Strong vaccine responses during chemotherapy are associated with prolonged cancer survival.

Therapeutic cancer vaccines have effectively induced durable regressions of premalignant oncogenic human papilloma virus type 16 (HPV16)-induced anogenital lesions. However, the treatment of HPV16-induced cancers requires appropriate countermeasures to overcome cancer-induced immune suppression. We previously showed that standard-of-care carboplatin/paclitaxel chemotherapy can reduce abnormally high numbers of immunosuppressive myeloid cells in patients, allowing the development of much stronger therapeutic HPV16 vaccine (ISA101)-induced tumor immunity. We now show the clinical effects of ISA101 vaccination during chemotherapy in 77 patients with advanced, recurrent, or metastatic cervical cancer in a dose assessment study of ISA101. Tumor regressions were observed in 43% of 72 evaluable patients. The depletion of myeloid suppressive cells by carboplatin/paclitaxel was associated with detection of low frequency of spontaneous HPV16-specific immunity in 21 of 62 tested patients. Patients mounted type 1 T cell responses to the vaccine across all doses. The group of patients with higher than median vaccine-induced immune responses lived longer, with a flat tail on the survival curve. This demonstrates that chemoimmunotherapy can be exploited to the benefit of patients with advanced cancer based on a defined mode of action.

A peptide-based erythropoietin-receptor agonist for pure red-cell aplasia.

BACKGROUND: We investigated whether a novel, synthetic, peptide-based erythropoietin-receptor agonist (Hematide, Affymax) can stimulate erythropoiesis in patients with anemia that is caused by antierythropoietin antibodies. METHODS: In this open-label, single-group trial, we enrolled patients with chronic kidney disease who had pure red-cell aplasia or hypoplasia due to antierythropoietin antibodies and treated them with a synthetic peptide-based erythropoietin-receptor agonist. The agonist was administered by subcutaneous injection at an initial dose of 0.05 mg per kilogram of body weight every 4 weeks. The primary end point was a hemoglobin concentration above 11 g per deciliter without the need for transfusions. RESULTS: We treated 14 patients with the peptide agonist for a median of 28 months. The median hemoglobin concentration increased from 9.0 g per deciliter (with transfusion support in the case of 12 patients) before treatment to 11.4 g per deciliter at the time of the last administration of the agonist; transfusion requirements diminished within 12 weeks after the first dose, after which 13 of the 14 patients no longer required regular transfusions. Peak reticulocyte counts increased from a median of 10x10(9) per liter before treatment to peak counts of greater than 100x10(9) per liter. The level of antierythropoietin antibodies declined over the course of the study and became undetectable in six patients. One patient who initially responded to treatment had a diminished hematologic response a few months later despite increased doses of the agonist and required transfusions again; this patient was found to have antibodies against the agonist. One patient died 4 months after the last dose of the agonist, and a grade 3 or 4 adverse event occurred in seven other patients during the study period. CONCLUSIONS: This novel agonist of the erythropoietin receptor can correct anemia in patients with pure red-cell aplasia caused by antierythropoietin antibodies. (ClinicalTrials.gov number, NCT00314795.).

Population pharmacokinetics and pharmacodynamics of peptidic erythropoiesis receptor agonist (ERA) in healthy volunteers.

Peptidic erythropoiesis receptor agonist is a synthetic, PEGylated peptide that can promote red blood cell production upon binding to the erythropoietin receptor. The objective of this study was to characterize the pharmacokinetics and erythropoietic effects of peptidic erythropoiesis receptor agonist in healthy volunteers. Plasma concentrations of peptidic erythropoiesis receptor agonist and pharmacodynamic responses were obtained after single intravenous injections at doses of 0.025, 0.05, and 0.1 mg/kg. Population pharmacokinetic/pharmacodynamic modeling was performed using NONMEM. Peptidic erythropoiesis receptor agonist exhibited nonlinear pharmacokinetics described by a 1-compartment model with parallel elimination by Michaelis-Menten and linear processes. A catenary, life span-based, indirect response model reflecting bone marrow erythroid and blood cells reflected the pharmacodynamics of peptidic erythropoiesis receptor agonist. A modest tolerance and rebound phenomenon in reticulocytes was modeled with negative feedback regulation related to hemoglobin. This pharmacokinetic/pharmacodynamic model well characterized the prolonged disposition, intrinsic pharmacologic parameters, and typical hematological system properties following single doses of peptidic erythropoiesis receptor agonist in normal subjects.

Hematide is immunologically distinct from erythropoietin and corrects anemia induced by antierythropoietin antibodies in a rat pure red cell aplasia model.

OBJECTIVE: To evaluate the potential of Hematide, a PEGylated, synthetic peptide-based erythropoiesis-stimulating agent that is in clinical development for the treatment of anemia associated with chronic kidney disease and cancer, to correct antierythropoietin antibody-associated pure red cell aplasia (PRCA). MATERIALS AND METHODS: The binding of anti-Hematide antibodies (mouse, rabbit, and monkey) to recombinant human erythropoietin (rHuEPO) and of anti-rHuEPO antibodies (mouse, goat, rat, and human) to Hematide were evaluated. An anti-EPO antibody-mediated anemia rat model was developed by subcutaneously administering rHuEPO to rats three times weekly for 4 weeks. Sixty percent of the animals developed PRCA as characterized by severe anemia, reduced reticulocytes, anti-EPO antibodies, and limited bone marrow erythroid precursors. The effect of Hematide administration on the PRCA rats was evaluated. RESULTS: Antibodies to EPO do not cross react with Hematide and, conversely, antibodies to Hematide do not cross react with EPO. Hematide corrected antibody-induced anemia in a rat PRCA model. CONCLUSIONS: The data support the potential of Hematide to correct anti-EPO antibody-associated PRCA in humans. In addition, the data suggest a negligible risk for development of anti-EPO antibody-induced PRCA secondary to Hematide administration.

Evaluation of the safety and pharmacodynamics of Hematide, a novel erythropoietic agent, in a phase 1, double-blind, placebo-controlled, dose-escalation study in healthy volunteers.

Hematide is an investigational pegylated synthetic peptide that stimulates erythropoiesis in animal models and is being developed for the treatment of anemia associated with chronic renal failure and cancer. This study evaluated the safety and pharmacodynamics of single, intravenous doses (0.025, 0.05, and 0.1 mg/kg) of Hematide in 28 healthy male volunteers. All doses of Hematide were well tolerated, with safety profiles similar to those of placebo. Hematide showed a dose-dependent increase in reticulocytes. The 0.1-mg/kg dose was associated with a statistically significant increase in hemoglobin (Hgb) from baseline compared to the placebo group (13.6 +/- 3.9 g/L [1.36 +/- 0.39 g/dL] versus 3.9 +/- 3.8 g/L [0.39 +/- 0.38 g/dL]; P < .001) that was sustained for longer than 1 month. These results support phase 2 studies in patients with anemia associated with chronic kidney disease or cancer and suggest that Hematide administered as infrequently as once a month may result in a sustained elevation of Hgb levels. (Please note that Hematide is a proposed trade name; the compound does not yet have a nonproprietary name.).

Hematopoietic recovery following autologous bone marrow transplantation in a nonhuman primate: effect of variation in treatment schedule with PEG-rHuMGDF.

Mathematical modeling of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) pharmacokinetics (PK) and pharmacodynamics (PD) suggest that variations in the PEG-rHuMGDF treatment schedule could reduce the severity and duration of thrombocytopenia following myeloablation and bone marrow transplant (BMT). We tested this hypothesis in a rhesus monkey model of autologous (Au) bone marrow-derived mononuclear cell (BM-MNC) transplantation following lethal myeloablation. On day 0, animals were myeloablated by total body exposure to 920 cGy, 250 kVp x-irradiation (TBI). Four cohorts of animals were infused with 1 x 10(8) AuBM-MNC/kg body weight within 2 hours of TBI. The AuBMT-alone cohort received no cytokine, the daily dosage cohort received PEG-rHuMGDF (2.5 micro g/kg/day, s.c.) post TBI and AuBMT, and the pre/post-transplant cohort received PEG-rHuMGDF (2.5 micro g/kg/day, s.c.) pre (day -9 to day -5) and post TBI and AuBMT. The post-transplant PEG-rHuMGDF administration in the above cohorts was begun on day 1 post TBI and continued until platelet counts reached 200,000 micro l (range, 15-31 days). Another group received PEG-rHuMGDF (300 micro g/kg/day, s.c.) on days 1 and 3 only following TBI and AuBMT. The TBI controls received neither AuBMT nor cytokine therapy. In this model of AuBMT, with regard to the PEG-rHuMGDF administration schedule, the daily dosage of the post-transplant cohort did not significantly improve platelet recovery; the pre/post-transplant schedule and an abbreviated high-dosage, post-transplant schedule (days 1 and 3) significantly improved the duration and nadir of thrombocytopenia and platelet recovery. These data confirm predictions from PK/PD modeling of PEG-rHuMGDF that thrombocytopenia is preventable following AuBMT.