High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model

Abstract

Major efforts are underway to identify agents that can potentiate effects of immune checkpoint inhibition. Here, we show that ascorbic acid (AA) treatment caused genomewide demethylation and enhanced expression of endogenous retroviral elements in lymphoma cells. AA also increased 5-hydroxymethylcytosine (5hmC) levels of CD8+ T cells and enhanced their cytotoxic activity in a lymphoma coculture system. High-dose AA treatment synergized with anti-PD1 therapy in a syngeneic lymphoma mouse model, resulting in marked inhibition of tumor growth compared with either agent alone. Analysis of the intratumoral epigenome revealed increased 5hmC with AA treatment, consistent with in vitro findings. Analysis of the tumor immune microenvironment revealed that AA strikingly increased intratumoral infiltration of CD8+ T cells and macrophages, suggesting enhanced tumor immune recognition. The combination treatment markedly enhanced intratumoral infiltration of macrophages and CD8+ T lymphocytes, granzyme B production by cytotoxic cells (cytotoxic T cells and natural killer cells), and interleukin 12 production by antigen-presenting cells compared with single-agent anti-PD1. These data indicate that AA potentiates anti-PD1 checkpoint inhibition through synergistic mechanisms. The study provides compelling rationale for testing combinations of high-dose AA and anti-PD1 agents in patients with aggressive B cell lymphoma as well as in preclinical models of other malignancies.

Immune evasion in renal cell carcinoma: biology, clinical translation, future directions

“…ccRCC is characterized by deletions and under-expression of L-2-hydroxyglutarate dehydrogenase (L2HGDH) which results in the aberrant accumulation of L-2-hydoxyglutarate (L2HG) 44 . L2HG competitively inhibits the Ten-Eleven-Translocation (TET) enzymes, including TET2, which has been shown to have an important role in cancer immunity 15,45 . ccRCC is also characterized by loss of succinate dehydrogenase resulting in the accumulation of oncogenic succinate, which also inhibits the TET enzymes, further contributing to the widespread genomic aberrant hypermethylation in the malignancy 46,47 .…”

“…Agents that have shown remarkable pre-clinical efficacy in combination with checkpoint inhibition but are not 'patentable' or 'profitable' have a markedly tougher road to effective translation-even if they have been shown to be safe and well-tolerated in cancer patients. As an example, high dose ascorbic acid has been recently shown to synergistically enhance the efficacy of checkpoint inhibition 15,97 , is known to be safe and well tolerated in cancer patients 98 , and deserves clinical exploration in combination with checkpoint inhibition. However, financial considerations and logistics impede such exploration.…”

Low-dose ipilimumab plus nivolumab combined with IL-2 and hyperthermia in cancer patients with advanced disease: exploratory findings of a case series of 131 stage IV cancers – a retrospective study of a single institution

“…Parallel to local regional hyperthermia patients received 3 times weekly high dose vitamin C intravenously (0.5 g/ kg) and alpha lipoic acid 600 mg. High-dose vitamin C has been suggested as an adjuvant cancer treatment as it is toxic to tumor cells, since it targets many of the mechanisms that cancer cells utilize for their survival and growth. High-dose vitamin C delays cancer growth by enhancing infiltration of the tumor microenvironment by immune cells and cooperates with immune checkpoint therapy (ICT) in several cancer types [23][24][25][26]. Lipoic acid synergistically enhanced ascorbate cytotoxicity [27] and inhibited the enzyme pyruvate dehydrogenase kinase that is particularly upregulated in cancer cells and is the major determinant of the "Warburg effect", thus contributing to a higher vulnerability/decreased resilience of the neoplasm [28].…”

T Cell Metabolism in Cancer Immunotherapy

“…The combination of anti-PD-L1 monoclonal antibody and oltipraz or bezafibrate, two ligands of the PGC1α/Nrf2 and PGC1α/PPAR complexes, respectively, resulted in augmented tumor-suppression activity compared to either treatment alone, explained by the significant increase in both mitochondrial metabolism and glycolysis, driven by PGC1α/PPAR signaling [105]. Other studies showed that high-dose vitamin C in mouse tumor models synergized with anti-PD-1 to enhance cancer immunotherapy, but the exact mechanism of action remains unclear [106,107]. Similarly, adding metformin to PD-1 blockade regimen resulted in enhanced T cell anti-tumor immunity and tumor clearance in murine models by decreasing intra-tumoral hypoxia.…”