Allergy medicine may help ‘reinvigorate’ immunotherapy to treat lung cancer
Click Here to Manage Email Alerts
A preclinical study conducted at the Icahn School of Medicine at Mount Sinai has found an allergy pathway that, when blocked, triggers antitumor immunity in mouse models of non-small cell lung cancer.
Moreover, an early parallel study in humans demonstrated similar findings with a combination of immunotherapy and dupilumab, yielding significant tumor reduction in one out of six patients treated.
“The reasons patients respond to immune therapy and then stop eventually are very different from one patient to the other,” study co-senior author Thomas U. Marron, MD, PhD, director of the early phase trial unit at Mount Sinai’s Tisch Cancer Center, told Healio. “I don’t think there’s any such thing as a ‘silver bullet’ for cancer, but I do think we are learning that there are some common pathways that are shared among patients who are resistant,” he added. “We’re trying to understand the biomarkers of which patients will respond to this combination versus those who won’t.”
Marron spoke with Healio about the motivation for this study, plans for further research, and how this treatment could improve management of NSCLC for appropriate patients.
Healio: Why did you conduct this study?
Marron: It’s a very circuitous story. We were doing in-depth analysis to understand the immune system in lung tumors. We used single-cell sequencing, meaning you take a tumor out of the body, you divide it up and you look at each individual immune cell. We looked at millions of different immune cells across three dozen or so patients who had lung cancer but hadn’t received any treatment, because we wanted to better understand the immune system in patients at the time of diagnosis. We were specifically interested in the myeloid cells, such as macrophages, which are the very immunosuppressive within the tumor microenvironment.
Our group published a paper in Nature in 2020 showing that the immune cells, in particular dendritic cells — another myeloid immune cell that is required for response to standard immunotherapy — had this strong genetic (specifically RNA) signature that looked similar to the signature seen in allergic conditions like atopic dermatitis, eczema or asthma. Allergic signatures, classically called type 2 signatures, represent what is in many ways a vestigial part of the immune system. Type 2 immunity is very important for protection from parasites or worms; however, in the developed world this sort of defense is not as important. The central tenet of the hygiene hypothesis is that in a world where we are exposed to fewer infectious organisms — in part, due to excessive use of bleach and hand sanitizers — our underused type 2 immune response is overactive against benign things like peanuts, dust and other allergens. The result is people develop allergic conditions like food allergy and asthma. Type 2 immunity is also very bad for cancer, as it promotes cancer growth.
The results of our 2020 publication were interesting because it almost looked as though the cancer was an allergic lesion. During the analysis we saw in a mouse model that normally doesn’t respond to checkpoint blockade, tumors grew significantly slower if we blocked the type 2 response by neutralizing a key immune cytokine, interleukin-4.
In our latest paper published in Nature, we detailed a new preclinical study in a different mouse model showing that the combination of the immune therapy normally used for lung cancer — which blocks PD-1 and PD-L1 — with anti-interleukin-4 results in synergistic effect and is where we saw the lowest tumor growth.
To evaluate this in humans, we enrolled some patients with lung cancer into a clinical trial after immunotherapy had stopped working and continued the immune therapy they were already receiving. Then we added the allergy medicine, dupilumab (Dupixent; Sanofi, Regeneron). We administered just three injections, each 3 weeks apart, to see if could reinvigorate the immune response against the tumor.
Healio: What did you find?
Marron: In this trial, we obtained biopsies at baseline and approximately after 4 weeks of treatment to evaluate what is really happening in these patients. We also collected blood throughout the trial. The results are interesting because we’re seeing very similar changes in humans that we observed in mice. It’s rare to see mouse data recapitulated in humans — unfortunately, it’s rarer than we’d like it to be. We’re seeing a real change in the immune response systemically and in the tumor, from a type 2 response toward a type 1 response, which is what we want. Encouragingly, in the first six patients, we had one for whom the cancer shrunk significantly — the cancer is basically gone at this point. This patient had a very rapidly progressing squamous cell lung cancer and had been on immunotherapy. We continued immunotherapy and gave them three doses of dupilumab.
The first scan we did, about 56 days in, showed a significant response. It amounted to a partial response by RECIST, which was around a 40% shrinkage. Subsequent imaging showed the tumors continued to shrink. It’s an encouraging sign that even though we’re just using this therapy for a brief intervention of basically 9 weeks, it seems that at least for this one patient, we are hitting the “reset button.” This success allowed us to expand the study. The ongoing phase 2 trial should be wrapping up early next year, when we will look at a total of 21 patients to evaluate treatment response.
Healio: What are the potential long-term implications of this research?
Marron: We want to understand which patients will respond to this combination versus those who won’t. Eventually, if we identify a subset of patients with lung cancer who have a very strong type 2 immune signature or a very high level of interleukin-4, they could benefit from the use of this therapy in the front-line setting.
In addition to the trial we’re currently running, the Cancer Research Institute just gave us a grant to conduct a trial in the neoadjuvant setting. This will include patients having their tumors surgically resected, because we know that even when tumors are removed, there is a high chance of recurrence. These patients will be given an even more brief intervention comprising one dose of PD-1 blockade and one dose of interleukin-4 receptor alpha blockade with dupilumab, followed by surgery. Our goal is to increase the likelihood that surgery will cure these patients. By analyzing results from the neoadjuvant cohort and the cohort we have recently published the preliminary findings from, we hope to identify the patients who would benefit from the combination therapy.
Given the complexity of lung cancer, I believe there’s a discrete subset of patients who would respond well to this combination, whereas most patients unfortunately will not. To better understand the importance of this immune pathway in other types of tumors, we have collaborated with the Ontario Institute for Cancer Research. They just finished a trial in breast cancer using our treatment cocktail. We are currently looking at the samples in breast cancer with PD-1 and interlekkin-4 to see if there’s a signal. We think this isn’t necessarily something that is unique to lung cancer because that initial “allergic” signature that we saw in lung cancer can also be seen in bladder cancer and liver cancer. We’ve even seen it in colon cancer, which doesn’t respond to the immunotherapies available today. Our approach has potential in other settings as well to augment the response to checkpoint blockade. It’s important to note our cautious optimism; this is a very small study, and it’s very early on. I’m hoping with more patients we’ll be able to identify a biomarker that will allow us to determine which patients will respond best to this combination therapy.
Reference:
- LaMarche NM, et al. Nature. 2023;doi:10.1038/s41586-023-06797-9.
- Maier B, et al. Nature. 2020;doi:10.1038/s41586-020-2134-y.
For more information:
Thomas U. Marron, MD, PhD, can be reached at 1470 Madison Ave. 3rd Floor, New York, NY 10029; email: thomas.marron@mssm.edu.
Collapse
Healio interviews
Read more about
Click Here to Manage Email Alerts