Biology subjects

Bonifant, C.

Publications and source records attributed to Bonifant, C..

3 recordsLinked to original sources

bioRxiv2026

B7-H3-targeted natural killer cells effectively kill atypical teratoid / rhabdoid tumors and extend survival in orthotopic xenografts

BackgroundAtypical teratoid/rhabdoid tumors (AT/RTs) are the most common malignant CNS tumor in infants, and patients suffer from low survival rates and treatment-related morbidities. These tumors frequently overexpress the pan-cancer antigen B7-H3 (CD276), which can be targeted with immunotherapy. We hypothesized that adding a B7-H3-targeting cytotoxic chimeric antigen receptor (CAR) to NK cells can enhance killing against AT/RTs. MethodsWe designed a library of variable affinity B7-H3-targeted CARs, which were transduced into primary healthy donor-derived NK cells. We verified B7-H3 expression in a panel of AT/RT cell lines and further engineered luciferase and nuclear GFP-expressing AT/RT (CHLA-04, CHLA-06, BT12, BT37) as well as a CHLA-06-derived B7-H3 knockout. We tested CAR-NK cell functionality using in vitro co-culture cytotoxicity assays. We delivered anti-B7-H3 CAR-NK cells intratumorally or intracerebroventricularly (ICV) to AT/RT orthotopic xenografts and monitored for tumor growth and animal survival. ResultsB7-H3-targeted CAR-NK cells demonstrated target-specific cytotoxicity when compared to unmodified NK cells. Knockout of B7-H3 in target cells abolished the increased CAR-mediated target killing. When delivered intratumorally to CHLA-06 orthotopic xenograft-bearing mice, anti-B7-H3 CAR-NK cells eliminated tumor cells and prolonged survival. When CAR-NK cells were delivered ICV against a CNS disseminated tumor model of BT12, treated mice had significantly improved survival. ConclusionsAnti-B7-H3 CAR-NK cells effectively kill AT/RTs in multiple pre-clinical in vitro and in vivo models in an antigen-specific manner. Evidence of efficacy in translationally relevant models provides support for using B7-H3-targeting CAR-NK cells in high-risk AT/RT patients.

cancer biology↗

bioRxiv2025

Hyper-migratory CAR T cells alleviate ovarian cancer metastatic burden and improve prognosis

Cellular immunotherapy has shown remarkable efficacy in hematological malignancies but remains limited by infiltration issues in solid tumors, leading to poor treatment efficacy. We have recently shown that mesothelin-targeting CAR T cells co-transduced with cytokine-binding synthetic velocity receptors (VRs, referred to as CAR TV cells) demonstrate increased motility, improved infiltration in solid primary tumors, and lead to a better anti-tumor effect compared to CAR T cells that do not express VRs. However, it is metastasis that causes the vast majority of cancer related deaths and is difficult to target clinically, indicating an urgent unmet need. We show that these CAR T cells engineered to be hyper-migratory using VRs are highly effective against liver metastasis of ovarian cancer along different stages of the metastatic cascade. Mesothelin-targeting CAR TV cells expressing synthetic or native receptors responsive to the cytokine Interleukin-5 improved the survival of mice bearing an extremely high or terminal level of metastatic burden compared to CAR T cells that did not express VRs. Against newly established metastatic lesions and lesions undergoing metastatic outgrowth, CAR TV cells showed a robust anti-cancer effect resulting in an improved prognosis compared to control CAR T cells. Histopathological assessments showed a substantial reduction of metastasis number and lesion size with CAR TV treatment, concomitant with increased immune cell infiltration in the metastatic regions. Our work demonstrates the efficacy of high-motility CAR T cells in a metastatic setting and extends their scope to the treatment of metastasis of solid tumors.

bioengineering↗

bioRxiv2021

The role of the atypical chemokine receptor CCRL2 in myelodysplastic syndrome and secondary acute myeloid leukemia

The identification of new molecular pathways supporting the growth of myelodysplastic syndrome (MDS) stem and progenitor cells is needed to understand clinical variation and develop targeted therapies. Within myeloid malignancies, men have worse outcomes compared to women, suggesting male sex hormone driven effects in malignant hematopoiesis. The androgen receptor promotes the expression of five granulocyte-colony factor receptor regulated genes. Among them, CCRL2 encodes an atypical chemokine receptor that regulates cytokine signaling in differentiated granulocytes but its role in myeloid malignancies is unknown. Our study revealed that CCRL2 is upregulated in stem and progenitor cells from patients with MDS and secondary acute leukemia. CCRL2 knockdown suppressed the growth and clonogenicity of MDS92 and MDS-L cells in vitro and in vivo. Moreover, CCRL2 knockdown significantly suppressed the phosphorylation of JAK2, STAT3, and STAT5 in MDS cells. CCRL2 co-precipitated with JAK2 and its suppression decreased the interaction of JAK2 with STAT proteins. Cell lines expressing JAK2V617F showed less effect of CCRL2 knockdown on growth and clonogenicity compared to those expressing wild type. However, the selective JAK2 inhibitor fedratinib potentiated the effects of CCRL2 knockdown in MDS and leukemia cells expressing both wild type JAK2 and JAK2V617F. In conclusion, our results implicate CCRL2 as a mediator of MDS and secondary acute leukemia cell growth, in part through JAK2/STAT signaling.

cancer biology↗