Harnessing nanomedicine for enhanced immunotherapy for breast cancer brain metastases

Abstract

Brain metastases (BMs) are the most common type of brain tumor, and the incidence among breast cancer (BC) patients has been steadily increasing over the past two decades. Indeed, ~ 30% of all patients with metastatic BC will develop BMs, and due to few effective treatments, many will succumb to the disease within a year. Historically, patients with BMs have been largely excluded from clinical trials investigating systemic therapies including immunotherapies (ITs) due to limited brain penetration of systemically administered drugs combined with previous assumptions that BMs are poorly immunogenic. It is now understood that the central nervous system (CNS) is an immunologically distinct site and there is increasing evidence that enhancing immune responses to BCBMs will improve patient outcomes and the efficacy of current treatment regimens. Progress in IT for BCBMs, however, has been slow due to several intrinsic limitations to drug delivery within the brain, substantial safety concerns, and few known targets for BCBM IT. Emerging studies demonstrate that nanomedicine may be a powerful approach to overcome such limitations, and has the potential to greatly improve IT strategies for BMs specifically. This review summarizes the evidence for IT as an effective strategy for BCBM treatment and focuses on the nanotherapeutic strategies currently being explored for BCBMs including targeting the blood–brain/tumor barrier (BBB/BTB), tumor cells, and tumor-supporting immune cells for concentrated drug release within BCBMs, as well as use of nanoparticles (NPs) for delivering immunomodulatory agents, for inducing immunogenic cell death, or for potentiating anti-tumor T cell responses. Graphical abstract

Fn14-Directed DART Nanoparticles Selectively Target Neoplastic Cells in Preclinical Models of Triple-Negative Breast Cancer Brain Metastasis

“…While there are several targeted nanotherapeutics for BC BMs in preclinical development, studies employing flow cytometric or single-cell quantification of tumor cell NP targeting within TNBC BTs are lacking. However, similar studies performed 24 h after systemic administration in other tumor models reveal that our Fn14-targeting strategy may enable more preferential tumor cell targeting than other targeted nanotherapeutics.…”

“…A second study limitation worth noting is that our flow cytometry antibody panel was designed to only identify major immune populations within the brain TIME (Figure S2). Thus, while our results did not indicate significant Fn14 expression in any nontumor cell population, further analysis of Fn14 expression in nonimmune populations (endothelial cells, pericytes, astrocytes) and in additional immune system cell types (NK cells, dendritic cells) is necessary to fully define Fn14 expression not only in TNBC BM models, but also in human tumors. Finally, our characterization of Cy5-Abraxane and unlabeled Abraxane revealed slight differences in physiochemical properties upon Cy5 labeling, which may modulate tissue/cell distribution in vivo .…”

“…Indeed, if Fn14 is expressed by immune cells with antitumor activity, then Fn14-targeted, drug-loaded DART NPs would eliminate these cells, an undesirable outcome. Conversely, considering the progressively immunosuppressive nature of TAMs in TNBC BM, eliminating Fn14-positive tumor-supporting immune cells would be a beneficial effect of Fn14-targeted therapeutic NP delivery. Regardless of Fn14 expression, however, TAMs and other phagocytes present within the TIME are thought to be passively targeted by NPs .…”

Optimal timing and sequence of combining stereotactic radiosurgery with immune checkpoint inhibitors in treating brain metastases: clinical evidence and mechanistic basis

“…Besides SRS, emerging therapeutic techniques are being developed to overcome the obstacles in the ICI treatment of brain metastases. Nanomedicine can target the BBB/BTB, tumor cells, immunosuppressive cells, APCs, or T cells to boost ICD and the intracranial efficacy of ICIs [ 98 , 99 ]. A series of local treatments, such as focused ultrasound, tumor-treating fields, and laser therapy, can also modulate the permeability of the BBB/BTB and may have synergy with ICIs [ 13 ].…”

Research trends and prospects on brain metastasis from breast cancer: A bibliometric analysis

“…For patients with endocrine-resistant breast cancer who develop brain metastasis and are resistant to most chemotherapies, surgical tumor resection and stereotactic radiotherapy have demonstrated efficacy in improving overall survival and reducing symptoms associated with brain metastasis, which remains crucial in optimizing outcomes for this population ( 39 ). Keywords in the yellow cluster were mainly related to treatment optimization including nanoparticles and focused ultrasound , which were used in preclinical trials, and the multidisciplinary crosstalk seemed to improve the efficacy of treatment at present ( 40 , 41 ). The purple cluster was mainly related to epidemiology with keywords such as survival, risk, subtype, diagnosis , and recurrence .…”