In an exciting development in the field of cancer immunotherapy, researchers have engineered a new dual-target CAR T-cell therapy that simultaneously targets two key antigens, CD19 and CD20, in lymphoma cells. This innovative approach uses a bidirectional promoter within a single Sleeping Beauty transposon system to drive the expression of both CARs from a single vector, enhancing the therapy’s efficacy and simplifying its design.
The study, published recently in the top-tier journal, Journal for ImmunoTherapy of Cancer (JITC), the official journal of the Society for Immunotherapy of Cancer (SITC), details the development of second-generation CAR T cells that were tested both in vitro against cell lines and in vivo in immunodeficient mice bearing advanced Raji lymphomas. The dual CAR T cells, driven by the EF-1α promoter, exhibited superior cytotoxicity, cytokine production, and antigen-specific activation compared to traditional single-target CAR T cells.
Results show that the bidirectional EF-1α promoter optimally expressed both CAR constructs, with the dual-targeted approach proving significantly more effective in controlling tumor growth and extending survival in mice. This contrasts sharply with inferior outcomes from a unidirectional construct using the same promoter, which linked the CD19 and CD20 CARs with a self-cleaving peptide.
These findings underscore the potential of using bidirectional promoters to enhance CAR T-cell therapy’s effectiveness, suggesting a promising strategy for future cancer treatments. This dual-targeting approach not only improves therapeutic outcomes but also paves the way for other gene therapies utilizing similar technology.
Funding
All authors are members of the Thailand Hub of Talents in Cancer Immunotherapy (TTCI). The academic endeavours of TTCI receive support from the National Research Council of Thailand (N35E660102), the Ratchadaphiseksomphot Matching Fund (RA-MF-03/67), Thailand Research and Innovation Fund Chulalongkorn University (HEAF67300037), the Ratchadaphiseksomphot Matching Fund from the Faculty of Medicine, Chulalongkorn University (RA-MF 27/66) and the Program Management Unit for Human Resource & Institutional Development, Research and Innovation (PMU-B) (B16F640221), and an HRC Explorer 20-768 (ADM) and Royal Society NZ Marsden Fund 18-UOO-188 (ADM). AK and NH received the Second Century Fund (C2F) scholarship from Chulalongkorn University, Bangkok, Thailand. AK received an overseas research experience scholarship from Chulalongkorn University and a departmental single payment award from University of Otago, New Zealand.
Original Paper
Title of original paper: Development of a compact bidirectional promoter-driven dual chimeric antigen receptor (CAR) construct targeting CD19 and CD20 in the Sleeping Beauty (SB) transposon system
Journal: Journal for ImmunoTherapy of Cancer (JITC)
DOI: 10.1136/jitc-2023-008555