, which is basically reducing your T cell number, which is not good. No one knows exactly what is causing it, but we believe that Gal-1 has some role to play in it—I would not say that it is the only thing, because there are other mediators, but this is one of the important mediators of radiation-induced lymphopenia. We have this correlation and have done studies to show that. I think it is quite promising because it not only contributes to the immune cell coming into the tumor, but it also effects the systematic response of T cells. We started with head and neck cancers because that was the expertise of the lab and these immunotherapy drugs were recently approved for use in head and neck cancer. But, it only shows response in 20% to 30% of patients—most of them who get it do not respond. The next step is to look at what is causing these patients to not respond, or how can we differentiate between responders and nonresponders, because you do not want to give the drug to everyone and eventually realize that it is only working in a few of them. If we can predict response, we can design the trials and treatment plans better. The idea is that this protein can predict clinical response with the immunotherapeutic agents.
Right now, we have validated these factors in preclinical studies with head and neck cancer, and now we want to go into other cancers. We do not think that Gal-1 is limited to just this cancer type—we have seen this going up with aggressive cancers in the breast and lung, as well as in melanoma. This could be taken further, but needs much more validation. We want to work more to establish how far this can go, but it is definitely very promising.Radiation will eventually kill everything—we cannot use the highest dose in patients because of the toxicities, so you are limited by that. You have to weigh the effect versus the toxicities. The idea is to include things that improve the efficacy, without increasing the dose. I think Gal-1 has a combinatorial effect that works pretty synergistically with radiation.
Now we are looking more at mechanisms of this synergy. One of the reasons, we think, is because it affects immune response. When we give radiation and block Gal-1, we get a better response, and that is why the tumor response rate is much higher when you combine them instead of just using radiation by itself.Yes. The other good thing about Gal-1 is that it can be detected in the plasma of patients. We have seen in this the set of head and neck patients who retreated radiation with or without Gal-1. When you compare the levels, it actually goes up in the blood with radiation. If you correlate that with the number of T cells in the blood, like the CD3-positive cells, they go down with increasing Gal-1 levels. So, it kind of makes sense that if you have a higher level of Gal-1 in your blood that your T cell levels go down as well.I think that Gal-1 is an important mediator of immune response in tumors, and I think it is a good target. We should work harder on it—if only one person or group is working on this it will take a very long time to get into clinical trials.
The take-home message would be this is a good target to be developed in combinatorial approaches and it might be very important to study moving forward in different types of cancers. We can then expand this project to a much larger and broader population of patients.
DK Nambiar, T Aguilera, JD Bloomstein, et al. Stanford University, Stanford, CA. LB-180 - Targeting galectin-1 in combination with radiation and immune checkpoint therapy in head and neck cancers. Abstract presented at 2017 AACR Conference, April 1-5, Washington, DC.