Pharmacological ascorbate as a novel therapeutic strategy to enhance cancer immunotherapy

Abstract

Pharmacological ascorbate (i.e., intravenous infusions of vitamin C reaching ~ 20 mM in plasma) is under active investigation as an adjuvant to standard of care anti-cancer treatments due to its dual redox roles as an antioxidant in normal tissues and as a prooxidant in malignant tissues. Immune checkpoint inhibitors (ICIs) are highly promising therapies for many cancer patients but face several challenges including low response rates, primary or acquired resistance, and toxicity. Ascorbate modulates both innate and adaptive immune functions and plays a key role in maintaining the balance between pro and anti-inflammatory states. Furthermore, the success of pharmacological ascorbate as a radiosensitizer and a chemosensitizer in pre-clinical studies and early phase clinical trials suggests that it may also enhance the efficacy and expand the benefits of ICIs.

Non-pharmaceutical interventions to optimize cancer immunotherapy

“… 108–111 Evaluating vitamins as treatment adjuncts for ICB bases on rational assumptions (many vitamins are immune modulators) and is also supported by a wealth of quite promising early-stage data. 112–116 An important study recently found an association of vitamin E intake with improved survival of ICB-treated patients, with vitamin E enhancing anticancer immunity by targeting the DC-intrinsic immune checkpoint SHP1 and fostering cross-presentation of tumor antigens to up immune surveillance. 117 Similarly, a study involving 200 patients with advanced melanoma treated with PD-1 inhibitors (nivolumab or pembrolizumab) showed that vitamin D supplementation increased the objective response rate and significantly prolonged progression-free survival (PFS).…”

Targeting the Interplay of Independent Cellular Pathways and Immunity: A Challenge in Cancer Immunotherapy

“…Vit C enhances the cytotoxic activity of Tils in CAR-T therapy and cooperates with ICIs therapy. This has provided a rationale for clinical trials combining ICIs with high doses of Vit C, as this antioxidant protection treatment can convert ROS into less reactive species [33][34][35].…”

“…Interestingly, the potential pro-oxidant role of pharmacological doses of Vit C has been successfully harnessed as a radio-sensitizer and a chemo-sensitizer in preclinical studies and early-phase clinical trials. This has suggested that it may also increase both the efficacy and benefits of ICIs [33,34]. Furthermore, Vit C affects multiple immune cell functions and can help overcome resistance to ICIs due to cytotoxic T-lymphocyte antigen 4 (CLTA-4) and programmed cell death ligand 1 (PD-L1/PD-1) inhibitors.…”

“…In addition, contradictory epidemiological evidence shows that high doses of Vit C cause harmful effects over a long administration period and even increase the risk of cancer. Indeed, Vit C also regulates mechanisms through which cancer escapes T cells' immune response and resists ICIs [34].…”

Differential H2O2 Metabolism among Glioblastoma Subtypes Confers Variable Responses to Pharmacological Ascorbate Therapy Combined with Chemoradiation

“…Recently, pharmacological ascorbate (high-dose intravenous infusions of vitamin C resulting in plasma concentrations of ≈20 mM, P-AscH − ) has garnered attention as a potential anticancer agent to enhance the response to SOC therapy across various malignancies, including GBM [12][13][14][15][16]. When ascorbate is oxidized, it generates high levels of hydrogen peroxide (H 2 O 2 ), which can react with redox-active iron, primarily Fe 2+ , through Fenton chemistry, resulting in an excess of damaging hydroxyl radicals capable of disrupting biological macromolecules [12,13,16,17].…”