Nanoformulation improves antitumor efficacy of MAOI immune checkpoint blockade therapy without causing aggression-related side effects

James Brown; Zhe Li; Xi Wang; Yu Jeong Kim; Yu-Chen Wang; Yanning Zuo; Weizhe Hong; Pin Wang; Bo Li; Lili Yang

doi:10.3389/fphar.2022.970324

Nanoformulation improves antitumor efficacy of MAOI immune checkpoint blockade therapy without causing aggression-related side effects

Front Pharmacol. 2022 Sep 1:13:970324. doi: 10.3389/fphar.2022.970324. eCollection 2022.

Authors

James Brown¹, Zhe Li¹, Xi Wang¹, Yu Jeong Kim¹, Yu-Chen Wang¹, Yanning Zuo^{2

3}, Weizhe Hong^{2

3}, Pin Wang⁴, Bo Li¹, Lili Yang^{1

5

6

7}

Affiliations

¹ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, United States.
² Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA, United States.
³ Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, CA, United States.
⁴ Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, United States.
⁵ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, United States.
⁶ Jonsson Comprehensive Cancer Center, The David Geffen School of Medicine, University of California, Los Angeles, CA, United States.
⁷ Molecular Biology Institute, University of California, Los Angeles, CA, United States.

Abstract

MAOIs, a well-established class of antidepressant that operate through the inhibition of monoamine oxidase to increase available serotonin, have recently been identified as a surprisingly effective candidate for the circumvention of tumor-induced immune suppression due to their abilities to enhance antitumor T cell activity through autocrine serotonin signaling and depolarize alternatively activated tumor-associated macrophages through a reduction in reactive oxygen species production. However, this impressive class of antidepressants-turned-cancer-drugs can induce aggressive behavioral side effects when administered in immunotherapeutic doses. In this study, we investigated the possibility of avoiding these neurological side effects while simultaneously improving antitumor activity by establishing crosslinked multilamellar liposomal vesicles (cMLVs) containing the MAOI phenelzine (PLZ). Our results showed that cMLV-PLZ treatment increases antitumor efficacy in a B16-OVA mouse melanoma model compared to treatment with free phenelzine. We also found that nanoformulation resulted in the complete elimination of MAOI-related aggression. These findings suggest a promising direction for the future of MAOIs repurposed for cancer immunotherapies.

Keywords: cancer immunotherapy; crosslinked multilamellar liposomal vesicles; immune checkpoint blockade; monoamine oxidase inhibitors; nanoformulation; neurological side effects; phenelzine; serotonin.