Could TNF Blocker Cure Immunotherapy-Induced Diabetes?

The anti-inflammatory agent infliximab (Remicade, Janssen) could be a novel treatment for immune checkpoint inhibitor-induced diabetes, a single case study suggests.

Immune checkpoint inhibitors have been hailed as breakthrough cancer treatments, but insulin-requiring diabetes is among a growing list of potentially serious side effects reported for these immunotherapies.

The current report is of such a case of a 53-year-old man who went into diabetes remission by taking infliximab, a tumor necrosis factor (TNF) alpha blocker.

The finding suggests the etiology of diabetes linked to immune checkpoint blockade (ICB) is different from that of type 1 diabetes, Becky Trinh, MD, Division of Endocrinology, Diabetes, and Metabolism, University Hospital Basel, Switzerland, and colleagues, say in their report, published online July 15 in Diabetes Care.

Indeed, in a separate study, recently published in the Journal of Clinical Endocrinology and Metabolism, Venessa H.M. Tsang, MBBS, PhD, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales, Australia, and colleagues followed over 500 patients treated with ICB. Ten patients (1.9%) developed checkpoint inhibitor-associated autoimmune diabetes, which the researchers determined is "distinct from type 1 diabetes."

The fact that ICB-induced diabetes could be cured using infliximab "is of relevance because many patients undergoing ICB treatment for melanoma will have a long-lasting remission, and quality of life is therefore strongly influenced by side effects," Trinh and coauthors say. "It also indicates that some specific patient populations with [diabetes] may particularly benefit from anti-inflammatory treatments," they add.

Trinh told Medscape Medical News, "We recommend discussing the potential benefits and side effects with the treating oncologists and individual patient. Certainly, a larger cohort will clarify what the success rate is, but the chance of diabetes remission speaks in favor of a treatment trial with infliximab in any future cases of ICB-associated diabetes."

Infliximab Reversed Beta-Cell Dysfunction and Insulin Resistance

In the case report by Trinh and colleagues, the patient had received combination ICB with ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab (Opdivo, Bristol-Myers Squibb) to treat advanced melanoma with metastasis to the liver, lung, and lymph nodes.

He experienced a complete metabolic remission of the melanoma.

He also had immune-related colitis requiring treatment with corticosteroids and was also given two doses of infliximab. After tapering the corticosteroids, he was continued on nivolumab for several weeks.

He subsequently developed a seronegative oligoarthritis in his right knee and both ankles, and was treated with local corticosteroid injections but not systemic corticosteroids. The ICB was stopped.

Several days later, he experienced progressive fatigue. Laboratory testing revealed mild hyponatremia, a random blood glucose of 22.3 mmol/L (401 mg/dL), HbA_1c of 11.6% (103 mmol/mol), and C-peptide of 933 pmol/L.

A mixed-meal tolerance test (MMTT) identified both impaired insulin secretion and reduced peripheral insulin sensitivity, along with positive islet cell autoantibodies.

C-reactive protein levels were low, so systemic inflammation was ruled out as a cause of the hyperglycemia.

Steroid-induced diabetes was also deemed unlikely, Trinh told Medscape Medical News, because the last dose of systemic corticosteroid was given more than 6 months before the diabetes diagnosis and the patient's glucose levels were normal while he was receiving corticosteroid.

The patient was started on insulin injections. And because his oligoarthritis had become more active, he was again given infliximab 7 days later.

This led to reversal of both the beta-cell dysfunction and insulin resistance, allowing insulin therapy to be stopped after 46 days. The diabetes remained in remission 2 months after the last insulin injection and infliximab dose.

As of July 2019, the patient's blood glucose remains normal without therapy. He had one recurrent single lung metastasis removed and is now being treated with adjuvant BRAF/MEK inhibitors.

"We report the first successful treatment, to our knowledge, of an ICB-induced [diabetes] with infliximab. In this lean patient, insulin treatment could be stopped, and MMTT indicated a recovery of pancreatic beta-cell function and peripheral insulin sensitivity with consecutive normalization of HbA_1c," Trinh and colleagues write.

While cautioning that "certainly, larger cohorts are needed to determine the success rate," they nonetheless say the current report "advocates for the use of infliximab in patients with ICB-induced [diabetes] to restore beta-cell function and insulin sensitivity."

Checkpoint Inhibitor-Associated Diabetes Is Different From Type 1 Diabetes

In their article, Tsang and colleagues note that "checkpoint inhibitors have made a dramatic impact in oncology, initially for metastatic melanoma but now also for a diverse spectrum of cancers."

They present the clinical biochemical findings of the 10 patients in their cohort who developed diabetes as a result of ICB.

"In contrast to type 1 diabetes, our cohort of patients with checkpoint inhibitor-associated autoimmune diabetes had characteristic features, including acute onset of hyperglycemia within 63 weeks of starting anti-programmed cell death 1 (PD-1) therapy [pembrolizumab or nivolumab alone, in combination with ipilimumab, or either in combination with ipilimumab or placebo]; rapid decline in C-peptide concentrations consistent with sudden beta-cell failure; high glycemic variability in keeping with absence of residual beta-cell function (ie, no honeymoon [period]); and infrequent association with diabetes-associated autoantibodies."

"Our data suggest that, in general, checkpoint inhibitor-associated autoimmune diabetes is a distinct pathophysiologic entity from type 1 diabetes," they note.

The mechanism of checkpoint inhibitor-associated autoimmune diabetes "is not clear although seems likely due to beta-cell auto-inflammation triggered by disruption of normal immune surveillance," they conclude.

Trinh has reported no relevant financial relationships.

Diabetes Care. Published online July 15, 2019. e-Letter

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