Selective inhibition of autoimmune exacerbation while preserving the anti-tumor clinical benefit using IL-6 blockade in a patient with advanced melanoma and Crohn’s disease: a case report

Checkpoint inhibitor (CPI) therapies targeting PD-1 and CTLA-4 have improved survival in patients with metastatic melanoma [1]. Immune-related adverse events (irAEs) are the most common toxicity associated with CPI therapies. IrAEs can affect any organ and result from immune dysregulation targeting normal tissue. Resultantly, patients with pre-existing autoimmunity are routinely excluded from CPI clinical trials for fear of exacerbating their underlying autoimmune condition and have limited treatment options. A notable, recently reported small retrospective review of 30 patients with pre-existing autoimmunity and advanced melanoma treated with ipilimumab (anti-CTLA-4 antibody) demonstrated that 27 % developed an autoimmune exacerbation and 33 % developed conventional grade 3–5 irAEs [2] including death. In specific relevance to this case, six of those patients had inflammatory bowel disease and two of them experienced a grade 3–5 irAE. Therefore, determining how to safely deliver immunotherapies to this unique population without exacerbating their autoimmune condition poses a significant clinical challenge and remains an unmet medical need.

Previous studies report Th-17, a helper T cell subset that releases interleukin-17 (IL-17), as a key mediator of many autoimmune diseases, including inflammatory bowel disease and CPI-induced colitis [3‐5]. Importantly, IL-6 plays an essential role in inducing Th-17 from naïve CD4⁺ T cells [6]. Because of this, there has been recent interest in targeting this differentiated T cell pathway as novel therapy for autoimmunity [3]. In addition, IL-6 blockade has shown efficacy in reversing cytokine release syndrome, a clinical by-product of excessive immune activation seen with adoptive T cell therapies [7, 8], and has also shown preliminary efficacy against Crohn’s disease in an early pilot trial [9]. Here, we report a case in which pembrolizumab (anti-PD-1 antibody) was co-administered with tocilizumab, an anti-IL-6 receptor antibody that is FDA-approved for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, and polyarticular juvenile rheumatoid arthritis, in a patient with concomitant advanced melanoma and refractory Crohn’s disease. The patient showed a significant, durable antitumor response with limited Crohn’s disease exacerbation. This suggests that anti-PD-1 therapies, when combined with selective immune inhibitors, can have clinical benefit while possibly delaying autoimmune exacerbation in patients with concurrent advanced melanoma and Crohn’s disease.

A 49-year-old woman with history of severe, refractory Crohn’s disease was diagnosed with stage IIA cutaneous left shoulder melanoma (Breslow thickness 2.8 mm without ulceration) in 2013. She previously had experienced multiple Crohn’s-related fistulas and required anti-TNF alpha therapy. She underwent wide local excision with sentinel lymph node biopsy showing no residual melanoma and was then placed on surveillance. In January 2015, she developed multiple extremity skin nodules and presented to our center. On presentation, her Crohn’s disease was managed with immunosuppressive therapy including 6-mercaptopurine and low-dose oral prednisone. Her Crohn’s disease was under moderate control and she experienced only mild diarrheal symptoms. Biopsies confirmed metastatic melanoma and mutational analyses revealed wild-type BRAF, NRAS, and c-KIT. Staging evaluation revealed multiple brain, liver, and lung metastases. She underwent stereotactic brain radiosurgery and initiated chemotherapy. Frontline anti-PD-1 or anti-CTLA-4 therapies were not chosen over concerns about exacerbating her Crohn’s disease (anti-PD-1 therapies are notably associated with Th-17 induction [10]). In May 2015, restaging imaging showed progressive brain and multi-organ metastases after receiving two cycles of chemotherapy.

She then initiated whole brain radiotherapy immediately followed by concurrent pembrolizumab (administered IV at 2 mg/kg every 21 days) and tocilizumab (administered IV at 8 mg/kg IV every 21 days) in July 2015 after discontinuing her previous immunosuppressive regimen. Anti-TNF agents and corticosteroids were avoided over concerns about possibly abrogating the anti-tumor response to anti-PD-1 agents, a phenomenon seen in a previous clinical trial that evaluated ipilimumab and corticosteroids in patients with metastatic melanoma to the brain [11]. After two treatment doses, significant anti-tumor responses were seen in the brain, liver, lung, and subcutaneous lesions without clinical evidence of Crohn’s disease exacerbation. Peripheral blood analysis demonstrated an expected increase in IL-6 but without a significant increase in IL-17, suggesting possible suppression of Th-17 induction (Fig. 1). Interestingly, tocilizumab did not inhibit the effector CD4⁺ or CD8⁺ T cells as demonstrated by immune phenotyping.

Sixteen weeks after initiating therapy, she presented with an intra-abdominal abscess requiring drainage and antibiotics. We discontinued pembrolizumab and tocilizumab over concerns for possible Crohn’s disease exacerbation and initiated adalimumab, an anti-TNF monoclonal antibody. She subsequently recovered uneventfully. In January 2016, despite being off systemic therapy for 3 months, restaging evaluation showed near complete response of all metastatic sites, including the brain (Fig. 2). Pembrolizumab was then re-started along with concurrent adalimumab and her most recent imaging in March 2016 showed complete response to therapy.

This case illustrates that co-administration of anti-PD-1 with anti-IL-6R in patients with advanced melanoma and Crohn’s disease can be well tolerated and may attenuate or delay autoimmune exacerbation without impacting a positive anti-tumor effects. Because this is a report of one patient only, the results described are purely descriptive and we are unable to draw any definitive conclusions about the impact of this intervention on disease-specific outcomes. In summary, the IL-6 - Th-17 - IL-17 pathway may play a pathogenic role in mediating the irAEs and/or autoimmune exacerbations of patients with an underlying autoimmune disease treated with immunotherapy and deserves further study.