Management of HER2-positive breast cancer that has metastasized to the brain and/or central nervous system (CNS) is a major clinical challenge. Following CNS metastases, most patients survive ≤2 years.1,2
Chimeric antigen receptor T-cell (CAR T-cell) therapy is under investigation as immunotherapy for the treatment of patients with solid tumors, including HER2-positive cancers.3,4 However, this treatment approach needs to be optimized to minimize on-target, off-tumor activity.
Priceman and colleagues evaluated the design of CAR molecules and the route of administration of CAR T-cells for HER2-positive breast cancer that has metastasized to the brain. HER2 CAR T-cells that contained either CD28 or 4-1BB intracellular co-stimulatory signaling domains were compared based on a variety of end points. Additionally, HER2 CAR T-cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that had metastasized to the brain were also evaluated.1
In vitro tumor killing assays showed that “in contrast to CD28 co-stimulation, 4-1BB co-stimulation selectively kills HER2-expressing tumor cells, with lower levels of T-cell exhaustion and superior in vitro antigen-dependent proliferation.”
In another experiment, Priceman and colleagues engrafted female mice with BBM1 cells via injection in the brain, and found that local and progressive BBM1 tumors developed with high levels of HER2 expression. Eight days following tumor engraftment, HER2 CAR T-cells were delivered intracranially, and complete tumor regression occurred, with antitumor responses within the first week in most mice. The researchers concluded that these findings “support local intracranial delivery of HER2 CAR T-cells as an effective method of targeting breast cancer brain metastasis in mice.” They noted, however, that a limitation of the experiment was the lack of a comparator arm.
The researchers also evaluated HER2 CAR T-cell regional intraventricular delivery versus local intracranial delivery and found equivalent antitumor responses. Even with larger tumor burdens at 14 days, intraventricular delivery of HER2-BB CAR T-cells provided antitumor activity in mice. These data in animal models provide support for the potential efficacy of intraventricular HER2 CAR T-cells therapy for HER2-positive breast cancer brain metastasis.1
The authors concluded that their study demonstrated “robust antitumor responses in human xenograft models of HER2+ breast cancer metastasis to the brain after local intratumoral or regional intraventricular delivery of HER2-BB CAR T-cells. By contrast, intravenous delivery of HER2 CAR T-cells achieved only partial anti-tumor responses in mice.”
1. Priceman SJ, Tilakawardane D, Jeang B, et al. Regional delivery of chimeric antigen receptor-engineered T cells effectively targets HER2+ breast cancer metastasis to the brain. Clin Cancer Res. 2017 Oct 23. Epub ahead of print.
2. Leone JP, Leone BA. Breast cancer brain metastases: the last frontier. Exp Hematol Oncol. 2015;4:33.
3. Maus MV, June CH. Making better chimeric antigen receptors for adoptive T-cell therapy. Clin Cancer Res. 2016;22:1875-1884.
4. Priceman SJ, Forman SJ, Brown CE. Smart CARs engineered for cancer immunotherapy. Curr Opin Oncol. 2015;27:466-474.