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Novel immunotherapy delivery approach safe and beneficial for some melanoma patients with leptomeningeal disease
A novel approach to administer intrathecal (IT) immunotherapy (directly into the spinal fluid) and intravenous (IV) immunotherapy was safe and improved survival in a subset of patients with leptomeningeal disease (LMD) from metastatic melanoma, according to interim analyses of a led by researchers at Â鶹ӳ» MD?Anderson Cancer Center.
The study, published today in , represents the first-in-human trial of concurrent IT and IV nivolumab (anti-PD-1) in melanoma patients with LMD. Across 25 patients, the median overall survival (OS) was 4.9 months, with OS rates of 44% at 26 weeks and 26% at 52 weeks. Four patients survived to 74, 115, 136 and 143 weeks after their first IT dose, which is significantly longer than expected.
¡°This represents a major path forward for our patients, as there is a crucial unmet clinical need for better treatments for patients with LMD,¡± said corresponding author , associate professor of Melanoma Medical Oncology. ¡°We are encouraged by these preliminary results for a disease that has been notoriously difficult to study due to its highly aggressive nature. This approach is safe, and we¡¯re seeing a small subset of our patients who have had outstanding results, so we hope to learn from each and every one of them.¡±
Leptomeningeal disease is a complication of cancer that occurs when cancer cells from primary tumors migrate into the cerebrospinal fluid (CSF) and leptomeninges, the outer lining of the brain and spinal cord. These cells can quickly spread throughout the CSF and cause a wide variety of neurological symptoms. Roughly 10% of patients with stage IV melanoma will be diagnosed with LMD, which also commonly derives from metastatic lung cancer and breast cancer.
There is no cure for LMD, but treatments such as targeted therapy and immunotherapy may improve quality of life. While immune checkpoint inhibitors are beneficial in patients with metastatic melanoma, little is known about their potential use for treating LMD.??
Intrathecal administration has been studied in other settings. A previous by Glitza Oliva and colleagues at MD Anderson demonstrated that IT administration of interleukin-2 in patients with LMD had encouraging results but was associated with serious side effects. This new study showed that injecting nivolumab directly into the spinal fluid increases its concentration within the CSF, since these antibodies cannot otherwise easily penetrate the blood-brain barrier
The current trial enrolled 25 patients with a median age of 43 and all but two had received prior systemic therapy, including immune checkpoint inhibitors (84%), BRAF/MEK inhibitors (64%) and chemotherapy (12%). The dose-expansion cohort evaluated four doses of IT nivolumab concurrent with a flat dose of IV nivolumab.
The drug was well tolerated at the highest IT nivolumab dose, with only mild grade 1 or 2 side effects and no dose-limiting toxicities. The most common treatment-related adverse events were nausea, dizziness and vomiting.
¡°Until recently there have been limited resources to develop clinical trials in this space, but we owe it to patients with very challenging diseases to push the unknown and to advocate for them when they don¡¯t have many options,¡± Glitza Oliva said. ?¡°We are optimistic that these results, along with further clinical trials, will lead us to a better understanding of LMD and, ultimately, more effective ways of helping our patients.¡±
Recently, the study completed enrollment for the dose-expansion cohort; analysis is underway to provide an opportunity for further insights. Ongoing research will seek to identify biomarkers that may predict patients most likely to benefit from this treatment approach.
This work was supported by Bristol-Myers Squibb Foundation, Inc. Additional funding was provided by the National Cancer Institute (1P50CA221703-01A1), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and MD Anderson¡¯s Moon Shots Program?. A full list of collaborating authors and their disclosures can be found with the full paper .
Targeting interleukin-6 could help relieve immunotherapy side effects
Researchers at Â鶹ӳ» MD Anderson Cancer Center have identified a novel strategy to reduce immune-related adverse events from immunotherapy treatment by targeting the cytokine interleukin-6 (IL-6). The study, published today in , establishes a proof of concept for combining immune checkpoint blockade with cytokine blockers to selectively inhibit inflammatory autoimmune responses.
While combination immunotherapy with anti-PD-1 and anti-CTLA-4 agents has revolutionized treatment for multiple cancer types, it also has high toxicity rates, which can affect quality of life and lead to treatment discontinuation. Often, patients whose cancers respond to combination immunotherapy also experience high-grade side effects. Immune-related enterocolitis (irEC), an inflammatory bowel condition, is the most common serious complication.?
¡°We need to overcome immune toxicity, first and foremost, to support patients and reduce their symptom burden,¡± said senior author , associate professor of Melanoma Medical Oncology. ¡°Secondly, we know that there are multiple, non-overlapping mechanisms of resistance in the tumor microenvironment. In order to build an effective multi-agent immunotherapy regimen, we have to overcome the barrier of immune-related toxicity so that patients can continue receiving the optimum treatment.¡±
The translational study analyzed patient tissue, preclinical models and retrospective data to determine how the IL-6 T-helper 17-cell (Th17) pathway contributes to toxicity and can be inhibited to separate the inflammatory autoimmune response from the antitumor immune response.
Preclinical studies reveal immunobiology of immune-related adverse events
IL-6 has been associated with immunotherapy resistance in preclinical models, but the mechanism was not well understood. IL-6 also is associated with several autoimmune diseases, and IL-6 blockers are approved to treat rheumatologic disorders and other autoimmune conditions.
Comprehensive immune profiling of matched samples of irEC tissue and normal tissue from patients treated with immune checkpoint blockade (12 patients in the observation cohort and 11 in the validation cohort) revealed distinct immune signatures in the inflamed tissue (where IL-6 and Th17 were upregulated) compared to normal tissue. Furthermore, the IL-6 gene signature was upregulated in those whose tumors did not respond to immunotherapy, but the increased levels were not seen in responders.
Based on this observation, the researchers then used several preclinical models to evaluate the effect of an IL-6 blockade on autoimmunity and on response to anti-CTLA-4 therapy. The combination of an IL-6 blocker with immune checkpoint inhibitor decreased experimental autoimmune encephalomyelitis (EAE) symptoms and improved tumor control, indicating that the combination could suppress inflammatory response and potentially enhance antitumor immunity.
Observational cohort validates IL-6 strategy, prospective clinical trial in progress
To validate the findings, the researchers performed a retrospective analysis of 31 patients with melanoma who were treated with immune checkpoint blockade between January 2004 and March 2021 and also received an IL-6 blocker to treat inflammatory arthritis and other immune-related adverse events. Patients in the cohort received IL-6 blockade a median of 3.7 months after beginning to experience side effects, and the researchers noted a 74% improvement in symptoms after a median of two months on IL-6 blockade therapy.
Of the 26 patients with evaluable tumor response before (or early in) IL-6 blockade therapy and at follow-up, the best overall response rate to immune checkpoint blockade was 57.7% before IL-6 blockade initiation and 65.4% after therapy. These clinical results supported the preclinical findings, which determined that targeting IL-6 can alleviate immune-related adverse events without compromising the efficacy of immunotherapy.
¡°Cytokine blockers have been well established to block autoimmunity. The novelty of this study is bringing cytokine targeting to tumor immunity and demonstrating that autoimmunity and antitumor immunity are not necessarily overlapping immune responses but can be decoupled at the cytokine level,¡± Diab said. ¡°IL-6 is only one cytokine, but this work offers proof of principle for taking the science to the next level by targeting multiple cytokines in a multi-layered approach.¡±
Based on these results, Diab is leading an investigator-initiated Phase II prospective clinical trial () to assess the safety and efficacy of IL-6 blockade in combination with anti-PD-1 and anti-CTLA-4 therapy in several different cancer types.
This study was supported by 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 National Institute of Allergy and Infectious Diseases (K01AI163412). Diab reports research support and advisory board fees from Bristol Myers Squibb. A full list of co-authors and disclosures is available in the .