Systemic Immunotherapy for the Treatment of Brain Metastases
Background
Significant progress has been made in the treatment of selected malignancies with immune-modulating antibodies. Phase III trials of anti-CTLA-4 in melanoma and anti-PD-1 in melanoma, renal cell carcinoma (RCC), and non-small cell lung cancer (NSCLC) showed improved overall survival (OS) compared to standard therapies (1–5). As a result, immune checkpoint inhibitors are now approved for the treatment of these diseases. Blockade of CTLA-4 (ipilumimab and tremelimumab), PD-1 (nivolumab, pembrolizumab, pidilizumab and others), and PD-L1 [BMS 936559 (6), durvalimumab (7), and atezolizumabes (8–11)] can produce durable responses in patients with metastatic cancer. Clinical trials with these agents, alone and in combination, are ongoing. Moreover, additional immune checkpoint modulators are in pre-clinical and clinical development. Other approved immunotherapies include high-dose bolus interleukin-2 (IL-2), interferon alpha-2b, and Sipuleucel-T. There are limited data, however, on the impact of immunotherapy in patients with measurable metastatic disease to the brain. Registration trials of immune therapies excluded patients with active brain metastases based on a historical poor prognosis in this patient population coupled with uncertainty about the ability of the drugs to cross the blood brain barrier (BBB). These active therapies might however have benefited patients with microscopic brain deposits.
Brain metastases were historically managed with whole brain radiation therapy (WBRT) or surgical resection, depending on the size, number, histology, symptoms, and location. The availability of high-resolution magnetic resonance imaging (MRI) and stereotactic radiosurgery (SRS) to small, emerging lesions has improved local lesional control. These modalities allow higher doses of radiation. In many institutions, WBRT is reserved for patients with multiple or larger lesions not amenable to SRS (12, 13). These treatments are not without limitations and consequences. For example, WBRT has been associated with cognitive decline, while SRS can result in radiation necrosis, cerebral edema, and delayed tumor hemorrhage (14, 15). More often, however, focal therapies are limited in efficacy due to distant cerebral relapse and lack of treatment of microscopic tumor foci not evident on imaging. As new systemic treatments, particularly immune-modulating agents, show prolonged survival of patients with aggressive extra-cerebral disease, these drugs need to be assessed for efficacy in active brain metastases. There are a number of ongoing investigations to determine if these antibodies cross the leaky BBB found in tumors despite their size (16, 17). Alternatively, although brain metastases might contain pre-existing tumor infiltrating lymphocytes (TILs), immune modulation induced by these agents may allow cytotoxic T cells into the tumor microenvironment in the brain, resulting in antitumor immunity. Several lines of evidence suggest that T cells within the tumor microenvironment are responsible for the responses seen with these therapies (18, 19). To date, there have been no published pharmacokinetic or pharmacodynamic studies in on-treatment brain tissue to allow determination of drug penetration into the tumor, primarily due to the difficulty accruing patients to trials requiring brain biopsies, particularly from patients who are responding to therapy. Although animal studies have been done, drug distribution and T cell activation might not reflect that of humans.
Metastatic melanoma is the solid tumor with the highest propensity for dissemination to the brain (20). The only chemotherapy widely used for melanoma known to definitively cross BBB is temozolamide, which induced responses in 7% of melanoma brain metastasis patients (21). Other anti-neoplastic drugs that cross the BBB include fotemustine, etoposide, cisplatin, vinblastine, and motoxantrone and can be used depending on tumor cell sensitivity (22–26). Targeted therapies such as erlotinib, afatinib, and lapatinib have also shown evidence of ability to cross the BBB (27–29).
https://www.ncbi.nlm.nih.gov/pmc/articl ... po=25.8929
Systemic Immunotherapy for the Treatment of Brain Metastases
Systemic Immunotherapy for the Treatment of Brain Metastases
Last edited by D.ap on Thu Nov 16, 2017 8:59 am, edited 3 times in total.
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