Combinatorial Immunotherapy of Anti-MCAM CAR-modified Expanded Natural Killer Cells and NKTR-255 Against Neuroblastoma

Overview

Journal Mol Ther Oncol

Date 2024 Nov 18

PMID 39554906

Authors

Wen Luo

Aliza Gardenswartz

Hai Hoang

Yaya Chu

Meijuan Tian

Yanling Liao

Janet Ayello

Jeremy M Rosenblum

Xiaokui Mo

A Mario Marcondes

Willem W Overwijk

Timothy P Cripe

Dean A Lee

Mitchell S Cairo

Affiliations

Soon will be listed here.

Abstract

Pediatric patients with recurrent metastatic neuroblastoma (NB) have a dismal 5-year survival. Novel therapeutic approaches are urgently needed. The melanoma cell adhesion molecule (MCAM/CD146/MUC18) is expressed in a variety of pediatric solid tumors, including NB, and constitutes a novel target for immunotherapy. Here, we developed a chimeric antigen receptor (CAR) expressing natural killer (NK) cell-targeting MCAM by non-viral electroporation of CAR mRNA into expanded NK cells. Expression of anti-MCAM CAR significantly enhanced NK cell cytotoxic activity compared to mock NK cells against MCAM but not MCAM NB cells . Anti-MCAM-CAR-NK cell treatment significantly decreased tumor growth and prolonged animal survival in an NB xenograft mouse model. NKTR-255, a polymer-conjugated recombinant human interleukin-15 agonist, significantly stimulated NK cell proliferation and expansion and further enhanced the cytotoxic activity and anti-tumor efficacy of anti-MCAM-CAR-NK cells against NB. Our preclinical studies demonstrate that expanded and modified anti-MCAM-CAR-NK cells alone and/or in combination with NKTR-255 are promising novel alternative therapeutic approaches to targeting MCAM malignant NB.

References

Nayyar G, Chu Y, Cairo M . Overcoming Resistance to Natural Killer Cell Based Immunotherapies for Solid Tumors. Front Oncol. 2019; 9:51. PMC: 6378304. DOI: 10.3389/fonc.2019.00051. View

Sechler M, Parrish J, Birks D, Jedlicka P . The histone demethylase KDM3A, and its downstream target MCAM, promote Ewing Sarcoma cell migration and metastasis. Oncogene. 2017; 36(29):4150-4160. PMC: 5519422. DOI: 10.1038/onc.2017.44. View

McGary E, Heimberger A, Mills L, Weber K, Thomas G, Shtivelband M . A fully human antimelanoma cellular adhesion molecule/MUC18 antibody inhibits spontaneous pulmonary metastasis of osteosarcoma cells in vivo. Clin Cancer Res. 2003; 9(17):6560-6. View

Melaiu O, Chierici M, Lucarini V, Jurman G, Conti L, De Vito R . Cellular and gene signatures of tumor-infiltrating dendritic cells and natural-killer cells predict prognosis of neuroblastoma. Nat Commun. 2020; 11(1):5992. PMC: 7689423. DOI: 10.1038/s41467-020-19781-y. View

Liu E, Marin D, Banerjee P, Macapinlac H, Thompson P, Basar R . Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. N Engl J Med. 2020; 382(6):545-553. PMC: 7101242. DOI: 10.1056/NEJMoa1910607. View

Fry T, Shah N, Orentas R, Stetler-Stevenson M, Yuan C, Ramakrishna S . CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2017; 24(1):20-28. PMC: 5774642. DOI: 10.1038/nm.4441. View

Orentas R, Yang J, Wen X, Wei J, Mackall C, Khan J . Identification of cell surface proteins as potential immunotherapy targets in 12 pediatric cancers. Front Oncol. 2012; 2:194. PMC: 3523547. DOI: 10.3389/fonc.2012.00194. View

Park J, Kreissman S, London W, Naranjo A, Cohn S, Hogarty M . Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients With High-Risk Neuroblastoma: A Randomized Clinical Trial. JAMA. 2019; 322(8):746-755. PMC: 6714031. DOI: 10.1001/jama.2019.11642. View

Sanjana N, Shalem O, Zhang F . Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods. 2014; 11(8):783-784. PMC: 4486245. DOI: 10.1038/nmeth.3047. View

10.

Chu Y, Hochberg J, Yahr A, Ayello J, van de Ven C, Barth M . Targeting CD20+ Aggressive B-cell Non-Hodgkin Lymphoma by Anti-CD20 CAR mRNA-Modified Expanded Natural Killer Cells In Vitro and in NSG Mice. Cancer Immunol Res. 2014; 3(4):333-44. DOI: 10.1158/2326-6066.CIR-14-0114. View

11.

Yu A, Gilman A, Ozkaynak M, London W, Kreissman S, Chen H . Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010; 363(14):1324-34. PMC: 3086629. DOI: 10.1056/NEJMoa0911123. View

12.

Geller M, Knorr D, Hermanson D, Pribyl L, Bendzick L, McCullar V . Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. Cytotherapy. 2013; 15(10):1297-306. PMC: 3775496. DOI: 10.1016/j.jcyt.2013.05.022. View

13.

Zhao Y, Moon E, Carpenito C, Paulos C, Liu X, Brennan A . Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res. 2010; 70(22):9053-61. PMC: 2982929. DOI: 10.1158/0008-5472.CAN-10-2880. View

14.

Miyazaki T, Maiti M, Hennessy M, Chang T, Kuo P, Addepalli M . NKTR-255, a novel polymer-conjugated rhIL-15 with potent antitumor efficacy. J Immunother Cancer. 2021; 9(5). PMC: 8130760. DOI: 10.1136/jitc-2020-002024. View

15.

Tang F, Zhao L, Jiang Y, Ba D, Cui L, He W . Activity of recombinant human interleukin-15 against tumor recurrence and metastasis in mice. Cell Mol Immunol. 2008; 5(3):189-96. PMC: 4651289. DOI: 10.1038/cmi.2008.23. View

16.

Denman C, Senyukov V, Somanchi S, Phatarpekar P, Kopp L, Johnson J . Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS One. 2012; 7(1):e30264. PMC: 3261192. DOI: 10.1371/journal.pone.0030264. View

17.

Cho D, Shook D, Shimasaki N, Chang Y, Fujisaki H, Campana D . Cytotoxicity of activated natural killer cells against pediatric solid tumors. Clin Cancer Res. 2010; 16(15):3901-9. PMC: 3168562. DOI: 10.1158/1078-0432.CCR-10-0735. View

18.

Chu Y, Nayyar G, Jiang S, Rosenblum J, Soon-Shiong P, Safrit J . Combinatorial immunotherapy of N-803 (IL-15 superagonist) and dinutuximab with ex vivo expanded natural killer cells significantly enhances in vitro cytotoxicity against GD2 pediatric solid tumors and in vivo survival of xenografted immunodeficient.... J Immunother Cancer. 2021; 9(7). PMC: 8268924. DOI: 10.1136/jitc-2020-002267. View

19.

Sivori S, Parolini S, Marcenaro E, Castriconi R, Pende D, Millo R . Involvement of natural cytotoxicity receptors in human natural killer cell-mediated lysis of neuroblastoma and glioblastoma cell lines. J Neuroimmunol. 2000; 107(2):220-5. DOI: 10.1016/s0165-5728(00)00221-6. View

20.

Whittle S, Smith V, Doherty E, Zhao S, McCarty S, Zage P . Overview and recent advances in the treatment of neuroblastoma. Expert Rev Anticancer Ther. 2017; 17(4):369-386. DOI: 10.1080/14737140.2017.1285230. View