Dr Forsyth on a Phase 1 Study Evaluating Intrathecal cDC1s in Leptomeningeal Disease

"We are lucky that we have seen people quickly and early, so they're still in pretty good shape. Sometimes when people have this disease, it's too advanced by the time you see them or by the time they get the appropriate care, because it's hard to recognize this disease. It's a huge challenge."

Peter Forsyth, MD, chairman, Neuro-Oncology Program, Moffitt Cancer Center; professor of oncology, the University of South Florida, discusses the design of a first-in-human phase 1 trial (NCT05809752) evaluating HER2/HER3–targeted dose-escalating intrathecal dendritic cells in patients with leptomeningeal disease from triple-negative breast cancer (TNBC) or HER2-positive breast cancer.

This ongoing trial employs a standard 3 + 3 dose-escalation design, with an initial safety cohort at a low dose and escalates to 4 dose levels, Forsyth begins. Patients will receive intrathecal dendritic cells weekly for 12 weeks, with doses ranging from 1 x 10⁶ to 5 x 10⁷ cells. To enroll onto the study, patients must be 18 years of age or older and have leptomeningeal disease from TNBC or HER2-positive breast cancer, an ECOG performance status of 3 or lower, and a life expectancy of at least 8 weeks, he says.

Safety and dose-limiting toxicities are the primary end points, Forsyth continues. Secondary end points include survival beyond 15 weeks, response rates, immune response markers such as IFNγ, and the presence and activation status of immunocytes and tumor cells in cerebrospinal fluid, he details. Early data from the study were presented at the 

The trial benefits from early patient recruitment, enabling treatment at a less advanced disease stage, Forsyth notes, adding that this is critical given the challenges of recognizing and managing leptomeningeal disease promptly.

Overall, this marks the first study exploring intrathecal immune cellular therapy specifically for leptomeningeal disease, a rare and challenging condition caused by cancer spreading to the membranes surrounding the brain and spinal cord. Continued data read out from this trial could provide valuable insights into the safety and efficacy of immune cellular therapy in this high-need population.

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Peter Forsyth, MD, discusses the design of a first-in-human phase 1 trial evaluating HER2/HER3–targeted intrathecal dendritic cells in leptomeningeal disease.
 

Dr Forsyth on the Potential Utility of Intrathecal cDC1s in Leptomeningeal Disease

Peter Forsyth, MD, chairman, Neuro-Oncology Program, Moffitt Cancer Center; professor of oncology, the University of South Florida, discusses next steps for the investigation of dose-escalating intrathecal dendritic cells (cDC1s) targeting HER2/HER3 in patients with leptomeningeal disease.

, Forsyth and colleagues presented information on a first-in-human phase 1 trial (NCT05809752) that is evaluating this intrathecally administered immune cellular therapy in patients with leptomeningeal disease from triple-negative breast cancer (TNBC) or HER2-positive breast cancer. This study is the first to explore an immune cellular therapy delivered intrathecally specifically for leptomeningeal disease, a condition characterized by the spread of cancer to the membranes surrounding the brain and spinal cord.

The trial focuses primarily on safety, which means that efficacy outcomes are not yet clear and will only be determined as a secondary end point, Forsyth clarifies. The optimal dosing still needs to be identified, and this will require further research with a larger cohort of patients, he adds. Given the rarity of leptomeningeal disease, expanding the study to include additional cancer centers and collaborating with other institutions will be necessary to enroll more patients and gather comprehensive data, Forsyth explains.

Forsyth emphasizes the potential for dendritic cells in the management of leptomeningeal disease, expressing optimism about the therapy’s effects. Although this study is an initial step, adding other therapeutic agents, such as antibody therapies, to the dendritic cells may enhance their efficacy, Forsyth says. This approach underscores a broader strategy to innovate and intensify treatments for leptomeningeal disease.

The first step towards curing this disease is a commitment to understanding and addressing it with serious, dedicated efforts, Forsyth argues. He stresses the importance of leveraging the field of immune-cellular therapies, noting that Moffitt Cancer Center’s substantial program in this area positions them well to tackle leptomeningeal disease with new vigor. The ability to apply this potent therapeutic approach specifically to leptomeningeal disease for the first time marks a hopeful new chapter in the fight against this challenging condition, he concludes.

Peter Forsyth, MD, discusses the evaluation of intrathecal dendritic cells for patients with TNBC/HER2-positive leptomeningeal disease.
 

Dr Forsyth on Leptomeningeal Disease in HER2+ Breast Cancer and TNBC

Peter Forsyth, MD, chairman, Neuro-Oncology Program, Moffitt Cancer Center; professor, oncology, the University of South Florida, discusses the importance of evaluating leptomeningeal disease in a first-in-human phase 1 trial (NCT05809752) of dose-escalating intrathecal dendritic cells (cDC1s) targeting HER2/HER3 in patients with triple-negative breast cancer (TNBC) or HER2-positive breast cancer.

, Forsyth and colleagues delved into the topic, presenting background on the first-in-human trial investigating dose escalating cDC1s primed against HER2/HER3 in leptomeningeal disease from triple-negative or HER2-positive breast cancer.

Leptomeningeal disease, though relatively uncommon, affects approximately 5% of patients, Forsyth begins. However, the incidence of this complication appears to be on the rise, Forsyth says. This increase is partly due to improvements in systemic treatments for cancer, which allow patients to live longer, giving more time for this condition to develop, he reports. Leptomeningeal disease is a significant concern because it is poorly understood, devastating, and rapidly fatal, making treatments for it a major unmet medical need, Forsyth explains. As breast cancer treatments continue to improve, the incidence of leptomeningeal disease may also increase, underscoring the urgency of addressing it now, he adds.

This study represents a significant milestone as it is the first of its kind—a first-in-human study of an immune cellular therapy administered intrathecally specifically for leptomeningeal disease, Forsyth expands. Due to its pioneering nature, the study is proceeding with caution to ensure safety and to determine the therapy’s effectiveness, Forsyth elucidates, noting that this careful approach is essential given the novelty and potential impact of the treatment.

Leptomeningeal disease is becoming more prevalent due to extended patient survival from improved cancer treatments, but it remains a critical and poorly understood medical issue, he continues. The innovative first-in-human study of intrathecal immune cellular therapy offers hope, but it requires meticulous progress to confirm both safety and efficacy, Forsyth concludes.

Peter Forsyth, MD, discusses the importance of evaluating leptomeningeal disease caused by TNBC and HER2+ breast cancer.

Peter Forsyth, MD, discusses a study of intrathecal dendritic cells in patients with leptomeningeal disease from TNBC or HER2-positive breast cancer.

Dr Forsyth on the Investigation of Intrathecal Dendritic Cells for HER2+/TNBC Leptomeningeal Disease

Peter Forsyth, MD, chairman, Neuro-Oncology Program, Moffitt Cancer Center; professor of oncology, the University of South Florida, discusses the rationale for conducting a first-in-human phase 1 trial (NCT05809752) of dose-escalating intrathecal dendritic cells (cDC1s) targeting HER2/HER3 in patients with leptomeningeal disease from triple-negative breast cancer (TNBC) or HER2-positive breast cancer.

Leptomeningeal disease is a challenging and poorly understood condition, characterized by an inflammatory response, where patients utilize the innate immune system to fight the tumor, Forsyth begins. Although they activate natural killer cells and other innate immune cells, these patients lack a robust adaptive immune response, he notes. Recent insights from single-cell analysis of cell profiles in murine models and human studies, particularly in breast cancer, suggest the necessity of incorporating an adaptive immune response to improve treatment outcomes, Forsyth explains.

This single-arm, non-randomized dose escalation multicenter study was designed to establish the safety of administering intrathecal cDC1s in patients with leptomeningeal disease as well as associations between clinical outcomes & translational cerebrospinal fluid (CSF) studies. This includes single-cell RNA sequencing and cytokine/chemokine arrays, Forsyth states.

The study was supported by preclinical data from murine studies, which demonstrated that cDC1 was safe to be administered intrathecally and produced a Th1-associated adaptive response that cured most mice with HER2-positive leptomeningeal disease and prevented disease recurrence. Accordingly, it was hypothesized that this dendritic cell therapy could increase adaptive immunological responses in the CSF, potentially introducing more effective mechanisms for combating tumor cells, Forsyth says.

The ongoing study will enroll patients at least 18 years of age with HER2-positive disease or TNBC, cytologic or MRI diagnosis of leptomeningeal disease, prior exposure to definitive radiotherapy, and an ECOG performance score of 2 or less. The study's primary end point is to determine the safety and dose-limiting toxicities (DLT) of intrathecal cDC1. Key secondary end points included the proportion of patients surviving at 15 weeks or greater; the association between IFNy and Th1 responses in CSF and serum as well as clinical efficacy outcomes; the amount and activation status of immunocytes or tumor cells in the CSF; and response rates for non–central nervous system tumors according to RANO-LM and RECIST criteria. Patients will receive intrathecal cDC1s once a week for 12 weeks at 1 of 4 dose levels until disease progression, a DLT, or patient withdrawal.

Peter Forsyth, MD

Articles

Dr Forsyth on a Phase 1 Study Evaluating Intrathecal cDC1s in Leptomeningeal Disease

Dr Forsyth on the Potential Utility of Intrathecal cDC1s in Leptomeningeal Disease

Dr Forsyth on Leptomeningeal Disease in HER2+ Breast Cancer and TNBC

Dr Forsyth on the Investigation of Intrathecal Dendritic Cells for HER2+/TNBC Leptomeningeal Disease