Targeting brain lesions of non-small cell lung cancer by enhancing CCL2-mediated CAR-T cell migration

Abstract

Metastatic non-small cell lung cancer (NSCLC) remains largely incurable and the prognosis is extremely poor once it spreads to the brain. In particular, in patients with brain metastases, the blood brain barrier (BBB) remains a significant obstacle for the biodistribution of antitumor drugs and immune cells. Here we report that chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR) exhibit antitumor activity in vitro against tumor cell lines and lung cancer organoids, and in vivo in xenotransplant models of orthotopic and metastatic NSCLC. The co-expression of the CCL2 receptor CCR2b in B7-H3.CAR-T cells, significantly improves their capability of passing the BBB, providing enhanced antitumor activity against brain tumor lesions. These findings indicate that leveraging T-cell chemotaxis through CCR2b co-expression represents a strategy to improve the efficacy of adoptive T-cell therapies in patients with solid tumors presenting with brain metastases.

Extracellular Vesicles Derived from Lung Cancer Cells Induce Transformation of Normal Fibroblasts into Lung Cancer-Associated Fibroblasts and Promote Metastasis of Lung Cancer by Delivering lncRNA HOTAIR

“…Since the clinical symptoms of early LC are not obvious and difficult to identify, most patients with LC are commonly diagnosed at an advanced stage [ 8 , 9 ]. In recent years, despite progress in the treatment options, the prognosis of patients with advanced LC is still poor [ 10 ]. Moreover, due to delayed diagnosis, the 5-year survival rate of LC is less than 5%, which is much lower than other cancer patients [ 11 , 12 ].…”

Identification of the effects of COVID-19 on patients with pulmonary fibrosis and lung cancer: a bioinformatics analysis and literature review

“…SCLC is a rapidly fatal disease with few treatment options 129 . The combination of a platinum drug and etoposide remains the mainstay treatment for SCLC 130 .…”

Lung Cancer Organoids: The Rough Path to Personalized Medicine

“…LCOs were also developed from extrapulmonary sites, such as metastases (lymph nodes, brain, and bone marrow) and malignant effusions [ 35 , 36 ], recapitulating tumor-like histology and drug responses. Shortly after those pioneer studies, an increasing number of publications described the use of LCOs to investigate drug responses [ 35 , 37 , 38 , 39 , 40 , 41 , 42 ] and to test immunotherapeutic strategies in co-cultures with autologous T cells [ 43 , 44 , 45 ].…”

“…Co-cultures of LCOs with autologous T cells can be used to dissect the mechanisms that determine tumor sensitivity or resistance to immunotherapy and possibly to generate patient-specific T cell products for adoptive T cell transfer. One step further in this direction was reported by Li H. and coworkers, who co-cultivated LCOs with CAR-T cells within a strategy to achieve T-cell-mediated targeting of NSCLC brain metastases [ 45 ]. Notably, organoid cultures in submerged Matrigel domes do not retain stromal or immune components of the primary tumor.…”

“…Others: adenoid cystic carcinoma, sarcomatoid carcinoma, atypical carcinoid, mucoepidermoid carcinoma, large-cell neuroendocrine carcinoma. Not all the relevant references were reported in the figure due to space issues; we apologize to the authors who we were unable to cite [ 16 , 17 , 34 , 35 , 39 , 40 , 41 , 45 , 50 , 57 , 58 , 59 , 60 , 61 , 63 , 65 , 74 ].…”