Glioblastoma-mediated Immune Dysfunction Limits CMV-specific T Cells and Therapeutic Responses: Results from a Phase I/II Trial.

PURPOSE: Cytomegalovirus (CMV) antigens occur in glioblastoma but not in normal brains, making them desirable immunologic targets. PATIENTS AND METHODS: Highly functional autologous polyclonal CMV pp65-specific T cells from patients with glioblastoma were numerically expanded under good manufacturing practice compliant conditions and administered after 3 weeks of lymphodepleting dose-dense temozolomide (100 mg/m2) treatment. The phase I component used a 3+3 design, ascending through four dose levels (5 × 106-1 × 108 cells). Treatment occurred every 6 weeks for four cycles. In vivo persistence and effector function of CMV-specific T cells was determined by dextramer staining and multiparameter flow cytometry in serially sampled peripheral blood and in the tumor microenvironment. RESULTS: We screened 65 patients; 41 were seropositive for CMV; 25 underwent leukapheresis; and 20 completed ≥1 cycle. No dose-limiting toxicities were observed. Radiographic response was complete in 1 patient, partial in 2. Median progression-free survival (PFS) time was 1.3 months [95% confidence interval (CI), 0-8.3 months]; 6-month PFS was 19% (95% CI, 7%-52%); and median overall survival time was 12 months (95% CI, 6 months to not reached). Repeated infusions of CMV-T cells paralleled significant increases in circulating CMV+ CD8+ T cells, but cytokine production showing effector activity was suppressed, especially from T cells obtained directly from glioblastomas. CONCLUSIONS: Adoptive infusion of CMV-specific T cells after lymphodepletion with dose-dense temozolomide was well tolerated. But apparently CMV seropositivity does not guarantee tumor susceptibility to CMV-specific T cells, suggesting heterogeneity in CMV antigen expression. Moreover, effector function of these T cells was attenuated, indicating a requirement for further T-cell modulation to prevent their dysfunction before conducting large-scale clinical studies.

Window-of-opportunity clinical trial of pembrolizumab in patients with recurrent glioblastoma reveals predominance of immune-suppressive macrophages.

BACKGROUND: We sought to ascertain the immune effector function of pembrolizumab within the glioblastoma (GBM) microenvironment during the therapeutic window. METHODS: In an open-label, single-center, single-arm phase II "window-of-opportunity" trial in 15 patients with recurrent (operable) GBM receiving up to 2 pembrolizumab doses before surgery and every 3 weeks afterward until disease progression or unacceptable toxicities occurred, immune responses were evaluated within the tumor. RESULTS: No treatment-related deaths occurred. Overall median follow-up time was 50 months. Of 14 patients monitored, 10 had progressive disease, 3 had a partial response, and 1 had stable disease. Median progression-free survival (PFS) was 4.5 months (95% CI: 2.27, 6.83), and the 6-month PFS rate was 40%. Median overall survival (OS) was 20 months, with an estimated 1-year OS rate of 63%. GBM patients' recurrent tumors contained few T cells that demonstrated a paucity of immune activation markers, but the tumor microenvironment was markedly enriched for CD68+ macrophages. CONCLUSIONS: Immune analyses indicated that pembrolizumab anti-programmed cell death 1 (PD-1) monotherapy alone can't induce effector immunologic response in most GBM patients, probably owing to a scarcity of T cells within the tumor microenvironment and a CD68+ macrophage preponderance.

Switching from methadone to a different opioid: what is the equianalgesic dose ratio?

INTRODUCTION: Methadone (ME) is a highly effective opioid agonist used for difficult pain syndromes. However, in the management of cancer pain with strong opioids, rotation to a different opioid (opioid rotation) may be required because of side effects or poor pain control. Rotation from methadone to another opioid has received limited study and therefore may be difficult because of the absence of a uniformly accepted dose conversion ratio. METHODS: Retrospectively reviewed consecutive medical records of patients undergoing an opioid rotation from methadone to an alternative opioid were evaluated. For inclusion, patients were required to have received methadone for at least 3 days and have reached stable dose of the alternative opioid(s) during the 7 days following. Stable dose was defined as a 30% or less change in opioid dose from one day to the next. RESULTS: Records of 39 patients met inclusion criteria. Excluded from analysis were 5 patients who were restarted on methadone within 7 days, 2 with irregular opioid use resulting in negligible regular opioid doses post-switch, and 3 due to concerns about reliability of multiple routes used for fentanyl. Data from 29 patients, 10 female, mean age 48 +/- 14.4 years, were evaluable. The mean dose ratio for oral methadone to oral morphine equivalent daily dose (MEDD) was 1:4.7 (95% confidence interval [CI], 3.0-6.5; n = 16), and for intravenous (IV) methadone to MEDD was 1:13.5 (95% CI, 6.6-20.5; n = 13), p = 0.06. Methadone dose was significantly correlated to stable MEDD after switching opioids for both methadone IV and oral (Spearman = 0.86, p = 0.0001 and Spearman = 0.72, p = 0.0024), respectively. Mean day of achieving stable dose was day 2.5 +/- 0.2 for IV methadone and day 2.6 +/- 0.3 for oral methadone. CONCLUSION: These dose ratios are new findings that may assist in switching patients more safely to alternative opioids when side effects or pain problems occur when patients are receiving methadone. An important difference in analgesic potency appears to exist between IV and oral ME. Future research with prospective studies is required.

Interval between first palliative care consult and death in patients diagnosed with advanced cancer at a comprehensive cancer center.

PURPOSE: Most referrals to palliative care and hospice occur late in the trajectory of the disease although an earlier intervention could decrease patients' symptom distress. The purpose of this study was to determine the interval between first palliative care consult (PC1) and death (D) in patients diagnosed with advanced cancer (aCA) at our comprehensive cancer center and if such interval has increased over time. METHODS: The study group was 2868 consecutive patients who had their PC1 during a 30-month period. We reviewed the charts for information about demographics, cancer type, date of cancer (CA) diagnosis, aCA diagnosis, PC1, and D. aCA was defined as locally recurrent or metastatic. RESULTS: One thousand four hundred four patients (49%) were female, 1791 (62%) were less than 65 years old, 2563 (89%) had solid tumors, and 2004 (70%) were white. The median PC1-D, aCA-PC1, aCA-D, and CA-D intervals were 42, 147, 250, and 570 days, respectively. The median PC1-D interval was longer in patients with solid tumors (p < 0.0001), less than 65 years old (p = 0.002), and females (p = 0.004). PC1-D was not affected by ethnicity (p = 0.42). The median PC1-D interval in 5 consecutive half-years was 46, 56, 42, 41, and 34 days, respectively (p = 0.02). The number of PC1 in this period increased from 544 to 654 (20%). The ratio of PC involvement in the aCA-D period (PC1-D/aCA-D) decreased from 0.30 to 0.26 over the 5 half-year periods (p = 0.0004). CONCLUSIONS: The first palliative care consultation to death interval has decreased over time at our center. Education is needed among our referring physicians for earlier access to palliative care. Prospective studies are needed to establish the appropriate timing of the first palliative care consultation.

Clinical findings of a palliative care consultation team at a comprehensive cancer center.

BACKGROUND: Palliative care consultation teams (PCCTs) are being established in cancer centers for the management of patients' physical and psychosocial distress. As clinical findings of these teams have been reported infrequently, we aim to describe the experience of our high-volume inpatient PCCT. PATIENTS AND METHODS: We obtained clinical and demographic data on patients referred to our PCCT from the palliative care departmental database from September 1, 2003, to August 31, 2004. RESULTS: In 1 year, 1067 consultations took place for 922 hospitalized patients. The patients' mean age was 60 (range, 3-98) years. The most common cancers were thoracic/head and neck, gastrointestinal, genitourinary, gynecologic cancers, and lymphoma. Thirty-four percent of the patients were transferred to the inpatient palliative care unit, while the remainder were followed by the PCCT as consultants. The main problems requiring PCCT consultation were pain (56%), delirium (34%), dyspnea (25%), fatigue (14%), and end-of-life psychosocial (EOL) issues (12%). Twenty-four percent of patients died during the hospitalization. Death during the hospitalization was more common in patients with delirium, dyspnea, and EOL issues and less likely in patients referred to the PCCT for pain or depression. Constipation was more common in patients with solid tumors, whereas EOL issues were more common in patients with hematologic malignancies. Of the patients who were able to be discharged, 56% went home, 37% to hospice, and 7% elsewhere. CONCLUSIONS: These results provide insight into the demand and utility of this service for those considering the establishment of a PCCT.

Donepezil for cancer fatigue: a double-blind, randomized, placebo-controlled trial.

PURPOSE: To evaluate the effectiveness of donepezil compared with placebo in cancer patients with fatigue as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F). PATIENTS AND METHODS: Patients with fatigue score >or= 4 on a scale of 0 to 10 (0 = no fatigue, 10 = worst possible fatigue) for more than 1 week were included. Patients were randomly assigned to receive donepezil 5 mg or placebo orally every morning for 7 days. A research nurse contacted the patients by telephone daily to assess toxicity and fatigue level. All patients were offered open-label donepezil during the second week. FACIT-F and/or the Edmonton Symptom Assessment System (ESAS) were assessed at baseline, and days 8, 11, and 15. The FACIT-F fatigue subscale score on day 8 was considered the primary end point. RESULTS: Of 142 patients randomly assigned to treatment, 47 patients in the donepezil group and 56 in the placebo group were assessable for final analysis. Fatigue intensity improved significantly on day 8 in both donepezil and placebo groups. However, there was no significant difference in fatigue improvement by FACIT-F (P = .57) or ESAS (P = .18) between groups. In the open-label phase, fatigue intensity continued to be low as compared with baseline. No significant toxicities were observed. CONCLUSION: Donepezil was not significantly superior to placebo in the treatment of cancer-related fatigue.