LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer.

Therapeutic harnessing of adaptive immunity via checkpoint inhibition has transformed the treatment of many cancers. Despite unprecedented long-term responses, most patients do not respond to these therapies. Immunotherapy non-responders often harbor high levels of circulating myeloid-derived suppressor cells (MDSCs)-an immunosuppressive innate cell population. Through genetic and pharmacological approaches, we uncovered a pathway governing MDSC abundance in multiple cancer types. Therapeutic liver-X nuclear receptor (LXR) agonism reduced MDSC abundance in murine models and in patients treated in a first-in-human dose escalation phase 1 trial. MDSC depletion was associated with activation of cytotoxic T lymphocyte (CTL) responses in mice and patients. The LXR transcriptional target ApoE mediated these effects in mice, where LXR/ApoE activation therapy elicited robust anti-tumor responses and also enhanced T cell activation during various immune-based therapies. We implicate the LXR/ApoE axis in the regulation of innate immune suppression and as a target for enhancing the efficacy of cancer immunotherapy in patients.

Assessing the clinical benefits of erythropoietic agents using area under the hemoglobin change curve.

INTRODUCTION: In assessing erythropoietic agents for chemotherapy-induced anemia, traditional single time-point end points (e.g., hematopoietic response [HR]) fail to reflect clinical benefits over the entire therapy course. Area under the hemoglobin change curve (Hb AUC) is introduced as an alternative measure, and its reliability, clinical significance, and superiority are assessed. METHODS: Using data from a phase IV open-label epoetin alfa (EPO) trial, we tested Hb AUC reliability by comparing its values derived from primary patient data with those derived from aggregated data. Clinical significance of the Hb AUC was investigated in three phase IV EPO trials by examining the linear relationship between Hb AUC quartiles and established clinical end points. The superiority of the Hb AUC over HR in its association with blood transfusion was tested through logistic regressions and area under the receiver operating characteristic (ROC) curve analysis. RESULTS: The Hb AUC values derived from patient and aggregated data were similar. Strong and statistically significant linear trends of decreasing transfusion requirements, increasing quality-of-life improvements, and decreasing time to HR were found across Hb AUC quartiles. The Hb AUC rendered the HR variable insignificant when both were present in the same model. Area under the ROC curve analysis supported the superior performance of the Hb AUC. CONCLUSIONS: We found that the Hb AUC is an objective, reliable, clinically meaningful, and comprehensive summary statistic that may be used to quantify clinical benefits for patients receiving erythropoietic agents. Further prospective validation of the Hb AUC metric is recommended.

A pilot study to evaluate the safety and clinical outcomes of once-weekly epoetin alfa 80,000 u in anemic patients with cancer receiving chemotherapy.

BACKGROUND: Epoetin alfa is indicated for the treatment of chemotherapy-induced anemia at doses of 150 U/kg 3 times weekly or 40,000 U once weekly. Higher starting doses may lead to higher hematologic response rates (RRs), earlier hematologic responses, and earlier identification of nonresponders. The hematologic response and safety of epoetin alfa at a starting dose of 80,000 U once weekly in anemic patients (hemoglobin [Hb] 13 g/dL or increased > 1.3 g/dL in a 2-week period during the 12-week study. The primary efficacy endpoint was major hematologic response (Hb increase >/= 2 g/dL or Hb >/=12 g/dL, independent of transfusion). Secondary endpoints were minor hematologic response (Hb increase >/= 1 g/dL but > 2 g/dL) and incidence of transfusions. RESULTS: Of 69 patients enrolled, 47 (68%) completed the study. A majority of patients (72%) exhibited a major hematologic response with epoetin alfa 80,000 U once weekly. Mean Hb levels increased by 2.2 g/dL from baseline after 12 weeks of therapy. Six patients (8.8%) received packed red blood cell transfusions during the study. The dose of epoetin alfa was reduced, or held then reduced, per protocol in 48 patients (69.6%). Ten patients (14.5%) in the safety population experienced a total of 11 clinically relevant thrombotic vascular events. CONCLUSION: Epoetin alfa at a starting dose of 80,000 U once weekly (with appropriate dose reductions) increased Hb level, was associated with a packed red blood cell transfusion rate > 5% after 4 weeks of therapy, and was safe and generally well tolerated in anemic patients with cancer receiving chemotherapy. The hematologic RR, however, was not markedly improved compared with previous trials with 40,000-60,000 U once weekly, perhaps partly because of the high frequency of dose reductions.

Treatment of chemotherapy-related anemia with erythropoietic agents: current approaches and new paradigms.

Anemia is common among patients with cancer receiving chemotherapy (CT) and/or radiotherapy (RT) and may limit cancer treatment, clinical outcomes, and overall patient quality of life (QOL). In the United States, epoetin alfa and darbepoetin alfa are approved for the treatment of CT-induced anemia in patients with nonmyeloid malignancies. Goals of treatment are to reduce transfusions, increase hemoglobin (Hb) levels, and improve overall QOL. Results from ongoing head-to-head trials comparing these agents will allow for direct comparisons of Hb response profiles and overall QOL effects. To optimize patient benefits from erythropoietic therapy, new doses and schedules of these agents are being studied. Data from investigations of the use of a higher weekly starting dose ("front-loading") followed by maintenance dosing on a less frequent schedule (when Hb has increased to a specified level or by a specified amount after the higher initial starting dose) suggest that both agents can increase and subsequently maintain Hb levels on such schedules. This approach may lead to benefits for patients and healthcare providers, such as earlier increases in Hb and earlier identification of nonresponders. Consequently, evolving strategies with erythropoietic agents should ultimately improve overall QOL in anemic cancer patients receiving CT.