Liposome-based in situ antigen-modification strategy for “universal” T-cell-receptor engineered T cell in cancer immunotherapy

Abstract

T-cell receptor (TCR) engineered T-cell therapy, unlike chimeric antigen receptor T-cell therapy, relies on the inherent ability of TCRs to detect a wider variety of antigenic epitopes, such as protein fragments found internally or externally on cells. Hence, TCR-T-cell therapy offers broader possibilities for treating solid tumors. However, because of the complicated process of identifying specific antigenic peptides, their clinical application still encounters significant challenges. Thus, we aimed to establish a novel “universal” TCR-T “artificial antigen expression” technique that involves the delivery of the antigen to tumor cells using DSPE-PEG-NY-ESO-1^157-165 liposomes (NY-ESO-1 Lips) to express TCR-T-cell-specific recognition targets. In vitro as well as in vivo studies revealed that they could accumulate efficiently in the tumor area and deliver target antigens to activate the tumor-specific cytotoxic T-cell immune response. NY-ESO-1 TCR-T therapy, when used in combination, dramatically curbed tumor progression and extended the longevity of mice. Additionally, PD-1 blockage enhanced the therapeutic effect of the aforementioned therapy. In conclusion, NY-ESO-1 Lips “cursed” tumor cells by enabling antigenic target expression on their surface. This innovative technique presents a groundbreaking approach for the widespread utilization of TCR-T in solid tumor treatment.

Keywords

anti-PD-1 antibody / gastric cancer / liposome / NY-ESO-1 antigen delivery / NY-ESO-1 T-cell receptor (TCR) engineered T-cell therapy

References

1	Z Xiao, L Todd, L Huang, et al. Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors. Nat Commun. 2023;14(1):5110.
2	N Tang, C Cheng, X Zhang, et al. TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. 2020;5(4):e133977.
3	J Rossjohn, S Gras, JJ Miles, SJ Turner, DI Godfrey, J McCluskey. T cell antigen receptor recognition of antigen-presenting molecules. Annu Rev Immunol. 2015;33:169-200.
4	PF Robbins, SH Kassim, TL Tran, et al. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin Cancer Res. 2015;21(5):1019-1027.
5	PF Robbins, RA Morgan, SA Feldman, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011;29(7):917-924.
6	SP D'Angelo, L Melchiori, MS Merchant, et al. Antitumor activity associated with prolonged persistence of adoptively transferred NY-ESO-1 (c259)T cells in synovial sarcoma. Cancer Discov. 2018;8(8):944-957.
7	AP Rapoport, EA Stadtmauer, GK Binder-Scholl, et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med. 2015;21(8):914-921.
8	NB Nagarsheth, SM Norberg, AL Sinkoe, et al. TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. Nat Med. 2021;27(3):419-425.
9	X Li, S Zhang, YQ Song, H Tan, XH Hui. Anti-P0 antibody-conjugated nanoscale contrast agent targeting the myelin sheath for intraoperative visible delineation of cranial nerves. ACS Biomater Sci Eng. 2020;6(3):1744-1754.
10	R Thomas, G Al-Khadairi, J Roelands, et al. NY-ESO-1 based immunotherapy of cancer: current perspectives. Front Immunol. 2018;9:947.
11	C Uyttenhove, J Maryanski, T Boon. Escape of mouse mastocytoma P815 after nearly complete rejection is due to antigen-loss variants rather than immunosuppression. J Exp Med. 1983;157(3):1040-1052.
12	BS Han, S Ji, S Woo, JH Lee, JI Sin. Regulation of the translation activity of antigen-specific mRNA is responsible for antigen loss and tumor immune escape in a HER2-expressing tumor model. Sci Rep. 2019;9(1):2855.
13	D Nobuoka, T Yoshikawa, M Takahashi, et al. Intratumoral peptide injection enhances tumor cell antigenicity recognized by cytotoxic T lymphocytes: a potential option for improvement in antigen-specific cancer immunotherapy. Cancer Immunol Immunother. 2013;62(4):639-652.
14	P Rochigneux, B Chanez, B De Rauglaudre, E Mitry, C Chabannon, M Gilabert. Adoptive cell therapy in hepatocellular carcinoma: biological rationale and first results in early phase clinical trials. Cancers (Basel). 2021;13(2):271.
15	Q Wang, F Liu, L Wang, et al. Enhanced and prolonged antitumor effect of salinomycin-loaded gelatinase-responsive nanoparticles via targeted drug delivery and inhibition of cervical cancer stem cells. Int J Nanomed. 2020;15:1283-1295.
16	Q Wang, YT Yen, C Xie, et al. Combined delivery of salinomycin and docetaxel by dual-targeting gelatinase nanoparticles effectively inhibits cervical cancer cells and cancer stem cells. Drug Deliv. 2021;28(1):510-519.
17	K Bourzac. Nanotechnology: carrying drugs. Nature. 2012;491(7425):S58-S60.
18	KS Yadav, A Upadhya, A Misra. Targeted drug therapy in nonsmall cell lung cancer: clinical significance and possible solutions-part II (role of nanocarriers). Expert Opin Drug Deliv. 2021;18(1):103-118.
19	GE Flaten, TT Chang, WT Phillips, M Brandl, A Bao, B Goins. Liposomal formulations of poorly soluble camptothecin: drug retention and biodistribution. J Liposome Res. 2013;23(1):70-81.
20	H Liu, KD Moynihan, Y Zheng, et al. Structure-based programming of lymph-node targeting in molecular vaccines. Nature. 2014;507(7493):519-522.
21	Y Chu, L Qian, Y Ke, et al. Lymph node-targeted neoantigen nanovaccines potentiate anti-tumor immune responses of post-surgical melanoma. J Nanobiotechnology. 2022;20(1):190.
22	Z Sun, R Li, Y Shen, et al. In situ antigen modification-based target-redirected universal chimeric antigen receptor T (TRUE CAR-T) cell therapy in solid tumors. J Hematol Oncol. 2022;15(1):29.
23	X Wang, F Meng, X Li, et al. Nanomodified switch induced precise and moderate activation of CAR-T cells for solid tumors. Adv Sci (Weinh). 2023;10(12):e2205044.
24	N Nishida-Aoki, T Ochiya. Impacts of tissue context on extracellular vesicles-mediated cancer-host cell communications. Cancer Sci. 2024. doi:
25	C Théry, M Ostrowski, E Segura. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9(8):581-593.
26	H Kim, J Lee, C Oh, JH Park. Cooperative tumour cell membrane targeted phototherapy. Nat Commun. 2017;8:15880.
27	S EL Andaloussi, I M?ger, XO Breakefield, MJ Wood. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov. 2013;12(5):347-357.
28	EC Smyth, M Nilsson, HI Grabsch, NC van Grieken, F Lordick. Gastric cancer. Lancet. 2020;396(10251):635-648.
29	J Sun, Y Song, Z Wang, et al. Clinical significance of palliative gastrectomy on the survival of patients with incurable advanced gastric cancer: a systematic review and meta-analysis. BMC Cancer. 2013;13:577.
30	YN Zhang, W Poon, AJ Tavares, ID McGilvray, WCW Chan. Nanoparticle-liver interactions: cellular uptake and hepatobiliary elimination. J Control Release. 2016;240:332-348.
31	P Yingchoncharoen, DS Kalinowski, DR Richardson. Lipid-based drug delivery systems in cancer therapy: what is available and what is yet to come. Pharmacol Rev. 2016;68(3):701-787.
32	M Ahmed, Z Liu, AN Lukyanov, et al. Combination radiofrequency ablation with intratumoral liposomal doxorubicin: effect on drug accumulation and coagulation in multiple tissues and tumor types in animals. Radiology. 2005;235(2):469-477.
33	R Grantab, S Sivananthan, IF Tannock. The penetration of anticancer drugs through tumor tissue as a function of cellular adhesion and packing density of tumor cells. Cancer Res. 2006;66(2):1033-1039.
34	HW Kavunja, S Lang, S Sungsuwan, Z Yin, X Huang. Delivery of foreign cytotoxic T lymphocyte epitopes to tumor tissues for effective antitumor immunotherapy against pre-established solid tumors in mice. Cancer Immunol Immunother. 2017;66(4):451-460.
35	X Wang, J Gao, C Li, et al. In situ gelatinase-responsive and thermosensitive nanocomplex for local therapy of gastric cancer with peritoneal metastasis. Mater Today Bio. 2022;15:100305.
36	C Zhou, Q Liu, F Meng, N Ding, J Yan, B Liu. Modification of erythrocytes by internalizing Arg-Gly-Asp (iRGD) in boosting the curative effect of radiotherapy for gastric carcinoma. J Gastrointest Oncol. 2022;13(5):2249-2258.
37	J Shao, Q Xu, S Su, et al. Artificial antigen-presenting cells are superior to dendritic cells at inducing antigen-specific cytotoxic T lymphocytes. Cell Immunol. 2018;334:78-86.
38	S Su, Z Zou, F Chen, et al. CRISPR-Cas9-mediated disruption of PD-1 on human T cells for adoptive cellular therapies of EBV positive gastric cancer. Oncoimmunology. 2017;6(1):e1249558.