New method could help relieve side effects of immunotherapy

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Study shows combined blockade of IL-6 and immune checkpoint reduces toxicity while preserving anti-tumor immune response

Researchers at the University of Texas MD Anderson Cancer Center have developed a unique technique to reduce immune system-related secondary events associated with immunotherapy treatment by targeting the cytokine interleukin-6 (IL-6). The study, published in cancer cell on May 9, 2022, establishes a proof-of-concept to combine immune checkpoint blockade with cytokine blockers to selectively suppress inflammatory autoimmune responses.

Although combined immunotherapy with anti-PD-1 and anti-CTLA-4 agents has revolutionized the treatment of several types of cancer, it also has high toxicity rates, which can affect quality of life and lead to discontinuation of treatment. Often, patients whose cancers respond to combination immunotherapy also experience high-grade side effects. Immune-related enterocolitis (irEC), an inflammatory bowel disease, is the most common serious complication.

“We need to overcome immune toxicity, first and foremost, to support patients and reduce their symptom burden,” said lead author Adi Diab, MD, associate professor of melanoma medical oncology. “Second, we know that there are multiple, non-overlapping resistance mechanisms in the tumor microenvironment. In order to build an effective multi-agent immunotherapy regimen, we need to overcome the immune system barrier of toxicity so that patients can continue to receive the optimal treatment.

The translational study analyzed patient tissues, preclinical models, and retrospective data to determine how the IL-6 helper 17 T-cell (Th17) pathway contributes to toxicity and can be inhibited to separate autoresponse. -immune inflammatory antitumor immune response.

Adi Diab University of Texas MD Anderson

Adi Diab, MD, associate professor of melanoma medical oncology and lead study author. Credit: University of Texas MD Anderson

Preclinical Studies Reveal Immunobiology of Immune System-Related Adverse Events

In preclinical models, IL-6 has been linked to resistance to immunotherapy, although the mechanism has not been understood. IL-6 is also linked to a number of autoimmune diseases, and IL-6 blockers are approved for the treatment of rheumatological disorders and other autoimmune diseases.

Comprehensive immune profiling of paired samples of irEC tissue and normal tissue from patients treated with immune checkpoint blockade (12 patients in the observation cohort and 11 patients in the validation cohort) revealed distinct immune signatures in inflamed tissues (where IL-6 and Th17 were up-regulated) compared to normal tissues. Additionally, the IL-6 gene signature was increased in patients whose tumors failed to respond to immunotherapy, but this change was not present in responders.

Based on this observation, the researchers then used several preclinical models to assess the effect of blocking IL-6 on autoimmunity and on the response to anti-CTLA-4 therapy. The combination of an IL-6 blocker with an immune checkpoint inhibitor decreased symptoms of experimental autoimmune encephalomyelitis (EAE) and improved tumor control, indicating that the combination could suppress the inflammatory response and potentially enhance antitumor immunity.

An observational cohort validates the IL-6 strategy, prospective clinical trial in progress

To verify the results, the researchers conducted a retrospective analysis of 31 melanoma patients who were treated with immune checkpoint blockade between January 2004 and March 2021 and also obtained an IL-6 blocker to treat the inflammatory arthritis and other immune system side effects. Patients in the study began receiving IL-6 blockade treatment an average of 3.7 months after experiencing adverse effects, and researchers observed a 74% reduction in symptoms after a median of two months of IL-6 blockade therapy.

Of the 26 patients with an evaluable tumor response before (or at the start of) IL-6 blockade treatment and at follow-up, the best overall response rate to immune checkpoint blockade was 57.7% before the onset of IL-6 blockade and 65.4% after treatment. These clinical results confirmed the preclinical findings, which determined that targeting IL-6 can attenuate adverse events related to the immune system without compromising the efficacy of immunotherapy.

“Cytokine blockers have been well established to block autoimmunity. The novelty of this study brings cytokine targeting to tumor immunity and demonstrates that autoimmunity and antitumor immunity do not necessarily overlap immune responses but can be uncoupled at the cytokine level,” Diab said. “IL-6 is just a cytokine, but this work offers proof of principle to take the science to the next level by targeting multiple cytokines in a multi-layered approach.”

Based on these results, Diab is leading a prospective, investigator-initiated Phase II clinical trial (NCT04940299) to evaluate the safety and efficacy of IL-6 blockade in combination with anti-PD- 1 and anti-CTLA-4 in several different cancers. types.

This study was supported by the Wilkes Family Cancer Autoimmune Research Fund, with additional research support from the American Society of Clinical Oncology/Conquer Cancer Foundation, National Institutes of Health/National Cancer Institute (P30 CA016672, P50CA221703) and from the National Institute of Allergy and Infectious Diseases (K01AI163412). Diab reports research support and advisory board fees from Bristol Myers Squibb.

Reference: “Interleukin-6 Blockade Abrogates Immunotherapy Toxicity and Promotes Tumor Immunity” by Yared Hailemichael, Daniel H. Johnson, Noha Abdel-Wahab, Wai Chin Foo, Salah-Eddine Bentebibel, May Daher, Cara Haymaker, Khalida Wani, Chantal Saberian, Dai Ogata, Sang T. Kim, Roza Nurieva, Alexander J. Lazar, Hamzah Abu-Sbeih, Faisal Fa’ak, Antony Mathew, Yinghong Wang, Adewunmi Falohun, Van Trinh, Chrystia Zobniw, Christine Spillson, Jared K. Burks, Muhammad Awiwi, Khaled Elsayes, Luisa Solis Soto, Brenda D. Melendez, Michael A. Davies, Jennifer Wargo, Jonathan Curry, Cassian Yee, Gregory Lizee, Shalini Singh, Padmanee Sharma, James P. Allison, Patrick Hwu, Suhendan Ekmekcioglu, and Adi Diab, May 9, 2022, cancer cell.
DOI: 10.1016/j.ccell.2022.04.004

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