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Development of PD-1 blockade peptide-cell conjugates to enhance cellular therapies for T-cell acute lymphoblastic leukemia

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Abstract

Blockade of the interaction of the immune checkpoint receptor programmed cell death protein (PD)-1 and its ligand PD-L1 has been found to be a promising cancer treatment. Our previous studies identified that nABPD1 competed with PD-L1 to bind PD-1. The aim of this study was to evaluate the efficacy and safety of anti-tumor immunotherapy of ICIK cells conjugated with peptides in vivo and in vitro. Here, we synthesized the nABPD1 derivatives SBP1 and SBP2 and showed that their binding efficiency to PD-1-positive improving cytokine-induced killer (ICIK) cells was 98 and 82%, respectively. The cytotoxicity of ICIK cells to T-cell acute lymphoblastic leukemia (T-ALL) cells was increased by conjugating with SBP1 or SBP2, which was 2 times higher than that of ICIK cells alone. Furthermore, mice experiments showed that the fluorescence intensity of leukemia cells in T-ALL xenograft models was reduced by more than 95%, indicating that the peptides enhanced the therapeutic effect in vivo, while morphological evaluations showed that the peptides had no toxicity to important organs. Therefore, peptide-cell conjugates (PCCs) may be a novel method to improve the efficacy of cancer immunotherapy by blocking PD-1 in T-ALL patients.

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References

  1. Iacobucci I, Mullighan CG. Genetic basis of acute lymphoblastic leukemia. J Clin Oncol. 2017;35(9):975–83. https://doi.org/10.1200/jco.2016.70.7836.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Vadillo E, Dorantes-Acosta E, Pelayo R, Schnoor M. T cell acute lymphoblastic leukemia (T-ALL): new insights into the cellular origins and infiltration mechanisms common and unique among hematologic malignancies. Blood Rev. 2018;32(1):36–51. https://doi.org/10.1016/j.blre.2017.08.006.

    Article  CAS  PubMed  Google Scholar 

  3. Kennedy LB, Salama AKS. A review of cancer immunotherapy toxicity. CA Cancer J Clin. 2020;70(2):86–104. https://doi.org/10.3322/caac.21596.

    Article  PubMed  Google Scholar 

  4. Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol. 2020;17(8):807–21. https://doi.org/10.1038/s41423-020-0488-6.

    Article  CAS  PubMed Central  Google Scholar 

  5. Sharma A, Schmidt-Wolf IGH. 30 years of CIK cell therapy: recapitulating the key breakthroughs and future perspective. J Exp Clin Cancer Res. 2021;40(1):388. https://doi.org/10.1186/s13046-021-02184-2.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Tanaka J. Recent advances in cellular therapy for malignant lymphoma. Cytotherapy. 2021;23(8):662–71. https://doi.org/10.1016/j.jcyt.2020.12.007.

    Article  CAS  PubMed  Google Scholar 

  7. Sterner RM, Sakemura R, Cox MJ, et al. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood. 2019;133(7):697–709. https://doi.org/10.1182/blood-2018-10-881722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021;11(4):69. https://doi.org/10.1038/s41408-021-00459-7.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Lee JB, Vasic D, Kang H, Fang KK, Zhang L. State-of-art of cellular therapy for acute leukemia. Int J Mol Sci. 2021;22(9):4590. https://doi.org/10.3390/ijms22094590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Introna M. CIK as therapeutic agents against tumors. J Autoimmun. 2017;85:32–44. https://doi.org/10.1016/j.jaut.2017.06.008.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang Y, Schmidt-Wolf IGH. Ten-year update of the international registry on cytokine-induced killer cells in cancer immunotherapy. J Cell Physiol. 2020;235(12):9291–303. https://doi.org/10.1002/jcp.29827.

    Article  CAS  PubMed  Google Scholar 

  12. Zhang Y, Ellinger J, Ritter M, Schmidt-Wolf IGH. Clinical studies applying cytokine-induced killer cells for the treatment of renal cell carcinoma. Cancers (Basel). 2020;12(9):2471. https://doi.org/10.3390/cancers12092471.

    Article  CAS  Google Scholar 

  13. Sommaggio R, Cappuzzello E, Dalla Pietà A, et al. Adoptive cell therapy of triple negative breast cancer with redirected cytokine-induced killer cells. Oncoimmunology. 2020;9(1):1777046. https://doi.org/10.1080/2162402x.2020.1777046.

    Article  CAS  PubMed Central  Google Scholar 

  14. Zhang L, Ding J, Li HY, Wang ZH, Wu J. Immunotherapy for advanced hepatocellular carcinoma, where are we? Biochim Biophys Acta Rev Cancer. 2020;1874(2):188441. https://doi.org/10.1016/j.bbcan.2020.188441.

    Article  CAS  PubMed  Google Scholar 

  15. Yu SJ, Ma C, Heinrich B, et al. Targeting the crosstalk between cytokine-induced killer cells and myeloid-derived suppressor cells in hepatocellular carcinoma. J Hepatol. 2019;70(3):449–57. https://doi.org/10.1016/j.jhep.2018.10.040.

    Article  CAS  Google Scholar 

  16. Kim HM, Kang JS, Lim J, et al. Inhibition of human ovarian tumor growth by cytokine-induced killer cells. Arch Pharm Res. 2007;30(11):1464–70. https://doi.org/10.1007/bf02977372.

    Article  CAS  PubMed  Google Scholar 

  17. Jiang P, Zhang Y, Archibald SJ, Wang H. Adoptive cell transfer after chemotherapy enhances survival in patients with resectable HNSCC. Int Immunopharmacol. 2015;28(1):208–14. https://doi.org/10.1016/j.intimp.2015.05.042.

    Article  CAS  PubMed  Google Scholar 

  18. Huang X, Zhang J, Li X, et al. Rescue of iCIKs transfer from PD-1/PD-L1 immune inhibition in patients with resectable tongue squamous cell carcinoma (TSCC). Int Immunopharmacol. 2018;59:127–33. https://doi.org/10.1016/j.intimp.2018.04.011.

    Article  CAS  PubMed  Google Scholar 

  19. Ok CY, Young KH. Targeting the programmed death-1 pathway in lymphoid neoplasms. Cancer Treat Rev. 2017;54:99–109. https://doi.org/10.1016/j.ctrv.2017.01.009.

    Article  CAS  PubMed Central  Google Scholar 

  20. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704. https://doi.org/10.1146/annurev.immunol.26.021607.090331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311–9. https://doi.org/10.1056/NEJMoa1411087.

    Article  CAS  PubMed  Google Scholar 

  22. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018–28. https://doi.org/10.1056/NEJMoa1501824.

    Article  PubMed  Google Scholar 

  23. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359(6382):1350–5. https://doi.org/10.1126/science.aar4060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Verma V, Sprave T, Haque W, et al. A systematic review of the cost and cost-effectiveness studies of immune checkpoint inhibitors. J Immunother Cancer. 2018;6(1):128. https://doi.org/10.1186/s40425-018-0442-7.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kraehenbuehl L, Weng CH, Eghbali S, Wolchok JD, Merghoub T. Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways. Nat Rev Clin Oncol. 2022;19(1):37–50. https://doi.org/10.1038/s41571-021-00552-7.

    Article  CAS  PubMed  Google Scholar 

  26. Chang HN, Liu BY, Qi YK, et al. Blocking of the PD-1/PD-L1 interaction by a D-Peptide antagonist for cancer immunotherapy. Angew Chem Int Ed Engl. 2015;54(40):11760–4. https://doi.org/10.1002/anie.201506225.

    Article  CAS  Google Scholar 

  27. Chen Y, Huang H, Liu Y, et al. Engineering a high-affinity PD-1 peptide for optimized immune cell-mediated tumor therapy. Cancer Res Treat. 2022;54(2):362–74. https://doi.org/10.4143/crt.2021.424.

    Article  CAS  PubMed  Google Scholar 

  28. Zhang X, Schwartz JC, Guo X, et al. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity. 2004;20(3):337–47. https://doi.org/10.1016/s1074-7613(04)00051-2.

    Article  CAS  PubMed  Google Scholar 

  29. Li Y, Sharma A, Bloemendal M, Schmidt-Wolf R, Kornek M, Schmidt-Wolf IGH. PD-1 blockade enhances cytokine-induced killer cell-mediated cytotoxicity in B-cell non-Hodgkin lymphoma cell lines. Oncol Lett. 2021;22(2):613. https://doi.org/10.3892/ol.2021.12874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Han Y, Mu D, Liu T, et al. Autologous cytokine-induced killer (CIK) cells enhance the clinical response to PD-1 blocking antibodies in patients with advanced non-small cell lung cancer: a preliminary study. Thorac Cancer. 2021;12(2):145–52. https://doi.org/10.1111/1759-7714.13731.

    Article  CAS  PubMed  Google Scholar 

  31. Zhou L, Chen Q, Chen H, Wang L, Zhang J. Enhanced inhibitory effect of DC-CIK cells on lung adenocarcinoma via Anti-Tim-3 antibody and antiprogrammed cell death-1 antibody and possible mechanism. Evid Based Complement Alternat Med. 2022;2022:4097576. https://doi.org/10.1155/2022/4097576.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Dehno MN, Li Y, Weiher H, Schmidt-Wolf IGH. Increase in efficacy of checkpoint inhibition by cytokine-induced-killer cells as a combination immunotherapy for renal cancer. Int J Mol Sci. 2020;21(9):3078. https://doi.org/10.3390/ijms21093078.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Liu S, Meng Y, Liu L, et al. CD4(+) T cells are required to improve the efficacy of CIK therapy in non-small cell lung cancer. Cell Death Dis. 2022;13(5):441. https://doi.org/10.1038/s41419-022-04882-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li C, Zhang N, Zhou J, et al. Peptide blocking of PD-1/PD-L1 interaction for cancer immunotherapy. Cancer Immunol Res. 2018;6(2):178–88. https://doi.org/10.1158/2326-6066.Cir-17-0035.

    Article  CAS  PubMed  Google Scholar 

  35. Kotraiah V, Phares TW, Browne CD, et al. Novel peptide-based PD1 immunomodulators demonstrate efficacy in infectious disease vaccines and therapeutics. Front Immunol. 2020;11:264. https://doi.org/10.3389/fimmu.2020.00264.

    Article  CAS  PubMed Central  Google Scholar 

  36. Vlieghe P, Lisowski V, Martinez J, Khrestchatisky M. Synthetic therapeutic peptides: science and market. Drug Discov Today. 2010;15(1–2):40–56. https://doi.org/10.1016/j.drudis.2009.10.009.

    Article  CAS  PubMed  Google Scholar 

  37. Li CM, Haratipour P, Lingeman RG, et al. Novel peptide therapeutic approaches for cancer treatment. Cells. 2021;10(11):2908. https://doi.org/10.3390/cells10112908.

    Article  CAS  PubMed Central  Google Scholar 

  38. Alharbi N, Skwarczynski M, Toth I. The influence of component structural arrangement on peptide vaccine immunogenicity. Biotechnol Adv. 2022;60: 108029. https://doi.org/10.1016/j.biotechadv.2022.108029.

    Article  CAS  Google Scholar 

  39. De Groot AS, Roberts BJ, Mattei A, Lelias S, Boyle C, Martin WD. Immunogenicity risk assessment of synthetic peptide drugs and their impurities. Drug Discov Today. 2023;28(10): 103714. https://doi.org/10.1016/j.drudis.2023.103714.

    Article  CAS  Google Scholar 

  40. Aroda VR, Blonde L, Pratley RE. A new era for oral peptides: SNAC and the development of oral semaglutide for the treatment of type 2 diabetes. Rev Endocr Metab Disord. 2022;23(5):979–94. https://doi.org/10.1007/s11154-022-09735-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zaman R, Islam RA, Ibnat N, et al. Current strategies in extending half-lives of therapeutic proteins. J Control Release. 2019;301:176–89. https://doi.org/10.1016/j.jconrel.2019.02.016.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Yingxia Wu and Chuying Zhang (staff in the Instrument and Equipment Center, School of Life Sciences, Sun Yat-sen University, China) for their support in the process of using flow cytometry and confocal microscopy.

Funding

This research was funded by the Programs of Guangdong Science and Technology Department (No. 2016B030231001; No. 2017B020230002) and the Natural Science Foundation of China (31871413, 32100627), and the GuangDong Basic and Applied Basic Research Foundation (No. 2022A1515110025).

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Authors and Affiliations

  1. Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China

    Quanxiao Wang, Hongxing Huang, Peisheng Liang, Lili Wang & Hua Wang

  2. Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, 56 Lingyuan West Road, Guangzhou, 510055, Guangdong, China

    Quanxiao Wang, Hongxing Huang, Peisheng Liang, Lili Wang & Hua Wang

  3. Guangzhou Yidai Pharmaceutical Co., Ltd, Guangzhou, Guangdong, China

    Junheng Zheng & Hua Wang

  4. Zhuhai Taisujian Biotechnology Co., Ltd, Zhuhai, Guangdong, China

    Junheng Zheng & Hua Wang

  5. Cheerland Taisujian BioPharm. Co., Ltd, Shenzhen, Guangdong, China

    Junheng Zheng & Hua Wang

  6. Laboratory of Cancer and Stem Cell Biology, Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou Higher Education Mega Center, Guangzhou, China

    Yan Zhang

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  1. Quanxiao Wang
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Wang, Q., Huang, H., Liang, P. et al. Development of PD-1 blockade peptide-cell conjugates to enhance cellular therapies for T-cell acute lymphoblastic leukemia. Med Oncol 41, 14 (2024). https://doi.org/10.1007/s12032-023-02235-y

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