T cell modulation has revolutionized immunotherapy in multiple therapeutic directions1. For example, the use of immune checkpoint inhibitors has led to improved overall survival for cancer patients by targeting T cell coinhibitory pathways such as PD-1 and CTLA-41. Chimeric antigen receptor (CAR) T-cell therapy has been approved for treating certain types of acute lymphoblastic leukemia and B-cell lymphoma1. Despite these breakthrough therapies, effective delivery of therapeutically relevant modulators such as mRNA to T cells remains a formidable challenge.
To address this delivery barrier to T cells, Drs. Wenqing Li and Xinfu Zhang, two postdoctoral associates, brainstormed a wide variety of biomaterials. After careful considerations, phospholipids and glycolipids, natural components of the cell membrane2, became potential candidates. These compounds have several physicochemical features: great biocompatibility, high chemical diversity, and unique membrane interactions. Inspired by these characteristics, they synthesized and formulated one set of phospholipid derivatives and one set of glycolipid derivatives. Many pilot studies and formulation screenings in a T cell model eventually identified PL1 as a lead phospholipid derivative. These findings encouraged us to further explore the T cell delivery in animal models. With the support of Chengxiang Zhang and Jingyue Yan, two graduate students, we examined mRNA delivery in a B16F10 mouse melanoma tumor model. Importantly, PL1 formulated lipid nanoparticles (PL1 LNP) can significantly increase the delivery efficiency in the tumor microenvironment compared to free mRNA.
Next, how could we modulate T cells with PL1 LNP for therapeutic applications? In the past decades, researchers discovered a series of costimulatory receptors on T cells for cancer immunotherapy. These costimulatory receptors interact with their corresponding ligands, which activate clonal T cell expansion and differentiation. For instance, OX40 (also known as CD134) is a T cell costimulatory receptor and provides activating signals for CD8 T cells3. Although costimulatory signals are critical to stimulating T cells, the expression level is low in the tumor microenvironment, which might be the cause of the low response rate in clinical trials of OX40 agnostic antibody-mediated immunotherapy4. Hence, we hypothesize that local delivery of costimulatory receptor mRNA to tumor-infiltrating T cells would enhance the antitumor effects of agnostic antibodies and minimize the systemic side effects (Figure 1). Subsequently, we performed experiments in multiple mouse tumor models. The results demonstrate that the combination of PL1-OX40 mRNA and anti-OX40 antibody exhibit significantly improved antitumor activity compared to anti-OX40 antibody alone. Moreover, the therapeutic efficacy can be further enhanced when combined with immune checkpoint inhibitors. Lastly, we explored systemic administration of the treatment regimen, which showed strong antitumor activity in a lung metastasis mouse model. Overall, these proof-of-concept studies probe the challenges of mRNA delivery in T cells and immunotherapy regimens, which facilitate in-depth exploration of T cell modulation in the future. Many team members and collaborators from multiple disciplines have made significant contributions to this work. Please check the details via the following link.
Li, W., Zhang, X., Zhang, C., Yan, J., Hou, X., Du, S., Zeng, C., Zhao, Y., Deng, B., McComb, D.W., Zhang, Y., Kang, D.D., Li, J., Carson, W.E.III, Dong, Y.*, Biomimetic nanoparticles deliver mRNAs encoding costimulatory receptors and enhance T cell mediated cancer immunotherapy, Nature Communications, 10.1038/s41467-021-27434-x, (2021).
1 Waldman, A. D., Fritz, J. M. & Lenardo, M. J. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol 20, 651-668, doi:10.1038/s41577-020-0306-5 (2020).
2 Cooper, G. M. The Cell: A Molecular Approach. (Sinauer Associates is an imprint of Oxford University Press, 2018).
3 Kraehenbuehl, L., Weng, C. H., Eghbali, S., Wolchok, J. D. & Merghoub, T. Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways. Nat Rev Clin Oncol, doi:10.1038/s41571-021-00552-7 (2021).
4 Garber, K. Immune agonist antibodies face critical test. Nat Rev Drug Discov 19, 3-5, doi:10.1038/d41573-019-00214-5 (2020).