Adoptive cell therapy of triple negative breast cancer with redirected cytokine-induced killer cells

Abstract

Cytokine-Induced Killer (CIK) cells share several functional and phenotypical properties of both T and natural killer (NK) cells. They represent an attractive approach for cell-based immunotherapy, as they do not require antigen-specific priming for tumor cell recognition, and can be rapidly expanded in vitro. Their relevant expression of FcγRIIIa (CD16a) can be exploited in combination with clinical-grade monoclonal antibodies (mAbs) to redirect their lytic activity in an antigen-specific manner. Here, we report the efficacy of this combined approach against triple negative breast cancer (TNBC), an aggressive tumor that still requires therapeutic options. Different primitive and metastatic TNBC cancer mouse models were established in NSG mice, either by implanting patient-derived TNBC samples or injecting MDA-MB-231 cells orthotopically or intravenously. The combined treatment consisted in the repeated intratumoral or intravenous injection of CIK cells and cetuximab. Tumor growth and metastasis were monitored by bioluminescence or immunohistochemistry, and survival was recorded. CIK cells plus cetuximab significantly restrained primitive tumor growth in mice, either in patient-derived tumor xenografts or MDA-MB-231 cell line models. Moreover, this approach almost completely abolished metastasis spreading and dramatically improved survival. The antigen-specific mAb favored tumor and metastasis tissue infiltration by CIK cells, and led to an enrichment of the CD16a + subset. Data highlight the potentiality of this novel immunotherapy strategy where a nonspecific cytotoxic cell population can be converted into tumor-specific effectors with clinical-grade antibodies, thus providing not only a therapeutic option for TNBC but also a valid alternative to more complex approaches based on chimeric antigen receptor-engineered cells.

BL-01, an Fc-bearing, tetravalent CD20 × CD5 bispecific antibody, redirects multiple immune cells to kill tumors in vitro and in vivo

“…CIK cells have been reported to express FcgRs-in particular CD16-albeit at low levels compared with NK cells [25,49,50]. The authors cannot exclude that low levels of CD16 on CIK cells also participate in the synergistic activity of CD20 £ CD5 bsAb in vivo, although the lack of such synergy with rituximab suggests that this is not significant and that the CD5 moiety of BL-01 bsAb is required for the effect in vivo.…”

Targeting regulated cell death (RCD) with small-molecule compounds in triple-negative breast cancer: a revisited perspective from molecular mechanisms to targeted therapies

“…Small-molecule compounds could target p53 mutant protein, induce cell autophagy and promote cancer cell death. For example, it was reported that small-molecule compound, CP-31398, could reactivate wild-type p53 protein to induce autophagy, thereby enhancing natural killer cell (NK) lysis of p53-mutated MB-MDA-231 cells [ 169 , 170 ]. This finding suggested a new approach for future combination immunotherapy [ 171 ].…”

Arming Immune Cells for Battle: A Brief Journey through the Advancements of T and NK Cell Immunotherapy

“…Furthermore, a SB-engineered signaling lymphocytic activation molecule (SLAM) family member 7 (SLAMF7)-specific T cell product for treatment of patients suffering from multiple myeloma is currently under investigation in a phase I/II clinical trial CARAMBA-1 (NCT04499339; EU Horizon 2020 project). Additionally, CIK cells can be CAR-redirected through lentiviral and non-viral transposon system [ 224 ], and can exert relevant ADCC upon incubation with clinical-grade mAbs due to CD16 expression [ 225 , 226 ].…”