New Study Identifies Effective Treatments for Melanoma-Associated Leptomeningeal Disease
In an interview, Vincent Law, of Moffitt Cancer Center, discussed a new study that offers hope for patients with melanoma brain metastasis.
Melanoma: © David A Litman - stock.adobe.com
One obstacle in developing effective treatments for patients with leptomeningeal disease has been the lack of reliable models to study the disease. However, a recent study has addressed this challenge by establishing methods to culture melanoma cells derived from patient spinal fluid samples in both laboratory and preclinical models.
Researchers at the Moffitt Cancer Center were able to utilize these models and screen existing drugs, allowing them to identify several promising candidates. Some of these included ponatinib (Iclusig), sorafenib (Nexavar), ceritinib (Zykadia), and homoharringtonine (HHT).
According to Vincent Law, research associate at Moffitt Cancer Center, the results of this study were promising, with preclinical findings showing significantly extended survival with HHT via intrathecal delivery vs those in the control group.
“Leptomeningeal disease is still a relatively understudied area of cancer because it is what is considered as a rare form of tumor. We are still actively studying the biology of this disease overall, because there is so much that we have not known or has not been uncovered,” explained Law in an interview with Targeted OncologyTM.
In the interview, Law further discusses the background and findings from this study.
Targeted Oncology: Can you discuss what this study focused on?
Law: Our lab primarily focuses on leptomeningeal disease. This is an infiltration of cancer cells from the primary site into the cerebral spinal fluid. These cells embed, expand, and metastasize within the leptomeninges. People diagnosed with leptomeningeal disease generally have a poor prognosis. Overall survival is measured in months, if not weeks. Specifically, we are looking at leptomeningeal disease from breast cancer, lung cancer, and melanoma.
What were the goals of the analysis?
Currently, there is a huge unmet need for treatments for leptomeningeal disease. We are looking at breast cancer, specifically. In our poster today, we are studying the effect of dendritic cells as a cancer therapy to treat patients with breast cancer and leptomeningeal disease. We engineer and process dendritic cells harvested from patients. We then reintroduce these cells to train the patient's immune system to fight the disease. Our poster focuses on our preclinical study and a brief discussion of our phase 1 clinical trial, recently approved by the FDA.
Can you summarize some of your findings and takeaways from this?
In our [preclinical] model, we pulsed dendritic cells from mice with a peptide and re-injected them into the cerebral spinal fluid. The mice tolerated treatment well and responded by eradicating the tumor and prolonging survival. Some mice became cured, extending their lifespan from 2 weeks to 70-90 days. When re-challenged, these mice were resistant to tumor re-inoculation, suggesting the development of an immune response. Single-cell RNA sequencing of the cerebral spinal fluid [CSF] revealed a significant influx of adaptive immune cells, including T and B cells. We believe these cells orchestrate an antitumor response in the CSF environment. We also observed increased levels of pro-inflammatory cytokines, including interferon gamma, TNF-alpha, and IL-18. Interestingly, our phase 1 clinical trial showed a similar increase in pro-inflammatory cytokines, including TNF-alpha and interferon gamma, in treated patients. We are excited about this study and its potential to lead to a cure for leptomeningeal disease.
What are the next steps from this research?
Leptomeningeal disease is still a relatively understudied area of cancer because it is what is considered as a rare form of tumor. We are still actively studying the biology of this disease overall, because there is so much that we have not known or has not been uncovered. In terms of our trial right now, the FDA-approved phase 1 trial is ongoing, which is funded by the [Department of Defense (DoD)]. Hopefully, we will continue moving on this phase 1 trial. If everything goes well, we would like to pursue phase 2, obviously.
But also, [we are] working well in our animal model. We have not yet fully investigated the molecular mechanisms and cellular mechanisms of how our vaccine actually works. So, being able to map these pathways and mechanisms would allow us to better understand how this therapy works and perhaps ought to better optimize and improve the strategy of treating patients with…leptomeningeal disease.
