What Role for Anti-TNFs in Addressing Immune Checkpoint Inhibitor AEs?

While immune checkpoint inhibitors have shown great promise in treating cancer, they are associated with immune-related adverse events (AE), many of which can be severe. One of the most common AEs that leads to discontinuation of immune checkpoint inhibitors is immune-related enterocolitis, or inflammation of the digestive tract.

While high-dose glucocorticoid treatment is recommended to treat this AE, prolonged steroid use is linked with a number of potential complications, and some patients may find it difficult to taper their doses.

Given that anti—tumor necrosis factor (anti-TNF) agents are able to suppress mucosal inflammation, some have posited that these drugs could play a role in mitigating immune-related enterocolitis. Recently, authors from the Massachusetts General Hospital reported on experience with 5 patients with malignancies who were treated with anti-TNF agents and single or combination immune checkpoint inhibitors.¹

All 5 patients had different primary malignancies, including a right vestibular schwannoma and a large bifrontal atypical meningioma, colon cancer, melanoma, metastatic melanoma to the peritoneum and lungs, and cutaneous squamous cell carcinoma with metastasis to the lungs and lymph nodes. The patients were treated with pembrolizumab, ipilimumab and nivolumab (2 patients), ipilimumab only, or cemiplimab.

Each of the 5 patients developed immune-related enterocolitis within 40 days of their first immune checkpoint inhibitor dose, and they all had combined upper and lower gastrointestinal symptoms that led to endoscopy. For all patients, steroids were the first line of treatment as a result of the acute inflammatory changes observed in the gastrointestinal tract, and patients were then treated with infliximab, at a dose of 5 mg per kg, together with their immune checkpoint therapies once cancer therapy resumed, given patients’ difficulty with tapering their steroid doses and because of concerns about recurrences of enterocolitis.

The authors of the report write that, after starting concurrent infliximab, all patients were able to receive their immune checkpoint inhibitors without a recurrence of enterocolitis symptoms. In 3 of the patients, follow-up endoscopies showed resolution of acute inflammatory features.

The authors report that an ongoing phase 1 study is currently evaluating the safety and tolerability of treating metastatic melanoma with immune checkpoint inhibitors given in combination with either infliximab or its fellow anti-TNF agent, certolizumab, which should help add to the body of knowledge about how this treatment strategy may benefit patients.

Additionally, researchers from Spain recently reported that the prophylactic use of anti-TNFs in patients receiving combined nivolumab and ipilimumab may be able to help prevent AEs from ever arising.

The researchers used a mouse model given transferred human peripheral blood mononuclear cells, causing graft-versus-host disease. Treatment with ipilimumab and nivolumab exacerbated the disease. The research team then xenografted human colon cancer cells into the mice.

In mice that were given prophylactic anti-TNF therapy, colitis and hepatitis improved, and, notably, the immunotherapeutic control of their tumors was not compromised.

"We have verified that the prophylactic blocking of TNF before applying immunotherapy avoids adverse effects and improves the response to treatment in these animal models,” said Pedro Berraondo, PharmD, PhD, in a statement discussing the findings. “This allows us to adjust the doses of the medication better and thus achieve a more robust anti-tumor efficacy.”

While the clinical evidence to support this potential treatment approach is limited, said Berraondo, “Our results in the laboratory along with previous clinical experience suggest conducting a clinical trial to test the safety and efficacy of this combined immunotherapy treatment. In fact, we are evaluating a potential clinical trial protocol to study the effect of prophylactic TNF blockade upon treatment with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in humans," he said.

References

1. Badran YR, Cohen JV, Brastianos PK, Parikh AR, Hong TS, Dougan M. Concurrent therapy with immune checkpoint inhibitors and TNFα blockade in patients with gastrointestinal immune-related adverse events. J Immunother Cancer. 2019;7(1):226. doi: 10.1186/s40425-019-0711-0.

2. Perez-Ruiz E, Minute L, Otano I, et al. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature. 2019;569(7756):428-432. doi: 10.1038/s41586-019-1162-y.