Correspondence *Department of Medical Oncology, Dana–Farber Cancer Institute, 44 Binney Street, Boston, MA 02115

Email stephen_hodi@dfci.harvard.edu

The Case

A 63-year-old female presented to her primary physician with numbness and weakness in her left leg, which progressed over several days to involve her entire lower extremities. The patient's medical history included removal of a benign bone tumor as a child and the removal of a squamous cell skin cancer within the few weeks before presentation. There was no patient history of primary melanoma, but her mother and daughter had both had melanoma, which in both cases had been successfully treated by local excision. A spinal MRI scan revealed metastatic disease involving the spinal cord at C5 and T3, and an 8 mm focal-enhancing T1 metastasis. A brain MRI scan revealed four metastases, including a dominant 3.5 cm 2.2 cm 2.7 cm lesion in the right posterior parietal cortex. Since the patient had a symptomatic metastasis in a surgically accessible location, a neurosurgical evaluation was conducted and this determined that function of her legs could be restored by removal of the tumor. In addition, resection of the tumor would allow the associated edema to resolve. The parietal cortex lesion was surgically removed revealing metastatic melanoma. As the patient presented with three brain metastases and no evidence of leptomeningeal disease, she was offered either whole-brain radiation therapy (WBRT), or WBRT plus stereotactic radiosurgery (SRS), or SRS alone. Given the relatively low efficacy of WBRT in melanoma and her reluctance to undergo initial WBRT, SRS alone¹ was used to treat the gross lesions and tumor bed. The patient received radiation to her spine and SRS to the brain lesions. Following radiation, she received temozolomide orally at 200 mg/m² daily on days 1–5 of a 28-day cycle for 3 months. Restaging by chest, abdomen, pelvis, and head and spine MRIs revealed moderate disease progression in the lungs and central nervous system (CNS).

The patient then received compassionate-use ipilimumab (MDX-010, Bristol-Myers Squibb, New York, NY and Medarex Inc. Princeton, NJ), a fully human monoclonal antibody directed against CTLA-4, a key negative regulator of T-cell–mediated immune responses.² (See Supplementary Figure 1 online). Ipilimumab was administered intravenously at 3 mg/kg once every 3 weeks for four doses with maintenance dosing anticipated every 12 weeks. A month after starting ipilimumab treatment, the patient complained of decreased sensation in her left thigh. A repeat spinal MRI revealed slight edema surrounding the previously identified cord metastases. These symptoms subsided over the following 2 weeks without additional intervention while the patient remained under observation. At 3 months after treatment initiation, she began to experience complex partial seizures characterized by confusion, aphasia, gait apraxia, and automatisms (lip smacking and fidgeting). An electroencephalography (EEG) was consistent with interictal activity arising from the left frontal lobe and a brain MRI confirmed moderate edema surrounding the known metastases, with evidence of central tumor necrosis. The patient was treated with celecoxib (200 mg by mouth twice a day) and levetiracetam (1,500 mg by mouth twice a day), which resulted in an immediate and marked improvement in symptoms.

Over the following 3 months, the patient experienced intermittent confusion. Edema surrounding pre-existing CNS tumors was noted (Figure 1) and EEG revealed focal epileptic activity. Dexamethasone was added to the regimen and titrated (4 mg twice daily) to complete the resolution of symptoms. The patient returned to baseline function within 2 weeks of dexamethasone initiation. Several MRI scans of her spine over the following 6 months showed waxing and waning of the edema surrounding known spinal metastases with involution and complete disappearance of tumors in some areas (Figure 2). Her performance status continued to improve, such that she was able to play two rounds of golf each week while previously she had been home bound.

Figure 1 Radiographic changes to melanoma metastases in the brain with administration of CTLA-4 blockade.

Axial MRI images (top row) show T1 hyperintense enhancing metastases in the left frontal lobe and the right occipital lobe, with minimal surrounding edema before treatment with CTLA-4 blockade. Post-therapy images show an increase in the size of the left frontal lobe metastasis, with intense enhancement of the peripheral T1 hyperintense rim. The right occipital metastasis is stable in size. An axial FLAIR image demonstrates significant increase in the T2 prolongation within the frontoparietal white matter. There is increasing mass effect on the left frontal horn. Abbreviation: CTLA-4, cytotoxic T-lymphocyte antigen-4.

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Figure 2 MRI scans of the patient's spine 6 months after treatment with dexamethasone.

(A, B) Radiographic changes to melanoma spinal-cord metastases with the administration of CTLA-4 blockade. Sagital T2 (A) and T1 contrast-enhanced (B) MRI images of the cervicothoracic spine reveal enhancing intraspinal metastases with extensive cord edema before treatment with CTLA-4 blockade. (C, D) Post-therapy T2 (C) and T1 contrast-enhanced (D) MRI images demonstrate complete resolution of the metastases and the accompanying edema. There is mild cord atrophy. Abbreviation: CTLA-4, cytotoxic T-lymphocyte antigen-4.

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At 7 months after the initiation of treatment with ipilimumab, the patient experienced recurrent confusion with evidence of edema and focal seizure activity associated with a left frontal cortical brain metastasis. Surgical removal of this lesion revealed focal areas of necrosis with marked infiltration of the tumor by lymphocytes and an abundance of melanophages throughout (Figures 3 and 4). This concerted immune-mediated response was dominated by CD8⁺ lymphocytes, with a paucity of FoxP3⁺ regulatory cells in the infiltrate of the brain lesion.

Figure 3 Pathological examination of resected brain metastasis following ipilimumab treatment.

All specimens are stained with hematoxylin and eosin. (A) A heavily pigmented tumor with extensive infiltrating lymphocytes and necrosis (10 ). (B) Resected brain metastasis following ipilimumab treatment (40 ) (C) Abundant melanophages (a small subset of which are circled) are present throughout the specimen and are indicative of response to tumor-cell death (40 ) (D) The focus of tumor necrosis (40 ).

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Figure 4 Pathological assessment of immune effector cells associated with melanoma brain metastases following ipilimumab treatment.

Most of the resected brain metastasis following treatment is disrupted by abundant CD8⁺ tumor-infiltrating lymphocytes. Given the heavy pigmentation of the tumor, staining development was performed by use of a blue chromagen (Alkaline Phosphatase Substrate Kit III SK-5300 Vector) (A) CD3⁺ infiltrating lymphocytes (polyclonal DAKO A0452; 20 ) (B) CD3⁺ lymphocytes at a greater magnification (40 ) (C) Occasional CD4⁺ lymphocytes (clone 1F6 Biocare CM1538;circled; 40 ) (D) Abundant CD8⁺-staining cells infiltrating the tumor mass (clone SP16 Biocare CM1548; 40 ) (E) Occasional CD20⁺ cells (clone L26 DAKO M755; circled; 40 ) (F) Rare FoxP3⁺-stained regulatory T cells (polyclonal Abcam 10563; circled; 40 ).

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This patient did not have an objective response as defined by standard Response Evaluation Criteria in Solid Tumors (RECIST), although she experienced stable disease for 7 months after starting ipilimumab and lived for 2 years following her initial presentation.

Discussion of Diagnosis

CNS metastases occur in more than 50% of patients diagnosed with advanced melanoma.³ The prognosis for these patients is poor, with a median survival of 4.4 months and a 5-year survival rate of approximately 3%.⁴ In a retrospective analysis of 702 patients with melanoma who presented with brain metastases, 94.5% had a CNS-related cause of death.⁵ Even when systemic therapy produces responses to visceral metastases, the CNS is a frequent site of tumor recurrence. For example, approximately 50% of patients with metastatic melanoma who initially responded to biochemotherapy regimens developed recurrence or progression in the CNS.⁶ Furthermore, single and multiple brain lesions can be treated with a combination of surgery and radiation, but tumor progression in the CNS is frequent even in heavily pretreated individuals, indicating the presence or recurrence of micrometastases that go undetected and are unaffected by the current standard therapies.

Pathological review of this case revealed a predominantly cytotoxic antitumor immune response in the CNS following CTLA-4 blockade. The tumor destruction associated with this immune response correlated with the radiographic findings. The paucity of regulatory T cells in the infiltrate, as assayed by FoxP3 immunohistochemistry, also supports the mechanism for effective immune recognition of tumor. This is consistent with experimental findings that suggest that anti-CTLA-4 blockade causes a relative decrease in the frequency of regulatory T cells through preferential expansion of cytotoxic CD8⁺ T cells² or by abrogating the function of regulatory T cells.⁷ In this case, the pathological changes in the resected melanoma specimen following treatment suggest that such processes might also be applicable to CNS malignancies despite the inability of most drugs to penetrate the blood–brain barrier. This case provides rare evidence that immunotherapy with ipilimumab to affect CTLA-4 blockade can result in the effective treatment of tumors involving the CNS. Clinical features that should alert the clinician to the possibility of ipilimumab-mediated antitumor immune activity in the CNS are listed in Box 1. The surgical pathology demonstrates the ability of immune effector cells to home to sites of CNS disease and contribute to tumor necrosis and edema; processes that, importantly, were associated with an improved outcome and extended survival in this patient.

Treatment and management

MRI staging of both the brain and spinal cord provides a useful radiographic correlate to the pathology and clinical course. The disease stabilization and performance status resulting from ipilimumab treatment far exceeded the expectations for patients presenting with multiple CNS metastases from advanced melanoma. It is worth noting that although this patient received ipilimumab through a single-patient compassionate protocol at a dosage that had previously demonstrated clinical activity (3 mg/kg), subsequent multicenter phase II and III trials examined ipilimumab at 10 mg/kg for both induction and maintenance therapy.

A significant lymphocytic infiltrate has occasionally been demonstrated in primary tumors of the CNS.⁸ Dendritic-cell vaccination strategies in animal models of melanoma and in patients with glioblastoma multiforme have resulted in the intratumoral infiltration of immune effector cells, thus, suggesting a new way to approach the treatment of CNS malignancies.^{9, 10} Although data are promising, it is becoming apparent that additional problems need to be addressed, such as the role of tumor-infiltrating immune regulatory cells in the CNS.^{11, 12}

An effective, systemic therapy that gives durable responses or disease stabilization simultaneously in CNS and non-CNS sites is needed. The enthusiasm for evaluating immune therapies for these patients, however, has been limited by the postulation/assumption that the CNS is an immune-privileged site. The blood–brain barrier offers mechanical protection and controls molecular transport between the vasculature and CNS.¹³ Even when systemic therapies are effective, the CNS is a frequent site of treatment failure.¹⁴ It is, therefore, not expected that immune components will reach brain metastases successfully and elicit a meaningful response.

Ipilimumab is under investigation to treat several types of cancers, with a particular focus on melanoma. In preclinical murine studies, CTLA-4 blockade using monoclonal antibodies has demonstrated antitumor activity.² Results of early trials in patients with metastatic melanoma show that ipilimumab alone or with other therapies (i.e. vaccines or chemotherapy) is generally well tolerated and results in objective responses and disease stabilization.¹⁵ Pathology analysis from a subset of patients whose pre-existing metastases were biopsied following treatment with ipilimumab revealed infiltrates of CD4⁺, CD8⁺, and CD20⁺ lymphocytes, neutrophils, and extensive (>90%) tumor necrosis.¹⁴ Potential effects of CTLA-4 blockade on melanoma metastases to the CNS have been unclear; however, this case suggests that the antitumor effect may be executed via CNS tumor infiltration by CD8⁺ lymphocytes.

Conclusions

This case describes pathological evidence of immune-mediated inflammation and edema with extensive tumor disruption and evidence of foci of necrosis within the CNS in response to ipilimumab therapy in a patient with advanced melanoma. Investigation of CTLA-4 blockade and other immune therapies to treat CNS metastases should be a focus of further clinical investigation.

Acknowledgments

We thank Rebecca Turner for editorial assistance. Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Subject areas under which this article appears: Immunotherapy