A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases

Abstract

Breast cancer brain metastases (BCBMs) are common in patients with metastatic breast cancer and indicate a poor prognosis. These tumors are especially resistant to currently available treatments due to multiple factors. However, the combination of chimeric antigen receptor (CAR)-modified immune cells and oncolytic herpes simplex virus (oHSV) has not yet been explored in this context. In this study, NK-92 cells and primary NK cells were engineered to express the second generation of EGFR-CAR. The efficacies of anti-BCBMs of EGFR-CAR NK cells, oHSV-1, and their combination were tested in vitro and in a breast cancer intracranial mouse model. In vitro, compared with mock-transduced NK-92 cells or primary NK cells, EGFR-CAR-engineered NK-92 cells and primary NK cells displayed enhanced cytotoxicity and IFN-γ production when co-cultured with breast cancer cell lines MDA-MB-231, MDA-MB-468, and MCF-7. oHSV-1 alone was also capable of lysing and destroying these cells. However, a higher cytolytic effect of EGFR-CAR NK-92 cells was observed when combined with oHSV-1 compared to the monotherapies. In the mice intracranially pre-inoculated with EGFR-expressing MDA-MB-231 cells, intratumoral administration of either EGFR-CAR-transduced NK-92 cells or oHSV-1 mitigated tumor growth. Notably, the combination of EGFR-CAR NK-92 cells with oHSV-1 resulted in more efficient killing of MDA-MB-231 tumor cells and significantly longer survival of tumor-bearing mice when compared to monotherapies. These results demonstrate that regional administration of EGFR-CAR NK-92 cells combined with oHSV-1 therapy is a potentially promising strategy to treat BCBMs.

CAR-Expressing Natural Killer Cells for Cancer Retargeting

“…Compared to monotherapies with CAR-NK cells, combinations of second-generation designed epidermal growth factor receptor-CAR-NK cells and oncolytic Herpes simplex virus led to higher killing rates against breast cancer cell lines and enhanced inhibition of the tumour progression in a breast cancer mouse model [91]. This seems to be an extensible application for CAR-NK cells in combination with oncolytic viruses to effectively eliminate resistant solid tumours [91].…”

“…This seems to be an extensible application for CAR-NK cells in combination with oncolytic viruses to effectively eliminate resistant solid tumours [91]. Moreover, it is urgent to include predominantly overexpressed TAAs from resistant cancer identities for the generation of target-oriented CAR constructs to induce redirected NK cell responses.…”

The Broad Spectrum of Human Natural Killer Cell Diversity

“…In order to circumvent the inherent clinical and immunological challenges related to allo-HSCT, alternative NK cell-based approaches to the treatment of AML and other forms of cancer have been developed. These include providing patients with recombinant interleukin (IL)-2 or IL-15 to augment endogenous NK cell function; adoptive transfer of fresh or cytokine-activated allogeneic NK cells derived from healthy umbilical cord blood (UCB) or adult peripheral blood (PB) donors; and infusing genetically modified chimeric antigen receptor NK cells into patients (Chen et al, 2016b; Fehniger and Cooper, 2016; Han et al, 2015; Knorr et al, 2014; Mehta et al, 2015; Moretta et al, 2014; Vasu and Blum, 2013). …”

Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy

“…The PDX model, which is established by transferring of primary tumors directly from the patient into an immunodeficient mouse, can retain the heterogeneity of primary tumor samples and more closely resembles the original clinical cancer than long-established cell lines and standard xenografts; thus, this model has emerged as a powerful tool for studying tumor xenografts [32] . Most CAR-NK cells are transferred to the PDX model to evaluate their safety and efficacy in pre-clinical trials, including CAR-targeting antigens from hematological cancers (eg, CD19, CD20, CD138, and CS-1) [33][34][35][36][37][38] and solid tumors (eg, HER2, EpCam, GD2, GPA7, PSCA, EGFR and EGFRvIII) [14,26,[39][40][41][42][43][44][45][46] (Table 1).…”