Our recent adoptive T cell transfer trial for mesothelioma revealed a striking anti-tumor response in a patient which was accompanied by anaphylaxis, suggesting endogenous histamine release. In animal models, histamine has direct and immune-based anti-tumor effects. In fact, histamine dihydrochloride is approved in Europe in combination with interleukin-2 (IL2) for leukemia treatment. We thus explored the anti-tumor role of histamine in mesothelioma. An in vitro MTT assay was used to measure cell proliferation. Daily doses of histamine (1 mg/kg) – alone, or in combination with other immunotherapies – was used to treat four subcutaneous flank tumor models in three different mouse strains. Flow cytometric analyses were subsequently performed on tumors. Histamine had in vitro anti-tumor activity against all five cell lines tested with an IC50 of 1.8 mM. Histamine also significantly reduced tumor volume in all four in vivo models without toxic side effects. Immunodepletion studies revealed that the effect was partially due to T cells. When combined with two immunotherapy approaches (adenovirally-delivered interferon-α or a tumor antigen), anti-tumor efficacy was augmented. Histamine resulted in more interferon-γ and IL2 production by tumor-infiltrating lymphocytes (TIL), downregulation of CD206 expression on tumor-infiltrating macrophages, and reduced numbers of T regulatory cells (Tregs). Histamine has direct anti-tumor effects and immune-stimulatory effects within the tumor microenvironment (as seen with macrophage polarization, increase in cytokine production, and reduction in Tregs). This pre-clinical data suggests that histamine alone, or in combination with immunotherapy, should be explored in the treatment of mesothelioma.
Citation Format: Kheng Newick, Shaun O'Brien, Veena Kapoor, Liang-chuan Wang, Edmund Moon, Andrew Haas, Evan Alley, Daniel Sterman, Steven Albelda. Histamine dihydrochloride in the treatment of mesothelioma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B78.
- ©2015 American Association for Cancer Research.