The Combination of IL-2 Nanoparticles and Palbociclib Enhances the Anti-tumor Immune Response for Colon Cancer Therapy

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2024 Feb 14

PMID 38352877

Authors

Di Wang

Xiaoshuang Wang

Yingyu Zhang

Le Yu

Jing An

Xiaodong Wang

Yue Huang

Xuemei Han

Affiliations

Soon will be listed here.

Abstract

Immunotherapy of tumors plays a pivotal role in the current treatment of cancer. While interleukin 2 (IL-2) demonstrated its efficacy as an immunotherapeutic drug in the early days, its short blood circulation time poses challenges in maintaining effective therapeutic concentrations. Additionally, IL-2's activation of regulatory T cells can counteract its anti-cancer effects. Therefore, the primary goal of this study was to formulate IL-2-carrying nanoparticles via boron-nitrogen coordination between methoxy poly (ethylene glycol) block poly-[(N-2-hydroxyethyl)-aspartamide]phenylboronic acid (mPEG-b-PHEA-PBA, P-PBA) and poly (L-lysine) (PLL). These nanoparticles are intended to be used in combination with CDK4/6 inhibitors to address the short blood circulation time of IL-2, reduce its immunosuppressive effects, and enhance the overall immune response. The envisaged outcome is a sustained and potent therapeutic effect, offering a novel and promising combination therapy strategy for tumor immunotherapy.

References

Hernandez R, Toomer K, Poder J, Santos Savio A, Hsiung S, Malek T . Sustained IL-2R signaling of limited duration by high-dose mIL-2/mCD25 fusion protein amplifies tumor-reactive CD8 T cells to enhance antitumor immunity. Cancer Immunol Immunother. 2020; 70(4):909-921. PMC: 7979461. DOI: 10.1007/s00262-020-02722-5. View

Finn R, Dering J, Conklin D, Kalous O, Cohen D, Desai A . PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009; 11(5):R77. PMC: 2790859. DOI: 10.1186/bcr2419. View

Solomon I, Amann M, Goubier A, Vargas F, Zervas D, Qing C . CD25-T-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity. Nat Cancer. 2021; 1(12):1153-1166. PMC: 7116816. DOI: 10.1038/s43018-020-00133-0. View

Li X, Zhou Q, Japir A, Dutta D, Lu N, Ge Z . Protein-Delivering Nanocomplexes with Fenton Reaction-Triggered Cargo Release to Boost Cancer Immunotherapy. ACS Nano. 2022; 16(9):14982-14999. DOI: 10.1021/acsnano.2c06026. View

Mo F, Yu Z, Li P, Oh J, Spolski R, Zhao L . An engineered IL-2 partial agonist promotes CD8 T cell stemness. Nature. 2021; 597(7877):544-548. PMC: 9172917. DOI: 10.1038/s41586-021-03861-0. View

Lelliott E, Kong I, Zethoven M, Ramsbottom K, Martelotto L, Meyran D . CDK4/6 Inhibition Promotes Antitumor Immunity through the Induction of T-cell Memory. Cancer Discov. 2021; 11(10):2582-2601. DOI: 10.1158/2159-8290.CD-20-1554. View

Overwijk W, Tagliaferri M, Zalevsky J . Engineering IL-2 to Give New Life to T Cell Immunotherapy. Annu Rev Med. 2020; 72:281-311. DOI: 10.1146/annurev-med-073118-011031. View

Vijayaraghavan S, Karakas C, Doostan I, Chen X, Bui T, Yi M . CDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers. Nat Commun. 2017; 8:15916. PMC: 5490269. DOI: 10.1038/ncomms15916. View

Deng J, Wang E, Jenkins R, Li S, Dries R, Yates K . CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation. Cancer Discov. 2017; 8(2):216-233. PMC: 5809273. DOI: 10.1158/2159-8290.CD-17-0915. View

10.

Goel S, DeCristo M, Watt A, BrinJones H, Sceneay J, Li B . CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017; 548(7668):471-475. PMC: 5570667. DOI: 10.1038/nature23465. View

11.

Codarri Deak L, Nicolini V, Hashimoto M, Karagianni M, Schwalie P, Lauener L . PD-1-cis IL-2R agonism yields better effectors from stem-like CD8 T cells. Nature. 2022; 610(7930):161-172. PMC: 9534752. DOI: 10.1038/s41586-022-05192-0. View

12.

VanDyke D, Iglesias M, Tomala J, Young A, Smith J, Perry J . Engineered human cytokine/antibody fusion proteins expand regulatory T cells and confer autoimmune disease protection. Cell Rep. 2022; 41(3):111478. PMC: 9631798. DOI: 10.1016/j.celrep.2022.111478. View

13.

Shi L, Sheng J, Chen G, Zhu P, Shi C, Li B . Combining IL-2-based immunotherapy with commensal probiotics produces enhanced antitumor immune response and tumor clearance. J Immunother Cancer. 2020; 8(2). PMC: 7542661. DOI: 10.1136/jitc-2020-000973. View

14.

Hernandez R, LaPorte K, Hsiung S, Santos Savio A, Malek T . High-dose IL-2/CD25 fusion protein amplifies vaccine-induced CD4 and CD8 neoantigen-specific T cells to promote antitumor immunity. J Immunother Cancer. 2021; 9(9). PMC: 8413969. DOI: 10.1136/jitc-2021-002865. View

15.

Heckler M, Ali L, Clancy-Thompson E, Qiang L, Ventre K, Lenehan P . Inhibition of CDK4/6 Promotes CD8 T-cell Memory Formation. Cancer Discov. 2021; 11(10):2564-2581. PMC: 8487897. DOI: 10.1158/2159-8290.CD-20-1540. View

16.

Leonard W, Lin J . Strategies to therapeutically modulate cytokine action. Nat Rev Drug Discov. 2023; 22(10):827-854. DOI: 10.1038/s41573-023-00746-x. View

17.

Yuan K, Wang X, Dong H, Min W, Hao H, Yang P . Selective inhibition of CDK4/6: A safe and effective strategy for developing anticancer drugs. Acta Pharm Sin B. 2021; 11(1):30-54. PMC: 7838032. DOI: 10.1016/j.apsb.2020.05.001. View

18.

Liu Z, Shen N, Tang Z, Zhang D, Ma L, Yang C . An eximious and affordable GSH stimulus-responsive poly(α-lipoic acid) nanocarrier bonding combretastatin A4 for tumor therapy. Biomater Sci. 2019; 7(7):2803-2811. DOI: 10.1039/c9bm00002j. View

19.

Bhuiyan A, Dougan M . Engineering T cell memory for antitumor immunity. Trends Pharmacol Sci. 2021; 43(1):1-3. DOI: 10.1016/j.tips.2021.11.003. View

20.

Hashimoto M, Araki K, Cardenas M, Li P, Jadhav R, Kissick H . PD-1 combination therapy with IL-2 modifies CD8 T cell exhaustion program. Nature. 2022; 610(7930):173-181. PMC: 9793890. DOI: 10.1038/s41586-022-05257-0. View