Interleukin-6 blockade could reduce adverse events from immunotherapy
Click Here to Manage Email Alerts
Interleukin-6 blockade appeared effective against immune-related adverse events among a small cohort of patients treated with immune checkpoint inhibitors for melanoma, according to study results published in Cancer Cell.
Rationale and methods
“Immunotherapy with checkpoint inhibitors is currently the best therapeutic strategy for treatment of multiple cancer types. However, durable remission rate with checkpoint inhibitor monotherapy remains low and, therefore, combination strategies for these agents are needed to overcome therapy resistance,” Adi Diab, MD, researcher in the department of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, told Healio.
Yet, the use of combination immune checkpoint inhibitors (ICIs) is limited due to the increased rate of immune-related adverse events, according to Diab.
“These adverse events can increase the patient’s symptom burden and can potentially, although rarely, be fatal,” he said. “In addition, these adverse events are associated with a high treatment discontinuation rate. For example, more than 50% of patients with melanoma receiving combined ipilimumab [Yervoy, Bristol Myers Squibb] plus nivolumab [Opdivo, Bristol Myers Squibb] can develop high-grade toxicities requiring treatment discontinuation. Thus, we recognized that the identification of strategies to treat these toxicities without sacrificing the antitumor immunity to immune checkpoint inhibitor therapy represents a critical unmet need.”
Diab said it is also known that the IL-6/T-helper 17 cells (Th17) pathway plays a major role in pathogenesis of various autoimmune diseases that could manifest clinically within the constellation of immune-related adverse events.
“Therefore, we sought to study its role in immune checkpoint inhibitor-related immune toxicity and then evaluate how IL-6 blockade can impact checkpoint inhibitor tumor immunity,” he said.
Investigators examined patient tissue, preclinical models and retrospective data to determine how the IL-6/Th17 pathway contributes to adverse events and whether the pathway can be inhibited to differentiate the inflammatory autoimmune response from the antitumor immune response.
The retrospective analysis included 31 patients with melanoma (median age, 62 years; 58% men) who received immune checkpoint blockade between January 2004 and March 2021 and IL-6 blockade a median 3.7 months after experiencing toxicities.
Key findings
After a median 2 months on IL-6 blockade therapy, researchers observed a 74% improvement in patient symptoms.
Among the 26 patients with evaluable tumor response before initiation of IL-6 blockade therapy and at follow-up, results showed an overall response rate to immune checkpoint blockade of 57.7% before IL-6 blockade initiation and 65.4% after treatment.
“Our multidisciplinary approach using clinical, preclinical and translational analyses implicated the role of the IL-6/Th17 pathway in both immune checkpoint inhibitor-related autoimmunity and resistance,” Diab said. “Briefly, our data showed a higher expression of IL-6, as well as neutrophil and chemotactic markers in colitis vs. noninflamed intestinal tissue, suggesting the IL-6/Th17 pathway is involved in immune-related adverse event development. We also found the genes upregulated in colitis were not upregulated in responding tumors, suggesting potential mechanistic differences between autoimmunity and tumor immunity. Furthermore, when comparing immune-related colitis in patients treated with anti-CTLA-4 based therapy vs. anti-PD-1 monotherapy, we found that the CD4 Th17 cells with memory phenotype are enriched more in the anti-CTLA-4 group.”
Implications
The study findings indicate that IL-6 blockade can be an effective targeted therapy for immune-related adverse events without dampening the tumor response to ICI therapy, according to Diab. However, prospective clinical trials are needed to further validate these findings, he said.
“We are currently conducting a phase 2, open-label, single-center study to evaluate the use of combination treatment with tocilizumab [Actemra, Genentech] and ipilimumab plus nivolumab as a front-line therapy for patients with solid tumors, including patients with treatment-naive advanced cutaneous melanoma, urothelial carcinoma and EGFR-mutant non-small cell lung cancer after tyrosine kinase inhibitors failure,” he said. “Our primary outcome is the safety and tolerability of the triple therapy, and our secondary outcomes are antitumor efficacy and OS. As an exploratory aim, we are collecting longitudinal tumor, blood and inflamed tissue samples from the study participants to identify predictive biomarkers of toxicity, treatment response and resistance. This trial opened at MD Anderson Cancer Center and is currently accruing. Future prospective studies with longitudinal immune analysis are warranted to compare all treatment options and help improve understanding of how we can effectively decouple auto- and antitumor immunities on cytokine levels, so patients can fully benefit from the efficacy of ICI therapy.”
References:
- Hailemichael Y, et al. Cancer Cell. 2022;doi:10.1016/j.ccell.2022.04.004.
- Targeting interleukin-6 could help relieve immunotherapy side effects (press release). Available at: www.mdanderson.org/newsroom/targeting-interleukin-6-could-help-relieve-immunotherapy-side-effects.h00-159539745.html#. Published May 9, 2022. Accessed June 24, 2022.
For more information:
Adi Diab, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030.
Perspective
Back to Top
James Isaacs, MD
Antibodies blocking PD-1 or CTLA-4 unleash T cells to generate anti-tumor activity and durable tumor control across many cancer types. However, these therapies also trigger immune-related adverse events. Understanding the specific immune pathways and cell subtypes that contribute to toxicity may allow targeted therapy to reduce toxicity without compromising anti-tumor immune activity.
This study takes a critical step forward by evaluating patient samples from checkpoint inhibitor-induced colitis as well as a separate cohort of melanoma tumor biopsies from patients treated with ipilimumab. The authors found that expression of the IL-6 gene and gene signature along with Th17 cells are upregulated in tissues with colitis but not in biopsies from melanoma that has responded to ipilimumab. They further showed in preclinical murine models that blocking IL-6 in combination with anti-CTLA-4 reduces autoimmune encephalomyelitis while improving tumor control. These findings are significant because antibodies blocking IL-6 already are FDA approved and clinically available as therapies to treat autoimmune disease.
Multiple pathways have been implicated as central drivers of checkpoint inhibitor immune-related adverse events. In addition to IL-6 and Th17 cells identified here, targets identified in other studies include tumor necrosis factor. Interleukin-1-beta, myeloid cells and T resident memory cells. It is likely that there will be significant heterogeneity across patients and subtypes of immune-related adverse events.
Biomarker approaches for optimal treatment selection are needed but remain challenging. For example, many inflammatory pathways are not induced until after checkpoint inhibitors have been administered. This may limit the use of a baseline biomarker to guide clinical trial enrollment. The results of forthcoming trials evaluating tocilizumab in combination with checkpoint inhibitors are eagerly awaited to provide translational insights that can further refine our understanding of immune-related adverse events.
Collapse
Click Here to Manage Email Alerts