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Immune Checkpoint Inhibitors in Brain Metastases: From Biology to Treatment
Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.
Abstract
Cancer immunotherapy has been a subject of intense research over the last several years, leading to new approaches for modulation of the immune system to treat malignancies. Immune checkpoint inhibitors (anti–CLTA-4 antibodies and anti–PD-1/PD-L1 antibodies) potentiate the host’s own antitumor immune response. These immune checkpoint inhibitors have shown impressive clinical efficacy in advanced melanoma, metastatic kidney cancer, and metastatic non–small cell lung cancer (NSCLC)—all malignancies that frequently cause brain metastases. The immune response in the brain is highly regulated, challenging the treatment of brain metastases with immune-modulatory therapies. The immune microenvironment in brain metastases is active with a high density of tumor-infiltrating lymphocytes in certain patients and, therefore, may serve as a potential treatment target. However, clinical data of the efficacy of immune checkpoint inhibitors in brain metastases compared with extracranial metastases are limited, as most clinical trials with these new agents excluded patients with active brain metastases. In this article, we review the current scientific evidence of brain metastases biology with specific emphasis on inflammatory tumor microenvironment and the evolving state of clinical application of immune checkpoint inhibitors for patients with brain metastases.
KEY POINTS
The inflammatory tumor microenvironment of brain metastases differs from extracranial metastases, as the brain is a highly regulated organ in terms of immune response, and is active in the majority of cases with dense infiltration of tumor-infiltrating lymphocytes.
The blood-brain barrier presents different challenges and unique opportunities for the treatment of patients with brain metastases.
Immune checkpoint inhibitors have shown intracranial activity in early clinical trials for patients with brain metastases from melanoma and non–small cell lung cancer.
Several retrospective case series suggest immune checkpoint inhibitors can be safely combined with radiation therapies.
As the prevalence of brain metastases increases, concerted research in this field of limited knowledge is of essence. Meanwhile, a multidisciplinary approach for the management of brain metastases is recommended.
Brain metastases are a long-known devastating complication of advanced malignancies that lead to substantial morbidity. As patients with metastatic cancer are expected to live longer with newer systemic therapeutic agents and with better and more sensitive imaging studies, it is expected that more patients will be diagnosed with brain metastases. In the past, traditional treatment approaches included surgery or radiation therapy, or a combination of the two. Chemotherapeutic agents were generally used for refractory disease. However, in the last few years, several treatment advances in targeted therapy and immunotherapy have changed the landscape of the management of brain metastases. Recently, the American Society of Clinical Oncology (ASCO) announced cancer immunotherapy as the “advance of the year,”1 and its role in the management of brain metastases is undergoing active investigation. There has been a paucity of research focused on brain metastases; as a result, there are several unanswered questions. In this article, we present the available evidence regarding the interactions between the immune system and brain parenchyma in brain metastases, the clinical application of immune checkpoint inhibitors in the management of brain metastases, and the potential of combining radiation with immune checkpoint inhibitors.
Immune responses in the brain parenchyma are tightly regulated to prevent overwhelming and potentially destroying immune reactions in this organ, which has little recovery capacity.2 Importantly, the brain parenchyma is not an immune privileged organ that actively suppresses any immune response, but, rather, it initiates and regulates immune responses. Therefore, targeting the inflammatory tumor microenvironment of brain metastases as a therapeutic target must consider several unique factors compared with the inflammatory tumor microenvironment of extracranial malignancies.3
Immune escape is an emerging hallmark of cancer.4 A brain metastasis–initiating cell has to facilitate the process of immune escape several times, first during initiation of the primary tumor, then during travel through the bloodstream, and, finally, during the extravasation and metastatic outgrowth process within the brain parenchyma. The process of metastatic spread may actually be supported by the immune system, as tumor-associated macrophages were shown to facilitate intravasation as well as extravasation from the vascular system.5,6 Further, cytokines promote site-specific metastatic behavior as the chemokine pair CXCR4/CXCL12 was shown to promote adhesion of the brain metastasis–initiating cells to brain vessels and further facilitated the migration through endothelial cells.7,8
In established brain macrometastases, the inflammatory tumor microenvironment is composed of the innate immune system, namely microglia and blood-derived myeloid cells/macrophages, and the adaptive immune system, which is mainly represented by T cells.9
The density of microglia in and around human and in vivo brain metastases were shown to be highly heterogeneous.10,11 Importantly, the differences in microglia accumulation were observed early during the process of extravasation in preclinical models, indicating that microglia may be involved in the process of extravasation and survival in the perivascular niche.11 The functions of microglia within the brain metastasis tumor microenvironment include antigen presentation, cytotoxicity via expression of nitric oxide (NO) and superoxide, and phagocytic function.12 Expression of HMGB1 by microglia cells, a factor involved in antigen presentation and activation of the adaptive immune system, was widely observed, indicating that in general the tumor microenvironment is able to alter an adaptive immune response. However, microglia and macrophages were also shown to express immunosuppressive factors like PD-L1.13
Infiltration with T cells or tumor-infiltrating T-lymphocytes (TILs) was shown to be highly heterogeneous, varying from total absence to very dense infiltration.10,14 Therefore, the inflammatory microenvironment of brain metastases differs between patients, showing active tumor-directed function in some, but not all, cases. Here, expression of the immune suppressive factor PD-L1 could be one mechanism whereby cancer cells facilitate an immune escape. PD-L1 tends to have higher expression in NSCLC-derived brain metastases compared with the matched primary tumor.15 Further, the composition of TIL subtypes differs. Infiltration with immune suppressive FOXP3+ TILs, as well as so-called exhausted PD-1+ TILs, has been observed in a large portion of specimens.14 Characteristics of the primary tumor probably influence the T cell response in brain metastases, as a denser TIL infiltration was observed in melanoma-derived brain metastases compared with those that are derived from breast cancer.14 Importantly, patients with brain metastases who present with dense infiltration with effector CD3+, cytotoxic CD8+, or memory CD45RO+ TILs had an improved survival prognosis from diagnosis compared with patients with little or absent infiltration of TILs.14 This finding is well in line with the effect of the inflammatory tumor microenvironment on survival prognosis in extracranial malignancies, as high density of TILs is associated with improved survival prognosis in various malignancies that frequently cause brain metastases, such as triple-negative breast cancer, NSCLC, or melanoma.16-18
Importantly, patients with extracranial metastatic melanoma and an active inflammatory tumor microenvironment, as defined by dense infiltration with TILs, have shown increased response rates to CTLA-4 immune checkpoint inhibitors.19 Further, expression of PD-L1 on tumor cells may be associated with a higher chance of response to a PD-1–axis modulating immune checkpoint inhibitor.20 Therefore, the potential tumor microenvironment preconditions for response to an immune checkpoint inhibitor are present in brain metastases, underscoring the importance of further clinical investigation of immune checkpoint–based therapy strategies in patients with brain metastases.
The inflammatory microenvironment is further influenced by the vascular properties in the brain parenchyma. The blood-brain barrier is composed of endothelial cells with tight junctions and astrocytes. Here, astrocytes are known to facilitate pro-inflammatory as well as anti-inflammatory aspects.21 However, data of the interaction of astrocytes and TILs in the inflammatory microenvironment of brain metastases is yet not available. Further, the vascular endothelium regulates the infiltration of T cells. Presence of so-called high endothelial venules, which are specialized blood vessels for lymphocyte extravasation, in melanoma specimens were shown to be associated with dense infiltration of TILs.22 Although neovascularization is a characteristic of brain metastases, with differing extent between primary tumor types, no functional studies have yet investigated the interaction of the blood-tumor barrier or the blood-brain barrier in the infiltration zone of a brain metastasis concerning their restriction of T-cell infiltration.
The clinical utility of immune-based therapies in the fight against cancer has been a fascinating story with ebb and flow. Historically, melanoma and kidney cancer were the two major malignancies that were thought to be susceptible to immune modulation. Indeed, melanoma has high mutational burden, with production of several neoantigens, making it an ideal candidate for immunotherapy. Interleukin (IL)-2 was one of the first immunotherapeutic agents to be used in melanoma. IL-2 is a cytokine that is produced by human T-lymphocytes and plays a pivotal role in expansion and activation of T cells.23 In the 1990s, high-dose IL-2 was studied in advanced melanoma and renal cell carcinomas with modest success.24 An extracranial complete response rate of 5% was seen, and some patients experienced substantial adverse effects, including death.24 Two single institution retrospective experiences have shown intracranial activity of IL-2; however, because of concerns of vascular leak syndrome and potential life-threatening thrombocytopenia, prospective studies excluded patients with brain metastases.25,26
With the advent of immune checkpoint inhibitors, immunotherapy has made substantial inroads in the management of advanced malignancies. Ipilimumab is a fully human monoclonal antibody against CTLA-4, which plays a pivotal role in downregulating the production of cytotoxic T cells.27 The intracranial activity of ipilimumab was first noted in the post hoc analysis of a phase III trial of ipilimumab with or without gp100 peptide vaccine compared with gp100 vaccine alone.28 This double-blinded randomized trial included 82 patients with asymptomatic central nervous system (CNS) metastases, of whom, 73 had received prior treatment for CNS metastases. Ipilimumab was administered to 61 of the 82 patients; 46 patients also received gp100 and 15 received ipilimumab alone. The hazard ratio (HR) for death in patients with brain metastases was 0.70 (95% CI, 0.41–1.20) in the ipilimumab plus vaccine group compared with 0.76 (95% CI, 0.38–1.54) in the ipilimumab alone group. This led to a single-agent, open-label phase II study of ipilimumab for patients with melanoma-derived brain metastases.29 Ipilimumab was administered at a dose of 10 mg/kg given every 3 weeks as a 12-week induction phase, followed by maintenance therapy every 12 weeks. A total of 72 patients were enrolled across 10 centers in the United States.30 The trials comprised of two cohorts: cohort A included 51 asymptomatic patients with active brain metastases who were not on corticosteroids, and cohort B included 21 patients with symptomatic melanoma-derived brain metastases taking a corticosteroid. A response rate of 18% (nine out of 51 patients) in cohort A and 5% (one out of 21 patients) in cohort B were reported using modified World Health Organization (WHO) criteria, but, when immune-related response criteria were used, the response rate improved to 25% (13 patients) and 10% (two patients) in cohorts A and B, respectively. The median overall survival (OS) was 7.0 months in cohort A and 3.7 months in cohort B. Ipilimumab was well tolerated and no unexpected adverse events were noted. Fatigue, nausea, vomiting, diarrhea, and rash were the common side effects noted in the study. As a part of the expanded access program, CA 184-045, 165 patients with stable brain metastases were treated with 10 mg/kg of ipilimumab. The preliminary results from this study reported a 1-year OS rate of 20%, similar to that reported in the open-label, phase II study.31
Another open-label, single-arm, phase II trial evaluated the combination of ipilimumab and fotemustine in advanced metastatic melanoma with and without brain metastases (NIBIT-M1).32 This Italian study enrolled a total of 83 patients; 20 of whom had asymptomatic brain metastases. Eleven of the 20 patients completed the induction phase of ipilimumab (four doses of 10 mg/kg every 3 weeks). Immune-related disease control was observed in 10 patients; five had undetectable brain lesions and five had stable disease. The median progression-free survival (PFS) in patients with brain metastases was 3.0 months (range, 0 to 10.9 months). Adverse reactions were reported in 18 out of 20 patients with brain metastases. Central nervous system events like intracranial hemorrhage, seizures, and headaches were reported in five patients, all of whom had intracranial disease progression. A 3-year follow-up of this trial was presented at the European Society for Medical Oncology (ESMO) Congress in 2015, and the group with brain metastases had a median OS of 12.7 months (95% CI, 2.7–22.7 months) and a 3-year survival rate of 27.8%.33 With the promising results from the phase II trial, a phase III trial of patients with melanoma-derived brain metastases (NIBIT-M2) is planned.34 The trial was initially designed with two arms; arm A with single-agent fotemustine and arm B with fotemustine and ipilimumab. However, with recent reports of high clinical activity with a combination of ipilimumab and the anti–PD-1 monoclonal antibody nivolumab, the protocol was amended to include a third arm, arm C, with a combination of nivolumab and ipilimumab.35 Table 1 reviews the published studies of immune checkpoint inhibitors in brain metastases.
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Another promising immune checkpoint target is the PD-1/PD-L1 pathway. Anti–PD-1/PD-L1 antibodies such as nivolumab and pembrolizumab have been approved for advanced melanoma, kidney cancer, and NSCLC. All of the early trials of anti–PD-1/PD-L1 agents excluded patients with brain metastases. In 2015, interim results of a single-center, phase II study of pembrolizumab of patients with melanoma and NSCLC with brain metastases was presented at the 2015 ASCO Annual Meeting.36,37 Patients with newly diagnosed asymptomatic or progressing brain metastases who did not require immediate treatment with steroids are being enrolled in this study. By December 2014, 17 patients with metastatic melanoma and 10 patients with NSCLC were enrolled. These patients were treated with 10 mg/kg of pembrolizumab administered every 2 weeks. Among the 12 evaluable patients in the melanoma arm, three were observed to have partial response and two had stable disease with a 6-month OS of 47%. In the NSCLC arm, nine patients were evaluated for response and four had partial response. Only one patient in both arms experienced grade 3 adverse events related to pembrolizumab (liver function abnormalities). The investigators presented updated results at the 16th World Conference on Lung Cancer in September 2015; 18 patients had sufficient follow-up time for response evaluation. The median OS was 7.7 months (95% CI, 3.5 months to not reached).38 These early results appear promising for the utility of pembrolizumab in patients with asymptomatic brain metastases. Another multicenter phase II clinical trial of ipilimumab plus nivolumab for patients with advanced melanoma with brain metastases (NCT02320058) is currently accruing patients.39 This study is planned to treat patients with asymptomatic brain metastases from melanoma with an induction phase of four cycles of 1 mg/kg of nivolumab and 3 mg/kg of ipilimumab every 3 weeks, followed by maintenance therapy of 3 mg/kg of nivolumab every 2 weeks. Table 2 provides a list of other important clinical trials in this setting.
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Radiation therapy has been the cornerstone of treatment for brain metastases. Stereotactic radiosurgery and whole-brain radiation therapy (WBRT) with or without surgery plays a crucial role in the management of symptomatic brain metastases.
Several retrospective single-center case series have shown that stereotactic radiation and ipilimumab can be combined safely in the management of brain metastases derived from melanoma.40-42 The safety of combining nivolumab with stereotactic radiation was reported in a recent single-center study.43 This retrospective report included patients who were treated in the context of a clinical trial of nivolumab for advanced melanoma. Twenty-six patients with brain metastases were treated with stereotactic radiation, with, prior to, or after nivolumab. The combination of nivolumab and stereotactic radiation was well tolerated. Distant intracranial recurrence and OS were improved compared with historical controls treated with radiation alone.
There are three important aspects to combining radiation with immune checkpoint inhibitors:
Can immunotherapy potentiate radiation therapy (radio-sensitizing effect) leading to better intracranial disease control?
Will the combination of radiation therapy and immunotherapy lead to better extracranial disease control (abscopal effect) and, thus, improved OS?
If the radiation potentiates the immunotherapy, what is the best fractionation schedule to achieve the most benefit?
The first question is relatively straightforward, and several clinical trials are currently underway to answer the potential intracranial responses of combining immunotherapy and radiation. The major confounder in this endeavor is the use of steroids. Relatively high doses of steroids have been used with radiation, especially WBRT, to reduce the intracranial edema. The detrimental effect of the concomitant use of steroids and immunotherapy was observed in the phase II trial of ipilimumab for patients with asymptomatic, melanoma-derived brain metastases.29 Since this study, the required steroid dose used with stereotactic radiation therapy has decreased, and they are used often for a shorter duration. In addition, many centers are now moving away from using steroids routinely for all patients with brain metastases.44
This second aspect of combining radiation and immunotherapy, the abscopal effect, is interesting and more challenging to evaluate in clinical trials. It has been well established that radiation causes DNA damage that leads to cell death. However, the interaction of radiation and the immune system is not well understood. Several preclinical data have reported that cancer cells release numerous chemokines and cytokines in response to radiation. The damaged cancer cells have also been shown to upregulate MHC-1 expression, hence increasing the interaction with CD8 T cells.45 In addition, radiation leads to the upregulation of PD-L1 on cancer cells, limiting their interaction with CD8 T cells.46,47 Nevertheless, the activated CD8 T cells can elicit a systemic antitumor effect, thereby leading to reduction in the tumor burden. Methods to reliably produce and potentiate this abscopal effect are a subject of intense research. However, increasing the interaction of CD8 T cells with radiated tumor cells by the use of immune checkpoint inhibitors may enhance the abscopal effect. A retrospective case series tried to evaluate this effect by following the single largest extracranial lesion after stereotactic radiation to the brain metastases and ipilimumab.44
The third aspect of combining radiation and immunotherapy and choosing the preferred fractionation schedule is being evaluated in preclinical models. Single session and fractioned radiation schedules with and without immunotherapy have been tested in a preclinical mouse model.48 TSA breast carcinoma and MCA38 colon cancer mouse models were used to test the various radiation fractionation schemes with and without anti–CTLA-4 antibody, 9H10. The mice were injected with tumor cells at two sites; a primary and a secondary site. They were then randomly assigned to receive radiation to the primary site at three different fractionation schedules (one cycle of 20 Gy, three cycles of 8 Gy, or five cycles of 5 Gy on consecutive days), immunotherapy alone, or a combination of radiation and immunotherapy. Only fractionated radiation with immunotherapy to the primary site produced abscopal effect at the secondary site. However, strong clinical data to support this preclinical model are lacking. Innovative clinical trials are needed to improve our understanding of the interaction of radiation and immunotherapy and the abscopal effect.
In summary, some brain metastases harbor an immune active microenvironment that in theory can be targeted by immune-modulating therapies like immune checkpoint inhibitors. However, a deeper insight of the specific mechanisms in the highly regulated microenvironment of the brain is needed to understand and overcome potential resistance mechanisms. Early results of immune checkpoint inhibitors in clinical trials have shown intracranial activity in brain metastases from melanoma and NSCLC. There are several ongoing clinical trials investigating the role of immune checkpoint blockade in brain metastases. Numerous retrospective case series suggest immune checkpoint inhibitors can be safely combined with radiation. Prospective studies are needed to further confirm the safety of such approaches and define the timing and the dose of the optimal radiation modality.
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc.
Travel, Accommodations, Expenses: Amgen, Roche
No relationship to disclose
Honoraria: GlaxoSmithKline, Roche
Consulting or Advisory Role: AbbVie, Bristol-Myers Squibb, CMC Contrast, Gerson Lehrman Group, GlaxoSmithKline, Mundipharma, Novartis, Roche
Research Funding: Boehringer Ingelheim (Inst), GlaxoSmithKline (Inst), Merck Sharp & Dohme, Roche (Inst)
Travel, Accommodations, Expenses: Bristol-Myers Squibb, GlaxoSmithKline, MSD, Mundipharma, Roche
Stock and Other Ownership Interests: MimiVax, MimiVax
Honoraria: Elsevier, Itamar Medical (I), Prime Oncology
Consulting or Advisory Role: Abbvie, AstraZeneca, Bristol-Myers Squibb, CBT Pharmaceuticals, Kadmon, Monteris Medical, VBI Vaccines
Research Funding: AstraZeneca, Boehringer Ingelheim, Lilly/ImClone, Novartis, Novocure, Spectrum Pharmaceuticals, TRACON Pharma
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