TY - JOUR
T1 - Cytokine conjugation to enhance T cell therapy
AU - Liu, Yutong
AU - Adu-Berchie, Kwasi
AU - Brockman, Joshua M.
AU - Pezone, Matthew
AU - Zhang, David K.Y.
AU - Zhou, Jingyi
AU - Pyrdol, Jason W.
AU - Wang, Hua
AU - Wucherpfennig, Kai W.
AU - Mooney, David J.
N1 - Funding Information:
ACKNOWLEDGMENTS. We are thankful to Dr. A. Najibi, Dr. M. Dellacherie, and Dr. S. Badrinath for sharing their knowledge on critical pieces of experiments. We thank M. Perez, T. Ferrante, and E. Zigon for technical support and discussions. We acknowledge funding from the NIH (R01 CA238039), the Food and Drug Administration (R01 FD006589), and the Wyss Institute.
Funding Information:
Author contributions: Y.L., H.W., K.W.W., and D.J.M. designed research; Y.L., K.A.-B., J.M.B., M.P., and D.K.Y.Z. performed research; Y.L., J.Z., J.W.P., H.W., and K.W.W. contributed new reagents/analytic tools; Y.L. analyzed data; D.J.M. supervison, funding acquisition; and Y.L. and D.J.M. wrote the paper. Competing interest statement: The authors declare competing interest. The authors have organizational affiliations to disclose, K.W.W. serves on the scientific advisory board of SQZ Biotech, Nextechinvest, Bisou Bioscience Company, and T-Scan Therapeutics, the authors have stock ownership to disclose, K.W.W. is a scientific co-founder of 阀mmunitas Therapeutics, the authors have patent filings to disclose, Y.L., H.W., and D.J.M. have applied through Harvard University for patents on this technology, the authors have research support to disclose, K.W.W. receives sponsored research funding from Novartis.
Publisher Copyright:
© 2022 the Author(s).
PY - 2023/1/3
Y1 - 2023/1/3
N2 - Adoptive T cell transfer (ACT) therapies suffer from a number of limitations (e.g., poor control of solid tumors), and while combining ACT with cytokine therapy can enhance effectiveness, this also results in significant side effects. Here, we describe a nanotechnology approach to improve the efficacy of ACT therapies by metabolically labeling T cells with unnatural sugar nanoparticles, allowing direct conjugation of antitumor cytokines onto the T cell surface during the manufacturing process. This allows local, concentrated activity of otherwise toxic cytokines. This approach increases T cell infiltration into solid tumors, activates the host immune system toward a Type 1 response, encourages antigen spreading, and improves control of aggressive solid tumors and achieves complete blood cancer regression with otherwise noncurative doses of CAR-T cells. Overall, this method provides an effective and easily integrated approach to the current ACT manufacturing process to increase efficacy in various settings.
AB - Adoptive T cell transfer (ACT) therapies suffer from a number of limitations (e.g., poor control of solid tumors), and while combining ACT with cytokine therapy can enhance effectiveness, this also results in significant side effects. Here, we describe a nanotechnology approach to improve the efficacy of ACT therapies by metabolically labeling T cells with unnatural sugar nanoparticles, allowing direct conjugation of antitumor cytokines onto the T cell surface during the manufacturing process. This allows local, concentrated activity of otherwise toxic cytokines. This approach increases T cell infiltration into solid tumors, activates the host immune system toward a Type 1 response, encourages antigen spreading, and improves control of aggressive solid tumors and achieves complete blood cancer regression with otherwise noncurative doses of CAR-T cells. Overall, this method provides an effective and easily integrated approach to the current ACT manufacturing process to increase efficacy in various settings.
KW - CAR-T
KW - adoptive T cell transfer
KW - metabolic labeling; anti-tumor cytokine
KW - nanoparticle
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U2 - 10.1073/pnas.2213222120
DO - 10.1073/pnas.2213222120
M3 - Article
C2 - 36577059
AN - SCOPUS:85145080645
SN - 0027-8424
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 1
M1 - e2213222120
ER -