High-Dose Ascorbate in Combination with Anti-PD1 Checkpoint Inhibition as Treatment Option for Malignant Melanoma

Abstract

Ascorbate acts as a prooxidant when administered parenterally at high supraphysiological doses, which results in the generation of hydrogen peroxide in dependence on oxygen. Most cancer cells are susceptible to the emerging reactive oxygen species (ROS). Accordingly, we evaluated high-dose ascorbate for the treatment of the B16F10 melanoma model. To investigate the effects of ascorbate on the B16F10 cell line in vitro, viability, cellular impedance, and ROS production were analyzed. In vivo, C57BL/6NCrl mice were subcutaneously injected into the right flank with B16F10 cells and tumor-bearing mice were treated intraperitoneally with ascorbate (3 g/kg bodyweight), immunotherapy (anti-programmed cell death protein 1 (PD1) antibody J43; 2 mg/kg bodyweight), or both treatments combined. The efficacy and toxicity were analyzed by measuring the respective tumor sizes and mouse weights accompanied by histological analysis of the protein levels of proliferating cell nuclear antigen (Pcna), glucose transporter 1 (Glut-1), and CD3. Treatment of B16F10 melanoma-carrying mice with high-dose ascorbate yielded plasma levels in the pharmacologically effective range, and ascorbate showed efficacy as a monotherapy and when combined with PD1 inhibition. Our data suggest the applicability of ascorbate as an additional therapeutic agent that can be safely combined with immunotherapy and has the potential to potentiate anti-PD1-based immune checkpoint blockades.

Blood Vitamin C Levels of Patients Receiving Immunotherapy and Relationship to Monocyte Subtype and Epigenetic Modification

“…Clinical trials using ascorbate intervention in patients with melanoma have not yet been reported, but results from animal studies are encouraging. Melanomas grew more slowly and were rejected more effectively [ 40 , 41 ] in ascorbate-treated mice, and immunotherapy treatment against melanoma tumours was enhanced by ascorbate injections in mice [ 42 , 43 ].…”

Ascorbic acid in cancer management – time for a second look

“…In a very recent study published, Burkard et al were able to verify the efficacy of high dose AA to kill melanoma cells both in vitro and in vivo; and how it also exert their effect either alone or in combination with the anti-mouse checkpoint inhibitor antibody synergistically. 122 In another study, Luchtel et al showed that the combination of AA with a checkpoint inhibitor could have significant activity in cancer treatment. Their evaluation was the combination of high dose AA with a checkpoint inhibitor in a lymphoma mouse model.…”

“…In pre-clinical studies, AA has been shown to have synergism with checkpoint inhibitors. 122,123 AA has also been shown to synergistically potentiate the cytotoxicity of targeted therapies ibrutinib, venetoclax and idelalisib in CLL. 188 Further clinical investigations would be needed to determine the clinical benefits.…”