Abstract
Physical barriers presented by solid tumors limit CAR T cell efficacy. Thus, technologies to increase CAR T cell access to solid tumors could have massive implications in advancing CAR T cell therapies. Here we demonstrate that treatment of solid tumor-bearing mice with our Junction Opener technology and CAR T cells enhances tumor control - potentially enabling CAR T cell immunotherapy for solid tumors.
Data availability
The data that support the findings of this study are included in the figures of this manuscript. Raw data files are available from the authors upon reasonable request and with permission of Xyphos, an Astellas company.
References
Jackson, H. J., Rafiq, S. & Brentjens, R. J. Driving CAR T-cells forward. Nat. Rev. Clin. Oncol. 13, 370–383 (2016).
Lavin, S. R., McWhorter, T. J. & Karasov, W. H. Mechanistic bases for differences in passive absorption. J. Exp. Biol. 210, 2754–2764 (2007).
Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 46, 3–26 (2001).
Green, S. K., Karlsson, M. C. I., Ravetch, J. V. & Kerbel, R. S. Disruption of cell-cell adhesion enhances antibody-dependent cellular cytotoxicity: Implications for antibody-based therapeutics of cancer. Cancer Res. 62, 6891–900 (2002).
Green, K. J. & Simpson, C. L. Desmosomes: New perspectives on a classic. J. Invest. Dermatol. 127, 2499–2515 (2007).
Chitaev, N. A. & Troyanovsky, S. M. Direct Ca2+-dependent heterophilic interaction between desmosomal cadherins, Desmoglein and Desmocollin, contributes to cell–cell adhesion. J. Cell Biol. 138, 193–201 (1997).
Cai, F. et al. Desmoglein-2 is overexpressed in non-small cell lung cancer tissues and its knockdown suppresses NSCLC growth by regulation of p27 and CDK2. J. Cancer Res. Clin. Oncol. 143, 59–69 (2017).
Brennan, D. & Mahoney, M. G. Increased expression of Dsg2 in malignant skin carcinomas: A tissue-microarray based study. Cell Adhes. Migr. 3, 148–54 (2009).
Han, C.-P. et al. Desmoglein-2 overexpression predicts poor prognosis in hepatocellular carcinoma patients. Eur. Rev. Med. Pharmacol. Sci. 22, 5481–5489 (2018).
Qin, S. et al. DSG2 expression is correlated with poor prognosis and promotes early-stage cervical cancer. Cancer Cell Int. 20, 206 (2020).
Tan, L. Y. et al. Desmoglein 2 promotes vasculogenic mimicry in melanoma and is associated with poor clinical outcome. Oncotarget 7, 46492–46508 (2016).
Wang, H. et al. Desmoglein 2 is a receptor for adenovirus serotypes 3, 7, 11, and 14. Nat. Med. 17, 96–104 (2011).
Wang, H. et al. Intracellular signaling and desmoglein 2 shedding triggered by human adenoviruses Ad3, Ad14, and Ad14P1. J. Virol. 89, 10841–59 (2015).
Coyne, C. B. & Bergelson, J. M. CAR: A virus receptor within the tight junction. Adv. Drug Deliv. Rev. 57, 869–882 (2005).
Beyer, I. et al. Coadministration of epithelial junction opener JO-1 improves the efficacy and safety of chemotherapeutic drugs. Clin. Cancer Res. 18, 3340–3351 (2012).
Wang, H. et al. Structural and functional studies on the interaction of adenovirus fiber knobs and desmoglein 2. J. Virol. 87, 11346–11362 (2013).
Richter, M. et al. Preclinical safety and efficacy studies with an affinity-enhanced epithelial junction opener and PEGylated liposomal doxorubicin. Mol. Ther. 2, 15005 (2015).
Fu, W. et al. CAR exosomes derived from effector CAR-T cells have potent antitumour effects and low toxicity. Nat. Commun. 10, 4355 (2019).
Duro-Sánchez, S., Alonso, M. R. & Arribas, J. Immunotherapies against HER2-positive breast cancer. Cancers 15, 1069 (2023).
Watanabe, N., Mo, F. & McKenna, M. K. Impact of manufacturing procedures on CAR T cell functionality. Front. Immunol. 13, 876339 (2022).
Landgraf, K. E. et al. ConvertibleCARs: A chimeric antigen receptor system for flexible control of activity and antigen targeting. Commun. Biol. 3, 296 (2020).
Pitner, R. et al. Structure-based design of JOC-x, a conjugatable tumor tight junction opener to enhance cancer therapy. Sci. Rep. 9, 6169 (2019).
Acknowledgements
We would like to thank Christopher Pirie and Charles Vacin for contributions in organizing the study and interpretation of results.
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SJR, MSD, KK, and DC authored the manuscript, all authors reviewed the manuscript. SJR, EN, NK, CN, SS, JK and MSD performed the research. All authors participated in the experimental design and write-up.
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HDT Bio Corp. holds a license for the JO-4 technology and is assisting in its clinical development. KK, NK, and EN are employees of Astellas. Astellas funded the research. SJR, CN, SS, AL, SGR, MSD, and DC hold shares in HDT Bio Corp.
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Reed, S.J., Sharma, S., Novák, C. et al. Junction opener enables CAR T cell treatment of solid tumors. Sci Rep (2026). https://doi.org/10.1038/s41598-026-43093-8
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DOI: https://doi.org/10.1038/s41598-026-43093-8
