Michael Dougan, MD, PhD

The use of immunotherapy in the treatment of cancer has significantly improved outcomes for patients. However, these agents are often accompanied by significant toxicities and immune-related adverse events (irAEs).^1,2

During a session at the 18th Annual New York Lung Cancers Symposium® titled, “Beyond Steroids: Management of irAEs,” Michael Dougan, MD, PhD, assistant professor, Department of Medicine, at Harvard Medical School, and assistant in medicine, Department of Medicine, Division of Gastroenterology at Massachusetts General Hospital, discussed the management of irAEs in patients with cancer, beyond just the standard use of steroids.¹

IrAEs vary in regard to the tissues and organs affected, severity, and time of onset relative to treatment. Although some irAEs develop quickly after checkpoint blockade is initiated in patients, including rash or colitis, others such as liver toxicity and hypophysitis occur much later. Further, toxicities of the heart and central nervous system remain a significant concern.³

For many irAEs, steroids are utilized in the first-line, especially for serious irAEs. However, it remains unclear if steroids allow for preservation of the antitumor immune response.

Lack of High-Quality Studies

According to Dougan, although there have not been high-quality studies looking at the management of irAEs, it does not mean there are not proven strategies. For the majority of toxicities, management is accomplished with the use of high-dose systemic glucocorticoids. These are typically given for the treatment of hepatitis, nephritis, colitis, enteritis, pneumonitis, and more.

When there are cardiac-related toxicities or AEs in the nervous system, experts typically increase the dose of systemic glucocorticoids. For the treatment of endocrine toxicities, hormones and enzymes are typically replaced. Then for dermatologic toxicities, topical steroids are mostly used.

“We are using too much steroids, I can almost guarantee, for a majority of our toxicities [and] we don’t know what the right dose is yet,” said Dougan during the presentation.

Lung Cancer: © Crystal Light - stock.adobe.com

Dougan proposed the question during his presentation, “Why not just treat everyone with high-dose steroids?” His answer had to do with the toxicity of these agents and additional AEs they can lead to for patients. According to retrospective data from Memorial Sloan Kettering Cancer Center, steroids may influence antitumor responses.

In the study, patients with melanoma treated with ipilimumab (Yervoy) only were given steroids if they had an AE, and all patients with a serious AE received steroids. The goal of the study was to determine the connection between toxicity and the likelihood of a good antitumor response.⁴

A total of 254 (85%) of the 298 patients with melanoma included in the study experienced an irAE of any grade, and 103 patients (35%) required systemic corticosteroid treatment for an irAE. An additional 29 (10%) patients also were treated with an anti-tumor necrosis factor (TNF)α therapy. The estimated median time to treatment failure (TTF) was 5.7 months, 12% of patients had long-term disease control without receiving additional anti-melanoma therapy, and the rates of overall survival (OS) and TTF were not affected by the occurrence of irAEs or the need for systemic corticosteroids.⁴

The doses of glucocorticoid steroids currently used are 0.5-2 mg/kg typically given in divided doses twice daily. However, as Dougan noted, there is essentially no known data to support the use of such doses. As a result, trials evaluating the optimal doses of steroids are the only way to address this unmet need.¹

“[Steroids] are dangerous, toxic things, we need to treat our patients, we need to get them better, and right now, we do not know anything better than frontline steroids. The goal of treating these toxicities should always be minimizing the morbidity and mortality, but we have to try to do this while minimizing the effect on antitumor [responses],” added Dougan.

Advancements with targeted therapies will require a more mechanistic understanding of irAEs, including further understanding of the mechanism of toxicities better than what we currently have.

Potential Therapeutic Options

TNFa Inhibitors

In immune checkpoint inhibitor (ICI)-induced colitis, infliximab (Remicade) is an anti- TNF-α that is highly effective in ipilimumab and anti-PD-1 mediated colitis following the failure of systemic glucocorticoids. In ipilimumab colitis, responses occur within days of treatment, showing the role for this cytokine.

However, the question of whether it is a more effective therapy than steroids remains as there is minimal data related to humans. In preclinical models, however, the combination of a TNF-α blockade with PD-1 blockade has shown potential and innate inflammation may lead to tumor growth.⁵

Dougan noted in his presentation that while it was in a mouse model, these data have been replicated by multiple groups and mice have currently predicted the success of immunotherapy in the past.

Vedolizumab (Entyvio), an anti-α4β7agent, is an effective treatment option in ICI enterocolitis. With the exception of gastrointestinal malignancies and metastasis, vedolizumab will not influence the tumor microenvironment for the majority of cancers.

“It's also very effective directly compared with infliximab,” said Dougan.

The cells driving colitis have been looked at in detail, including cytotoxic CD8 T cells, and they are generating large amounts of cytokines. Data demonstrate that these cells come from the resident memory pool. When checkpoint inhibitors are given, those resident memory cells become activated and start destroying the tissue.

These tissue-resident memory T cells are thought to recognize the gut microbiome, proposing that experts should begin to consider microbiome-based therapies in this space as well. A group at The University of Texas MD Anderson Cancer Center has already started looking at this, according to Dougan.

IFN-γ

Interferon gamma (IFN-γ) is a cytokine that plays a role in inducing and modulating an array of immune responses. Data have shown that blocking signaling downstream of IFN-γ does help with immune checkpoint colitis.

Data from France looking at a single-arm study also compared it with previous algorithms and showed that the combination of steroids, JAK inhibitors, blocking IFN-γ, and CTLA-4 dramatically improved OS among patients who developed checkpoint myocarditis.

“This is really exciting and provocative data for giving multiple types of treatments upfront… We've seen now in more cases than the original report that patients will develop wider immunity and acquired resistance to immunotherapy. This is one of the major mechanisms. So probably not the best strategy for treating non-life threatening toxicities, but for life threatening ones, this is actually very promising,” said Dougan.

CTLA-4/CTLA-Ig

Additionally, CTLA-4 Ig may be important as reversal agents for the treatment of severe irAEs. They also likely can inhibit antitumor responses.

CTLA-4 Ig is a sole agent for CTLA-4 blockade and according to Dougan, has some effect on PD-1 blockade by inhibiting co-stimulation. A randomized, control trial is now evaluating frontline steroids plus CTLA-4 IG or placebo in patients who have checkpoint inhibitor-associated myocarditis (ATRIUM; NCT05335928).

This multicenter study is ongoing and enrolling patients across the United States in a 1:1 ratio to receive corticosteroids with intravenous abatacept at 10 mg/kg or corticosteroids with placebo.

Dougan concluded his presentation by saying, “glucocorticoids are an effective treatment for many immune related adverse events, but they do have substantial limitations, losing the possibility of interfering with tumor responses. To develop better therapies, we do need to have more mechanistic detail about immune related adverse events.”

REFERENCES

1. Dougan M. Beyond steroids: management of irAEs. 18th Annual New York Lung Cancers Symposium®. November 11, 2023. New York, NY.

2. Pauken KE, Dougan M, Rose NR, Lichtman AH, Sharpe AH. Adverse events following cancer immunotherapy: obstacles and opportunities. Trends Immunol. 2019;40(6):511-523. doi:10.1016/j.it.2019.04.002

3. Luo J, Beattie JA, Fuentes P, et al. Beyond steroids: immunosuppressants in steroid-refractory or resistant immune-related adverse events. J Thorac Oncol. 2021;16(10):1759-1764. doi:10.1016/j.jtho.2021.06.024

4. Horvat TZ, Adel NG, Dang TO, et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol. 2015;33(28):3193-3198. doi:10.1200/JCO.2015.60.8448

5. Verheijden RJ, May AM, Blank CU, et al. Association of anti-TNF with decreased survival in steroid refractory ipilimumab and anti-PD1-treated patients in the Dutch melanoma treatment registry. Clin Cancer Res. 2020;26(9):2268-2274. doi:10.1158/1078-0432.CCR-19-3322