Kurt R. Gehlsen

Results from a randomized phase III study comparing Combined treatment with histamine dihydrochloride plus interleukin-2 versus interleukin-2 alone in patients with metastatic melanoma

PURPOSE Reactive oxidative species (ROS) produced by phagocytic cells have been ascribed a role in the localized suppression of lymphocyte function within malignant tumors. Histamine has been shown to inhibit ROS formation and possibly synergize with cytokines to permit activation of natural killer cells and T cells. This study was designed to determine whether the addition of histamine to a subcutaneous (SC) regimen of interleukin-2 (IL-2) would improve the survival of metastatic melanoma patients. PATIENTS AND METHODS A phase III, multicenter, randomized, parallel group study comparing IL-2 plus histamine with IL-2 alone was conducted in 305 patients with advanced metastatic melanoma. Patients were randomized to IL-2 (9 MIU/m(2) bid SC on days 1 to 2 of weeks 1 and 3, and 2 MIU/m(2) bid SC on days 1 to 5 of weeks 2 and 4) with or without histamine (1.0 mg bid SC days 1 to 5, weeks 1 to 4). The primary end point, survival, was prospectively applied to all randomized patients (intent-to-treat-overall population, ITT-OA) and all patients having liver metastases at randomization (ITT-LM population). Secondary end points included safety of the combined treatment, time to disease progression, and response rate. RESULTS Combined treatment with histamine plus IL-2 significantly improved overall survival in the ITT-LM population (P =.004) and showed a trend for improved survival in the ITT population (P =.125). Grade 3 and 4 adverse events were comparable in the two arms. CONCLUSION Use of histamine as an adjunct to IL-2 is safe, well tolerated, and associated with a statistically significant prolongation of survival compared with IL-2 alone in metastatic melanoma patients with liver involvement. Further trials to confirm and understand the role of histamine in this combination treatment are underway.

HISTAMINE PROTECTS T CELLS AND NATURAL KILLER CELLS AGAINST OXIDATIVE STRESS

Oxidative stress inflicted by monocytes/macrophages (MO) is recognized as an important immunosuppressive mechanism in human neoplastic disease. We report that two types of lymphocytes of relevance for protection against malignant cells, T cells and natural killer (NK) cells, became anergic to the T cell and NK cell activator interleukin-2 (IL-2) after exposure to MO-derived reactive oxygen metabolites and subsequently acquired features characteristic of apoptosis. The MO-induced anergy and apoptosis in T cells and NK cells were reversed by histamine, an inhibitor of reactive oxygen metabolite synthesis in MO. We propose that strategies to circumvent oxidative inhibition of lymphocytes may be of benefit in immunotherapy of neoplastic disease.

Histamine: A Novel Approach to Cancer Immunotherapy

Abstract The functions of intratumoral lymphocytes in many human malignant tumors are inhibited by reactive oxygen species (ROS), generated by adjacent monocytes/macrophages (MO). In vitro data suggest that immunotherapeutic cytokines such as interleukin-2 (IL-2) or interferon-α (IFN-α) only weakly activate T cells or natural killer (NK) cells in a reconstituted environment of oxidative stress and that inhibitors of the formation of ROS or scavengers of ROS synergize with IL-2 and IFN-α to activate T cells and NK cells. In this review, we focus on the immunoenhancing properties ofhistamine, a biogenic amine. Histamine inhibits ROS formation in MO via H2–receptors; thereby, histamine protects NK cells from MO-mediated inhibition and synergizes with IL-2 and IFN-α to induce killing of NK cell-sensitive human tumor cells in vitro. Histamine also optimizes cytokine-induced activation of several subsets of T cells by affording protection against MO-inflicted oxidative inhibition. The putative clinical benefit of histamine as an adjunct to immunotherapy with IL-2 and/or IFN-α is currently evaluated in clinical trials in metastatic malignant melanoma and acute myelogenous leukemia.

Immunotherapy with histamine and interleukin 2 in malignant melanoma with liver metastasis

Immunotherapy with histamine and interleukin 2 in malignant melanoma with liver metastasis.

Pharmacokinetics of Histamine Dihydrochloride in Healthy Volunteers and Cancer Patients: Implications for Combined Immunotherapy with Interleukin-2

Recent clinical trials in melanoma and leukemia have demonstrated potential for increased survival time and improved remission when histamine dihydrochloride is added to cytokine monotherapy. In the present study, the pharmacokinetics of subcutaneous histamine (1 mg) in 21 healthy subjects and 12 melanoma patients was determined via model‐dependent methods. Drug‐druginteractions with subcutaneous interleukin‐2 (1.1 mg) were evaluated in a combined cohort of patients with melanoma (n = 8) or renal cell carcinoma (n = 4). Histamine dihydrochloride administered over 10 minutes in healthy subjects peaked at 18 minutes (Cmax 38 nmol/L), attained a distribution volume of 59 L, and was eliminated at 6%/min. The results were similar in a 20‐minute infusion in melanoma patients. No gender effects were observed (p > 0.05). Interleukin‐2 injected either 10 minutes prior to or 10 minutes following histamine dihydrochloride had no effect on histamine kinetics. Histamine dihydrochloride administered 10 minutes priorto injection of interleukin‐2 also had no effect on interleukin‐2 kinetics. Maximal concentration of interleukin‐2 (2,442 pg/ml) occurred at 2.5 hours with an elimination half‐life of 1.7 hours, area under the curve (AUC) of 15,746 pg·h/ml, and volume of distribution and plasma clearance of 194 L and 74 L/h, respectively. However, interleukin‐2 Cmax (1,758 pg/ml) and AUC (12,448 pg·h/ml) were reduced when histamine dihydrochloride was infused 10 minutes following interleukin‐2, likely due to the pharmacodynamic effects of histamine, including increased heart rate and reduced blood pressure. It is concluded that histamine dihydrochloride and interleukin‐2 can be safely coadministered with minimal interaction.

Toxicology and Toxicokinetics of Acute and Subchronic Administration of Histamine Dihydrochloride in Rats

Abstract Histamine dihydrochloride is currently being evaluated as an adjuvant to immunotherapy regimens in neoplastic and infectious diseases. The no-observed-effect-level (NOEL), no-observable-adverse-effect-level (NOAEL), and pharmacokinetics of subcutaneously administered histamine dihydrochloride were determined via 5 and 28 day repeated dose studies in Sprague-Dawley rats. In the five day study, male rats received 0 (vehicle), 5, 30, 500, or 1000 mg/kg BID. Acute tissue damage was observed at one or more injection sites in the two highest dose groups after 24 h. At five days, animals in these groups displayed indications of pathological inflammation at the injection sites. In the 28 day study, male and female rats received 0 (vehicle), 0.5, 5, or 100 mg/kg BID. The most significant treatment-related pathological findings were signs of inflammation at the injection sites for animals in the 100 mg/kg BID group. Hematology and clinical chemistry changes in the highest dose groups in both studies were consistent with inflammation and anemia but were found to be reversible following a 14-day recovery. Plasma histamine levels were quantified from male and female animals receiving 0.5, 5, and 100 mg/kg injections on Day 1 and 28 of the twenty-eight day study. Cmax was achieved within 0.25 h and was dose-proportional. The elimination half-life and tmax were longer at the 100 mg/kg dose than the lower doses. No marked differences between genders or between Day 1 and 28 were found. Based on these findings, the NOEL and NOAEL were established at 0.5 mg/kg BID and 5 mg/kg BID, respectively. When converted to human equivalent dose, the NOAEL is 0.81 mg/kg which is 54 times the intended human dose. These studies support a wide safety margin for histamine dihydrochloride.