Can immunotherapy solve the challenges of leptomeningeal disease treatment?
The management of the leptomeningeal disease is complicated with challenges related to the concentration of chemotherapy drugs and the resistance of the tumor to them as well as the limited efficacy and adverse effects of radiotherapy. Immunotherapy provides a viable option to circumvent the limitations of conventional treatment modalities.
This blog looks into the clinical evidence of the efficacy of immunotherapy in leptomeningeal disease in an attempt to answer whether it is ready to provide relief against this devastating disease or not.
What is leptomeningeal disease?
The leptomeningeal disease is a condition characterized by the dissemination of cancerous cells to the leptomeninges (layers of protective tissue around the brain and the spine). The leptomeningeal disease is also referred to as leptomeningeal carcinomatosis, neoplastic meningitis, or carcinomatous meningitis. It is a rare but serious condition that results when cancer has advanced to a stage where the malignant cells set up secondary sites of proliferation in other parts of the body. Any type of cancer can give rise to leptomeningeal disease but the majority of patients have breast cancer, lung cancer, or melanoma as their primary malignancy.
Patients suffer from symptoms of hydrocephalus (raised intracranial pressure) and nerve dysfunction. These symptoms can be headache, seizures, weakness, back pain, abnormal gait, swallowing difficulties, and inability to maintain balance . The leptomeningeal disease is suspected in individuals who present these symptoms in the context of advanced cancer. The diagnostic workup includes imaging studies of the brain and the evaluation of the cerebrospinal fluid.
Current challenges in leptomeningeal disease treatment
The active treatment for leptomeningeal disease consists of radiotherapy and chemotherapy.
1. Radiotherapy: Radiotherapy of various types, such as involved field radiotherapy, whole brain radiotherapy, and craniospinal irradiation, is employed in the management of leptomeningeal disease but all of these modalities have some disadvantages:
Involved-filed radiation therapy is not very effective in diffuse tumors such as leptomeningeal disease, in which the cancer cells are freely floating in the cerebrospinal fluid with some forming clumps of solid masses. It destroys tumor masses and provides local relief but its effects are not long-lasting.
Whole brain radiation therapy is effective against tumor cells spread around the brain. It resolves the symptoms resulting from cerebellar dysfunction but the patients still require management of the tumor cells disseminated in the leptomeninges around the rest of the central nervous system.
Craniospinal irradiation can be effective against the tumor cells floating in the cerebrospinal fluid but it is associated with toxicities.
2. Chemotherapy: The chemotherapy consists of methotrexate, liposomal cytarabine, or thiotepa which can be delivered either directly into the CSF through a lumbar puncture or administered systemically. But both of these delivery routes have their downsides:
The delivery of drugs directly into the leptomeningeal compartment through a lumbar puncture (spinal tap) causes complications in patients already suffering from debilitating symptoms. Furthermore, there is no guarantee that the drug will be evenly distributed without being blocked by the tumor masses .
In systemic delivery, the drugs do not properly penetrate the barrier between the blood and the cerebrospinal fluid. Therefore, high doses are required to achieve adequate concentrations in a leptomeningeal compartment which leads to toxicities.
What is immunotherapy?
Our immune system is constantly on the look for mutated cells. Whenever it spots a malignant cell, it eliminates it to prevent cancer formation. Therefore, for a cancer cell to survive, it must evade the immune response. The cancerous cells do this by expressing certain ligands (a structure that gives a signal to a receptor), such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death-ligand 1 (PD-L1), on their surface which suppress the activation and proliferation of immune cells.
The goal of immunotherapy is to reverse the suppressive actions of cancer on the immune system by helping immune cells recognize cancer cells. It achieves this goal, in part, by blocking the CTLA-4 and PD-L1 ligands using drugs called immune checkpoint inhibitors.
Are immune checkpoint inhibitors ready to take down leptomeningeal disease?
Immune checkpoint inhibitors are relatively novel agents that are proven to be effective in brain metastasis resulting from melanoma, lung, and breast cancers . But leptomeningeal disease patients have traditionally been left out of these studies. Therefore, clinical evidence of immune checkpoint inhibitors for this patient population is scarce.
Recently, a phase 2 clinical trial has become one of a few trials of its kind by focusing on the safety and efficacy of immune checkpoint inhibitors in leptomeningeal disease patients (NCT02939300) . This study enrolled 18 patients from Massachusetts General Hospital and the Dana-Farber Cancer Institute between February 2018 and April 2019. The median age of the patients was 54 years and a majority of them were females. The most common primary malignancy was breast cancer. All the patients were heavily pre-treated as part of care for their primary cancer and systemic disease but none was on an active treatment during the course of the study.
As part of the study, the patients received ipilimumab and nivolumab (immune checkpoint inhibitors) intravenously. According to the reported results of this study:
Eight patients were alive at the 3-month mark after the start of the clinical trial. This overall survival time is greater than that in the historical controls.
Almost all of the patients experienced treatment-related adverse effects. The most common adverse effects were fatigue, fever, anorexia, and rash. Six patients suffered from treatment-related adverse effects that were of grade 3 or higher and in 2 of these patients, the treatment had to be discontinued due to hepatitis and colitis.
Immune checkpoint inhibitors have some activity in leptomeningeal disease patients.
The frequency and severity of adverse effects are a concern and more efforts are needed to diminish the unwanted outcomes of immunotherapy.
A larger clinical trial is required to assess the activity of immune checkpoint inhibitors in leptomeningeal disease arising from a broader set of primary cancer with diverse mutational profiles.
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Brastianos, P.K. et al. 'Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis'. Nature Communications. (2021) 12. DOI: 10.1038/s41467-021-25859-y.