The
lungs are major sites of metastases for several cancer types,
including breast cancer (BC). Prognosis and quality of life of BC
patients that develop pulmonary metastases are negatively impacted.
The development of strategies to slow the growth and relieve the symptoms
of BC lung metastases (BCLM) is thus an important goal in the management
of BC. However, systemically administered first line small molecule
chemotherapeutics have poor pharmacokinetic profiles and biodistribution
to the lungs and significant off-target toxicity, severely compromising
their effectiveness. In this work, we propose the local delivery of
add-on immunotherapy to the lungs to support first line chemotherapy
treatment of advanced BC. In a syngeneic murine model of BCLM, we
show that local pulmonary administration (p.a.) of PLX-3397 (PLX),
a colony-stimulating factor 1 receptor inhibitor (CSF-1Ri), is capable
of overcoming physiological barriers of the lung epithelium, penetrating
the tumor microenvironment (TME), and decreasing phosphorylation of
CSF-1 receptors, as shown by the Western blot of lung tumor nodules.
That inhibition is accompanied by an overall decrease in the abundance
of protumorigenic (M2-like) macrophages in the TME, with a concomitant
increase in the amount of antitumor (M1-like) macrophages when compared
to the vehicle-treated control. These effects with PLX (p.a.) were
achieved using a much smaller dose (1 mg/kg, every other day) compared
to the systemic doses typically used in preclinical studies (40–800
mg/kg/day). As an additive in combination with intravenous (i.v.)
administration of paclitaxel (PTX), PLX (p.a.) leads to a decrease
in tumor burden without additional toxicity. These results suggested
that the proposed immunochemotherapy, with regional pulmonary delivery
of PLX along with the i.v. standard of care chemotherapy, may lead
to new opportunities to improve treatment, quality of life, and survival
of patients with BCLM.
