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A. Falgàs et al.
logical alteration in normal organs, including the BM. The higher levels of CXCR4 expression in DLBCL cells, as compared to normal hematopoietic cells in the BM, were likely responsible for the cytotoxic activity, observed exclusively in tumor cells. These data confirm the capacity of the studied protein nanocarrier to be used as a platform for the delivery of antitumor agents to DLBCL cells. We have previously described also the potential use of T22- GFP-H6 as an antitumor drug delivery agent for the treat- ment of colorectal cancer and leukemia.18,38,39 To our knowledge, no protein-based therapeutic nanoparticle has been previously reported as a possible drug carrier for lymphoma therapy.
So far, most research studies for DLBCL therapy target- ing CXCR4 are performed with CXCR4 antagonists (e.g. plerixafor or BKT140)8,10,15 or inverse agonists (e.g. IQS- 01.01RS).40 Our approach differs from these studies since it is not focused on inhibiting signaling downstream of the CXCR4 receptor, but, instead, in delivering high concen- trations of potent therapeutic agents to specifically kill CXCR4+ lymphoma cells. The active delivery of the drug- loaded nanocarriers only to CXCR4+ cells should increase the therapeutic index compared to low molecular weight CXCR4 inhibitors, which biodistribute to all tissues inde- pendently of their CXCR4 expression.41,42 In conclusion, specifically eliminating CXCR4+ DLBCL cells could be an effective strategy to enhance the survival and cure rates observed in R-CHOP refractory or relapsed patients.
Acknowledgments
The authors would like to thank Annabel García-León (IIB-
Sant Pau, Barcelona) and Lola Mulero Pérez (histology unit from CMRB, Barcelona) for their technical support.
Funding
This work was supported by Instituto de Salud Carlos III (ISCIII, Co-funding from FEDER) [PI18/00650, PIE15/00028, PI15/00378 and EU COST Action CA 17140 to RM, FIS PI17/01246, RD12/0036/0071 and FIS PI14/00450 to JS; CP15/00163 to MVC; FIS PI15/00272 to EV]; Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) (grant BIO2016-76063-R, AEI/FEDER, UE) to AV; CIBER-BBN [CB06/01/1031 and 4NanoMets to RM, and VENOM4CANCER to AV]; AGAUR [2017 FI_B 00680 to AF; 2017-SGR-865 to RM, 2017-SGR-1395 to JS and 2017SGR-229 to AV]; Josep Carreras Leukemia Research Institute [P/AG to RM]; a grant from the Cellex Foundation, Barcelona [to JS]; a grant from La Generalitat de Catalunya (PERIS) [SLT002/16/00433 to JS]; a grant from Fundacion MMA [AP166942017 to MVC] and the Generalitat de Catalunya CERCA Programme. The work was also funded by Grants PERIS SLT006/17/00093 [to UU], Fundación Española de Hematología y Hemoterapia (FEHH) [to VP] and a Miguel Servet contract from ISCIII to MVC. The bioluminescent follow- up of cancer cells and nanoparticle biodistribution and toxicity studies have been performed in the ICTS-141007 Nanbiosis Platform, using its CIBER-BBN Nanotoxicology Unit (http://www.nanbiosis.es/portfolio/u18-nanotoxicology-unit/). Protein production has been partially performed by the ICTS “NANBIOSIS”, more specifically by the Protein Production Platform of CIBER-BBN/ IBB (http://www.nanbiosis. es/unit/u1-protein-production-platform-ppp/).
References
1. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classi- fication of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011;117(19):5019– 5032.
2. Nowakowski GS, Blum KA, Kahl BS, et al. Beyond RCHOP: A Blueprint for Diffuse Large B Cell Lymphoma Research. J Natl Cancer Inst. 2016;108(12).
3. Cultrera JL, Dalia SM. Diffuse large B-cell lymphoma: current strategies and future directions. Cancer Control J Moffitt Cancer Cent. 2012;19(3):204–213.
4. Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with dif- fuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 2005;23(18):4117– 4126.
5. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non- Hodgkin’s lymphoma. N Engl J Med. 1995;333(23):1540–1545.
6. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous trans- plantation for relapsed large B-cell lym- phoma in the rituximab era. J Clin Oncol. 2010;28(27):4184–4190.
7. Chen J, Xu-Monette ZY, Deng L, et al.
Dysregulated CXCR4 expression promotes lymphoma cell survival and independently predicts disease progression in germinal center B-cell-like diffuse large B-cell lym- phoma. Oncotarget 2015;6(8):5597–5614.
8. Moreno MJ, Bosch R, Dieguez-Gonzalez R, et al. CXCR4 expression enhances diffuse large B cell lymphoma dissemination and decreases patient survival. J Pathol. 2015; 235(3):445–455.
9. Xu Z-Z, Shen J-K, Zhao S-Q, Li J-M. Clinical significance of chemokine receptor CXCR4 and mammalian target of rapamycin (mTOR) expression in patients with diffuse large B-cell lymphoma. Leuk Lymphoma. 2018;59(6):1451–1460.
10. Reinholdt L, Laursen MB, Schmitz A, et al. The CXCR4 antagonist plerixafor enhances the effect of rituximab in diffuse large B-cell lymphoma cell lines. Biomark Res. 2016;4:12.
11. Domanska UM, Kruizinga RC, Nagengast WB, et al. A review on CXCR4/CXCL12 axis in oncology: No place to hide. Eur J Cancer. 2013;49(1):219–230.
12. Bertolini F, Dell’Agnola C, Mancuso P, et al. CXCR4 neutralization, a novel therapeutic approach for non-Hodgkin’s lymphoma. Cancer Res. 2002;62(11):3106–3112.
13. Kuhne MR, Mulvey T, Belanger B, et al. BMS-936564/MDX-1338: a fully human anti-CXCR4 antibody induces apoptosis in vitro and shows antitumor activity in vivo in hematologic malignancies. Clin Cancer Res. 2013;19(2):357–366.
14. Reinholdt LR, Laursen MB, Falgreen S, et al.
High expression of CXCR4 impairs anti- CD20 monoclonal antibody (Rituximab)- dependent cytotoxicity in diffuse large B-cell lymphoma. Blood. 2015; 126(23):1455–1455.
15. Beider K, Ribakovsky E, Abraham M, et al. Targeting the CD20 and CXCR4 pathways in non-hodgkin lymphoma with rituximab and high-affinity CXCR4 antagonist BKT140. Clin Cancer Res. 2013;19(13): 3495–3507.
16. Unzueta U, Céspedes MV, Ferrer-Miralles N, et al. Intracellular CXCR4+ cell targeting with T22-empowered protein-only nanoparticles. Int J Nanomedicine. 2012; 7:4533–4544.
17. Céspedes MV, Unzueta U, Tatkiewicz W, et al. In vivo architectonic stability of fully de novo designed protein-only nanoparti- cles. ACS Nano. 2014;8(5):4166–4176.
18. Sánchez-García L, Serna N, Álamo P, et al. Self-assembling toxin-based nanoparticles as self-delivered antitumoral drugs. J Control Release. 2018;274:81–92.
19. Serna N, Sánchez-García L, Unzueta U, et al. Protein-Based Therapeutic Killing for Cancer Therapies. Trends Biotechnol. 2018;36(3):318–335.
20. Rosenblum D, Joshi N, Tao W, Karp JM, Peer D. Progress and challenges towards targeted delivery of cancer therapeutics. Nat Commun. 2018;9(1):1410.
21. Pirollo KF, Chang EH. Does a targeting lig- and influence nanoparticle tumor localiza- tion or uptake? Trends Biotechnol. 2008; 26(10):552–558.
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