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Encapsulated Checkpoint Blocker Before Chemotherapy: The Optimal Sequence of Anti-CTLA-4 and Doxil Combination Therapy

Authors Alimohammadi R, Alibeigi R, Nikpoor AR, Chalbatani GM, Webster TJ, Jaafari MR, Jalali SA

Received 6 May 2020

Accepted for publication 9 July 2020

Published 27 July 2020 Volume 2020:15 Pages 5279—5288


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 4

Editor who approved publication: Prof. Dr. Anderson Oliveira Lobo

Reza Alimohammadi,1 Razieh Alibeigi,2 Amin Reza Nikpoor,3 Ghanbar Mahmoodi Chalbatani,4 Thomas J Webster,5 Mahmoud Reza Jaafari,6,7,* Seyed Amir Jalali1,*

1Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 2Department of Immunology, School of Medicine, Mashhad University of Medical Sciences, Tehran, Iran; 3Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran; 4Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; 5Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA; 6Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; 7Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

*These authors contributed equally to this work

Correspondence: Seyed Amir Jalali
Department of Immunology, Medical School, Shahid Beheshti University of Medical Sciences, Tehran 198571-7443, Iran
Tel +98 21-238 725 45
Fax + 98 21-224 399 70
Mahmoud Reza Jaafari
Biotechnology Research Center, Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 91775-1365, Iran
Tel +98 51-38823255
Fax +98 51-38823251

Introduction: Today, a new paradigm has emerged for cancer treatment introducing combination therapies. Doxil, a liposomal doxorubicin serving as a chemotherapeutic agent, is an effective immunogenic killer of cancer cells. Anti-CTLA-4 has been approved for the treatment of some cancers, including melanoma, but side effects have limited its therapeutic potential.
Methods: In this study, two approaches were utilized to increase treatment efficiency and decrease the side effects of anti-CTLA-4, combining it with chemotherapy and encapsulation in a PEGylated liposome. A different sequence of anti-CTLA-4 and Doxil was assessed in combination therapy using non-liposomal and liposomal anti-CTLA-4.
Results: Our results showed that liposomal anti-CTLA-4 reduced the size of established tumors and increased survival in comparison with non-liposomal anti-CTLA-4 in a well-established B16 mouse melanoma model. In combination therapy with Doxil, only the administration of anti-CTLA-4 before Doxil showed synergism in both non-liposomal and liposomal form and increased the CD8+/regulatory T cell ratio.
Discussion: In summary, our results demonstrate the potential of utilizing a nanocarrier system for the delivery of checkpoint blockers, such as anti-CTLA-4 which further showed potential in a combination therapy, especially when administered before chemotherapy.

Keywords: chemotherapy, anti-CTLA-4, checkpoint blockers, immunotherapy, liposome

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