Experimental Treatments for Leptomeningeal Metastases From Solid Malignancies

Solmaz Sahebjam, MD; Peter A. Forsyth, MD; Keiran S. Smalley, PhD; Nam D. Tran, MD, PhD

Disclosures

Cancer Control. 2017;24(1):42-46. 

In This Article

Immunotherapies

Checkpoint Inhibitors

Antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD1) have significant activity in extracranial metastatic melanoma. Anti-PD1 and anti–programmed cell death ligand 1 (PD-L1) antibodies have been approved for the treatment of metastatic melanoma, NSCLC, and renal cell carcinoma and are showing promising results in several other tumor types.

Two prospective, phase 2 trials have shown the efficacy of ipilimumab, an anti-CTLA-4 antibody, among patients with melanoma-associated brain metastasis.[32,33] In a phase 2 study by Margolin et al,[33] ipilimumab monotherapy resulted in a CNS response rate of 16%; a median overall survival of 7 months was observed in those with symptomatic brain metastases.[33] At present, multiple studies are investigating the efficacy of anti-PD-1/PD-L1 antibodies in patients with brain metastases (NCT02320058, NCT02374242, NCT02621515).

However, there are very limited data available in use of these antibodies in patients with leptomeningeal metastasis. In a case report by Bot et al,[34] a patient with melanoma-associated leptomeningeal metastasis received whole-brain radiotherapy (5 times 4 Gy) followed by 4 courses of ipilimumab 3 mg/kg every 3 weeks. Complete clinical and radiological responses were observed; the patient survived for more than 1.5 years.[34] At this time, no report has been published on the use of other immune checkpoint inhibitors in patients with leptomeningeal metastasis. Thus, future studies are required to assess the efficacy of these antibodies alone or in combination with other treatment strategies in patients with leptomeningeal metastasis.

Intrathecal Interleukin 2

Few data have been published on intrathecal interleukin 2 (IL-2) therapy. One study reported on 42 participants with melanoma-associated leptomeningeal metastasis who were treated with 1 to 5 doses of intrathecal IL-2 every week for 4 weeks, followed by weekly injections for 4 weeks, and then every other week.[35] The study patients continued to receive single-injection maintenance doses every 1 to 3 months. A median survival rate of 9.1 months (range, 0.7–86.2) was reported, and 16% of study patients had an overall survival of more than 24 months.[35] The authors reported that severe cases of increased intracranial pressure (an adverse event of treatment) requiring frequent CSF removal were observed.[35] Although this single-institution study is encouraging, more data are needed to confirm the efficacy of this treatment strategy.

Intrathecal Tumor-Infiltrating Lymphocyte Therapy

Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes (TILs) has emerged as a promising therapy for advanced solid tumors. TIL therapy has resulted in response rates of approximately 50% in patients with refractory melanoma.[36] However, few data are available on the intrathecal administration of TILs in patients with leptomeningeal metastasis.[37,38] Glitza et al[37] have reported that intrathecal autologous TILs in combination with intrathecal IL-2 were safe and feasible in an individual with refractory leptomeningeal metastasis from melanoma whose disease had progressed after monotherapy with intrathecal IL-2. This patient received 3 doses of intrathecal TILs (0.3 × 109 cells, 1.0 × 109 cells, and 3.0 × 109 cells) 1 week apart; the TILs consisted of 96% CD8+ T cells.[37] Injections of TILs were well tolerated. On days 1 and 4 after intrathecal TILs, intrathecal IL-2 (1.2 million U) was administered.

Intrathecal IL-2 was associated with nausea, vomiting, headache, chills, and transient changes in mentation requiring the serial removal of CSF due to elevated intracranial pressure.[37] The radiographic stabilization of leptomeningeal metastasis was observed after intrathecal TIL therapy; however, the therapy did not control the parenchymal brain metastases, which progressed approximately 3 months following therapy.[37]

Conclusions

Leptomeningeal metastasis is a major medical complication of systemic cancer that has become more com mon as major advances are made in cancer treatments.

Paradoxically, our understanding of the mechanisms of the development and biology of leptomeningeal metastasis is poor. The incidence of leptomeningeal metastasis is likely to continue to increase due to improved overall survival of patients with cancer and because of more effective systemic treatments with limited penetrance into the central nervous system. As such, effort should be made to develop novel molecules to improve central nervous system penetration and to optimize drug-delivery methods. Patients with leptomeningeal metastasis are generally excluded from clinical trials, thereby limiting the systematic assessment of novel therapies in this subgroup of patients with poor prognoses. Retrospective analyses involving a heterogeneous group of patients can provide information on possible treatment options that may be used for the treatment of patients with leptomeningeal metastasis; however, no significant conclusions about safety and predicted responses can be drawn with the data currently available. Moving forward, every effort should be made to enroll patients with leptomeningeal metastasis into trials investigating novel agents with the potential to penetrate the blood–brain barrier. The issues of the relatively poor prognosis and the complexity of assessing responses in this patient population may be further addressed by designating specific cohorts for patients with leptomeningeal metastasis from tumor types of interest.

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