April Coan

Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma

Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation widely expressed in glioblastoma multiforme (GBM) and other neoplasms, but absent from normal tissues. Immunotherapeutic targeting of EGFRvIII could eliminate neoplastic cells more precisely but may be inhibited by concurrent myelosuppressive chemotherapy like temozolomide (TMZ), which produces a survival benefit in GBM. A phase II, multicenter trial was undertaken to assess the immunogenicity of an experimental EGFRvIII-targeted peptide vaccine in patients with GBM undergoing treatment with serial cycles of standard-dose (STD) (200 mg/m(2) per 5 days) or dose-intensified (DI) TMZ (100 mg/m(2) per 21 days). All patients receiving STD TMZ exhibited at least a transient grade 2 lymphopenia, whereas those receiving DI TMZ exhibited a sustained grade 3 lymphopenia (<500 cells/μL). CD3(+) T-cell (P = .005) and B-cell (P = .004) counts were reduced significantly only in the DI cohort. Patients in the DI cohort had an increase in the proportion of immunosuppressive regulatory T cells (T(Reg); P = .008). EGFRvIII-specific immune responses developed in all patients treated with either regimen, but the DI TMZ regimen produced humoral (P = .037) and delayed-type hypersensitivity responses (P = .036) of greater magnitude. EGFRvIII-expressing tumor cells were also eradicated in nearly all patients (91.6%; CI(95): 64.0%-99.8%; P < .0001). The median progression-free survival (15.2 months; CI(95): 11.0-18.5 months; hazard ratio [HR] = 0.35; P = .024) and overall survival (23.6 months; CI(95): 18.5-33.1 months; HR = 0.23; P = .019) exceeded those of historical controls matched for entry criteria and adjusted for known prognostic factors. EGFRvIII-targeted vaccination induces patient immune responses despite therapeutic TMZ-induced lymphopenia and eliminates EGFRvIII-expressing tumor cells without autoimmunity.

Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients

After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.

Poor drug distribution as a possible explanation for the results of the PRECISE trial

OBJECT Convection-enhanced delivery (CED) is a novel intracerebral drug delivery technique with considerable promise for delivering therapeutic agents throughout the CNS. Despite this promise, Phase III clinical trials employing CED have failed to meet clinical end points. Although this may be due to inactive agents or a failure to rigorously validate drug targets, the authors have previously demonstrated that catheter positioning plays a major role in drug distribution using this technique. The purpose of the present work was to retrospectively analyze the expected drug distribution based on catheter positioning data available from the CED arm of the PRECISE trial. METHODS Data on catheter positioning from all patients randomized to the CED arm of the PRECISE trial were available for analyses. BrainLAB iPlan Flow software was used to estimate the expected drug distribution. RESULTS Only 49.8% of catheters met all positioning criteria. Still, catheter positioning score (hazard ratio 0.93, p = 0.043) and the number of optimally positioned catheters (hazard ratio 0.72, p = 0.038) had a significant effect on progression-free survival. Estimated coverage of relevant target volumes was low, however, with only 20.1% of the 2-cm penumbra surrounding the resection cavity covered on average. Although tumor location and resection cavity volume had no effect on coverage volume, estimations of drug delivery to relevant target volumes did correlate well with catheter score (p < 0.003), and optimally positioned catheters had larger coverage volumes (p < 0.002). Only overall survival (p = 0.006) was higher for investigators considered experienced after adjusting for patient age and Karnofsky Performance Scale score. CONCLUSIONS The potential efficacy of drugs delivered by CED may be severely constrained by ineffective delivery in many patients. Routine use of software algorithms and alternative catheter designs and infusion parameters may improve the efficacy of drugs delivered by CED.

Cardiopulmonary Function and Age-Related Decline Across the Breast Cancer Survivorship Continuum

PURPOSE To evaluate cardiopulmonary function (as measured by peak oxygen consumption [VO(2peak)]) across the breast cancer continuum and its prognostic significance in women with metastatic disease. PATIENTS AND METHODS Patients with breast cancer representing four cross-sectional cohorts--that is, (1) before, (2) during, and (3) after adjuvant therapy for nonmetastatic disease, and (4) during therapy in metastatic disease--were studied. A cardiopulmonary exercise test (CPET) with expired gas analysis was used to assess VO(2peak). A Cox proportional hazards model was used to estimate the risk of death according to VO(2peak) category (< 15.4 v ≥ 15.4 mL · kg(-1) · min(-1)) with adjustment for clinical factors. RESULTS A total of 248 women (age, 55 ± 8 years) completed a CPET. Mean VO(2peak) was 17.8 ± a standard deviation of 4.3 mL · kg(-1) · min(-1), the equivalent of 27% ± 17% below age-matched healthy sedentary women. For the entire cohort, 32% had a VO(2peak) less than 15.4 mL · kg(-1) · min(-1)--the VO(2peak) required for functional independence. VO(2peak) was significantly different across breast cancer cohorts for relative (mL · kg(-1) · min(-1)) and absolute (L · min(-1)) VO(2peak) (P = .017 and P < .001, respectively); VO(2peak) was lowest in women with metastatic disease. In patients with metastatic disease (n = 52), compared with patients achieving a VO(2peak) ≤ 1.09 L · min(-1), the adjusted hazard ratio for death was 0.32 (95% CI, 0.16 to 0.67, P = .002) for a VO(2peak) more than 1.09 L · min(-1). CONCLUSION Patients with breast cancer have marked impairment in VO(2peak) across the entire survivorship continuum. VO(2peak) may be an independent predictor of survival in metastatic disease.

Bevacizumab and daily temozolomide for recurrent glioblastoma.

The authors performed a phase 2 trial of combined protracted daily temozolomide and biweekly bevacizumab for patients with recurrent glioblastoma who had previously received radiation therapy and temozolomide.

Unmet spiritual care needs impact emotional and spiritual well-being in advanced cancer patients

PurposeSpiritual care is an important part of healthcare, especially when facing the crisis of advanced cancer. Do oncology inpatients receive spiritual care consistent with their needs? When inconsistent, are there deleterious effects on patient outcomes?MethodsPatients with advanced cancer (N = 150) were surveyed during their inpatient stay at a southeastern medical center using validated instruments documenting spirituality, quality of life, mood, and satisfaction with care. Relationships between the receipt of less spiritual care than desired and patient outcomes were examined.ResultsAlmost all patients had spiritual needs (91%) and the majority desired and received spiritual care from their healthcare providers (67%; 68%), religious community (78%; 73%), and hospital chaplain (45%; 36%). However, a significant subset received less spiritual care than desired from their healthcare providers (17%), religious community (11%), and chaplain (40%); in absolute terms, the number who received less care than desired from one or more sources was substantial (42 of 150). Attention to spiritual care would improve satisfaction with care while hospitalized for 35% of patients. Patients who received less spiritual care than desired reported more depressive symptoms [adjusted β (SE) = 1.2 (0.47), p = 0.013] and less meaning and peace [adjusted β (SE) = −2.37 (1.15), p = 0.042].ConclusionsA substantial minority of patients did not receive the spiritual care they desired while hospitalized. When spiritual needs are not met, patients are at risk of depression and reduced sense of spiritual meaning and peace. Spiritual care should be matched to cancer patients’ needs.

Prognostic significance of functional capacity and exercise behavior in patients with metastatic non-small cell lung cancer

BACKGROUND To investigate the prognostic importance of functional capacity and exercise behavior in patients with metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS Using a prospective design, 118 consecutive participants with histologically confirmed metastatic (inoperable) NSCLC and Eastern Cooperative Oncology group (ECOG) 0-3 completed a six-minute walk test to assess functional capacity and questionnaire that assessed self-reported exercise behavior. Cox proportional models were used to estimate the risk of all-cause mortality according to six-minute walk distance (6MWD) (<358.5m, 358.5-450 m, ≥450 m) and exercise behavior (MET-hrswk(-1)) categories with adjustment for important covariates. RESULTS Median follow-up was 26.6 months; 77 deaths were reported during this period. Functional capacity was an independent predictor of survival (P(trend)=0.003) and added incremental prognostic value beyond that provided by PS plus other traditional markers of prognosis (P(trend)=0.025). Compared with patients achieving a 6MWD <358.5m, the adjusted hazard ratio (HR) for all-cause mortality was 0.61 (95% CI, 0.34-1.07) for a 6MWD of 358.5-450 m, and 0.48 (95% CI, 0.24-0.93) for a 6MWD >450 m. In unadjusted analysis, there was a borderline significant effect of exercise behavior on survival (p=0.052). Median survival was 12.89 months (95% CI, 9.11-21.05 months) for those reporting <9MET-hrswk(-1) compared with 25.63 months (95% CI, 11.28 to ∞ months) for those reporting ≥9MET-hrswk(-1). CONCLUSIONS Functional capacity is a strong independent predictor of survival in advanced NSCLC that adds to the prediction of survival beyond traditional risk factors. This parameter may improve risk stratification and prognostication in NSCLC.

Prognostic Value of Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography Imaging in Patients With Advanced-Stage Non–Small-Cell Lung Carcinoma

PURPOSE To determine whether the amount of fluorine-18 fluorodeoxyglucose (FDG) uptake in the primary lung cancer on positron emission tomography (PET) imaging at the time of presentation has prognostic significance in patients with advanced-stage non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS A retrospective review identified 214 patients with advanced-stage NSCLC (stage IIIA, IIIB, and IV) who underwent FDG PET study at the time of diagnosis. Extensive clinical data, including tumor histologic cell type, pathologic stage at presentation, and treatment, were recorded. The maximum standardized uptake value (SUV(max)) in the primary tumor on FDG PET on survival was examined using Cox proportional hazards regression. RESULTS One hundred fifty-eight (74%) of the 214 patients died and 56 patients were reported alive at 27 months (range, 3 to 140 months) after the diagnosis of NSCLC. Using the median SUV(max) of 11.1, the patient population was subdivided. The median survival of the 106 patients with the primary tumor having an SUV(max) less than 11.1 was 16 months (95% CI, 12 to 21 months), whereas the median survival of the 108 patients with the primary tumor having an SUV(max) > or = 11.1 was 12 months (95% CI, 10 to 15 months). Univariate and multivariate analysis did not provide evidence that survival for patient subgroups defined by the median SUV(max) were significantly different (univariate P = .11; multivariate P = .45). CONCLUSION FDG uptake of the primary lesions in patients with a new diagnosis of advanced-stage NSCLC does not have a significant relationship with survival.

A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma.

Background Preclinical studies in mice have demonstrated that the prophylactic depletion of immunosuppressive regulatory T-cells (TRegs) through targeting the high affinity interleukin-2 (IL-2) receptor (IL-2Rα/CD25) can enhance anti-tumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2Rα expressing anti-tumor effector T-cells. Objective To determine if changes in the cytokine milieu during lymphopenia may engender differential signaling requirements that would enable unarmed anti-IL-2Rα monoclonal antibody (MAbs) to selectively deplete TRegs while permitting vaccine-stimulated immune responses. Methodology A randomized placebo-controlled pilot study was undertaken to examine the ability of the anti-IL-2Rα MAb daclizumab, given at the time of epidermal growth factor receptor variant III (EGFRvIII) targeted peptide vaccination, to safely and selectively deplete TRegs in patients with glioblastoma (GBM) treated with lymphodepleting temozolomide (TMZ). Results and Conclusions Daclizumab treatment (n = 3) was well-tolerated with no symptoms of autoimmune toxicity and resulted in a significant reduction in the frequency of circulating CD4+Foxp3+ TRegs in comparison to saline controls (n = 3)( p = 0.0464). A significant (p<0.0001) inverse correlation between the frequency of TRegs and the level of EGFRvIII specific humoral responses suggests the depletion of TRegs may be linked to increased vaccine-stimulated humoral immunity. These data suggest this approach deserves further study. Trial Registration ClinicalTrials.gov NCT00626015

Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy.

The efficacy of carboplatin, irinotecan, and bevacizumab among recurrent glioblastoma (GBM) patients after prior progression on bevacizumab therapy in a phase 2, open‐label, single‐arm trial was evaluated.