Intrathecal Dendritic Cells Under Evaluation for Leptomeningeal Disease in TNBC and HER2+ Breast Cancer


Peter Forsyth, MD, on the investigation of intrathecal dendritic cells for leptomeningeal disease in triple-negative and HER2-positive breast cancer.

Peter Forsyth, MD

Peter Forsyth, MD

A first-in-human phase 1 trial (NCT05809752) is investigating the use of intrathecal dendritic cells primed against HER2/HER3 for the treatment of patients with leptomeningeal disease from HER2-positive or triple-negative breast cancer (TNBC). Along with investigating a novel treatment modality, investigators also hope to gain increased understanding about this complication of breast cancer, according to Peter A. J. Forsyth, MD.

“As treatments for breast cancer improve, we think [the prevalence of leptomeningeal disease] is going to become more of a problem. Therefore, we need to do something about it now,” Forsyth said.

In a poster presentation at the 2024 ASCO Annual Meeting, Forsyth and colleagues outlined the ongoing dose-escalation trial, which is enrolling patients at least 18 years of age with leptomeningeal disease stemming from TNBC or HER2-positive breast cancer. Patients need to have an ECOG performance status of 3 or lower and a life expectancy of at least 8 weeks. Intrathecal dendritic cells are being administered once per week for 12 weeks at 1 of 4 dose levels ranging from 1 x 106 to 5 x 107 dendritic cells.

Safety and the incidence of dose-limiting toxicities are the trial’s primary end points. Secondary end points include the proportion of patients surviving at least 15 weeks; response rates; the association between IFNγ and other Th1 responses; and the amount and activation status of immunocytes and tumor cells in the cerebrospinal fluid.

In an interview with OncLive®, Forsyth elaborated on the phase 1 trial investigating intrathecal dendritic cells in the treatment leptomeningeal disease in patients with HER2-positive breast cancer and TNBC; and expanded on the unmet medical needs stemming from leptomeningeal disease.

Forsyth is the chairman of the Neuro-Oncology Program at Moffitt Cancer Center and professor of oncology at the University of South Florida in Tampa.

OncLive: How prevalent is leptomeningeal disease in patients with breast cancer?

Forsyth: Leptomeningeal disease is a bit uncommon, [found in] maybe 5% of patients. However, we think it's becoming more common as treatments improve, as if there's more time for this to happen [to patients]. Leptomeningeal disease is an important problem [to address] because it is not completely understood, and it is devastating and rapidly fatal, [making it] a huge unmet medical need.

What is the rationale for investigating intrathecal dendritic cells for the treatment of leptomeningeal disease?

This is a first-in-human study, so [intrathecal dendritic cells] haven’t been [investigated in this setting] before, and I don't think there have been other immuno-cellular therapies, administered intrathecally, and certainly not for [leptomeningeal] disease. It is a breakthrough study that is unique. Therefore, we have to proceed carefully and slowly to make sure it's safe and figure out if it's effective.

Leptomeningeal disease, which is a horrible disease, is not well understood. It is an inflammatory disease. Patients are using the innate arm of their immune system to try to fight the tumor, but [the immune system] is doing it ineffectively. Their [immune system] is turning on some natural killer cells and some other innate immune responses, but they don't have the other important thing, which is the adaptive immune response.

We’ve only recently understood [this innate immune response] by looking at cell profiles in mice and women with breast cancer, so we need to add this adaptive arm. [Having only the innate arm] is like trying to fight with one arm tied behind your back. The dendritic cell therapy brings out an adaptive immune response [that could] introduce more effective ways of fighting tumor cells.

What is the design of this first-in-human trial?

It's a standard phase 1, dose-escalation, 3 + 3 design. There's an initial safety cohort at a low dose, and then we are escalating to a total of 4 different doses. We will treat 3 patients [at 1 dose], see how they do, and then escalate to the next level.

[We are enrolling patients with] 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.

What are the next steps for this research?

This is just a safety study, so we can't tell [yet] if it's going to [be efficacious]. [Efficacy] is a secondary end point. We need to do a larger study once we figure out what the [optimal] dose is. We will need a larger number of patients involved and at least a couple other [cancer] centers [involved] because it's a rare disease. We'd have to branch out and work with our friends and collaborators. We will also need to see if there are other things, such as other antibody therapy, that we can add to dendritic cells to improve them.

We’re very hopeful that [dendritic cells] are going to be helpful [for patients with leptomeningeal disease], and we're going to learn a lot more about the disease while we [conduct this trial].

The other thing with leptomeningeal disease is that people have given up hope on it. The first step in thinking about curing a disease is you have to believe you can cure it, and you have to understand it. We need to stop messing around and take this problem seriously, and [we have to] throw everything we have at it. The immuno-cellular therapies are super exciting and very promising. Moffit Cancer Center has a huge immune-cellular therapy program. We want to turn the power of this therapy to [leptomeningeal] disease, which we can now do for the first time.


  1. Forsyth PAJ, Gandhi S, Wilcox J, et al. A first-in-human phase 1 trial of dose escalating intrathecal (IT) dendritic cells (cDC1s) primed against HER2/HER3 in patients (pts) with leptomeningeal disease (LMD) from triple-negative (TNBC) or HER2+ breast cancer (BC). J Clin Oncol. 2024;42(suppl 16):TPS2090. doi:10.1200/JCO.2024.42.16_suppl.TPS2090
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