Clinical trials that have a pharmacokinetic or a pharmacodynamic immunologic mechanism of action-based primary outcome could substantially improve the validity and efficiency of early development of ...immuno-oncology agents. Here, we outline different trial design options in this area, review examples from the literature and their unique immunologic aspects, and highlight how these trials have been underutilized. We illustrate how new technologies and translationally focused approaches can be successfully used to develop different classes of immunotherapeutic agents.
To demonstrate the efficacy, safety, and appropriate mode of instillation of talc for sclerosis in treatment of malignant pleural effusions (MPEs)
A prospective, randomized trial was designed to ...compare thoracoscopy with talc insufflation (TTI) to thoracostomy and talc slurry (TS) for patients with documented MPE
The primary end point was 30-day freedom from radiographic MPE recurrence among surviving patients whose lungs initially re-expanded ≥ 90%. Morbidity, mortality, and quality of life were also assessed
Of 501 patients registered, those eligible were randomized to TTI (n = 242) or TS (n = 240). Patient demographics and primary malignancies were similar between study arms. Overall, there was no difference between study arms in the percentage of patients with successful 30-day outcomes (TTI, 78%; TS, 71%). However, the subgroup of patients with primary lung or breast cancer had higher success with TTI than with TS (82% vs 67%). Common morbidity included fever, dyspnea, and pain. Treatment-related mortality occurred in nine TTI patients and seven TS patients. Respiratory complications were more common following TTI than TS (14% vs 6%). Respiratory failure was observed in 4% of TS patients and 8% of TTI patients, accounting for five toxic deaths and six toxic deaths, respectively. Quality-of-life measurement demonstrated less fatigue with TTI than TS. Patient ratings of comfort and safety were also higher for TTI, but there were no differences on perceived value or convenience of the procedures
Both methods of talc delivery are similar in efficacy; TTI may be better for patients with either a lung or breast primary. The etiology and incidence of respiratory complications from talc need further exploration
Conventional therapies for glioblastoma multiforme (GBM) fail to target tumor cells exclusively, such that their efficacy
is ultimately limited by nonspecific toxicity. Immunologic targeting of ...tumor-specific gene mutations, however, may allow
more precise eradication of neoplastic cells. The epidermal growth factor receptor variant III (EGFRvIII) is a consistent
and tumor-specific mutation widely expressed in GBMs and other neoplasms. The safety and immunogenicity of a dendritic cell
(DC)–based vaccine targeting the EGFRvIII antigen was evaluated in this study. Adults with newly diagnosed GBM, who had undergone
gross-total resection and standard conformal external beam radiotherapy, received three consecutive intradermal vaccinations
with autologous mature DCs pulsed with an EGFRvIII-specific peptide conjugated to keyhole limpet hemocyanin. The dose of DCs
was escalated in cohorts of three patients. Patients were monitored for toxicity, immune response, radiographic and clinical
progression, and death. No allergic reactions or serious adverse events were seen. Adverse events were limited to grade 2
toxicities. The maximum feasible dose of antigen-pulsed mature DCs was reached at 5.7 × 10 7 ± 2.9 × 10 7 SD without dose-limiting toxicity. EGFRvIII-specific immune responses were evident in most patients. The mean time from histologic
diagnosis to vaccination was 3.6 ± 0.6 SD months. Median time to progression from vaccination was 6.8 months 95% confidence
interval (C.I. 95 ), 2.5–8.8, and median survival time from vaccination was 18.7 months (C.I. 95 , 14.5–25.6). Overall median survival from time of histologic diagnosis was 22.8 months (C.I. 95 , 17.5–29). This study establishes the EGFRvIII mutation as a safe and immunogenic tumor-specific target for immunotherapy.
Mol Cancer Ther 2009;8(10):2773–9
Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10-20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO ...grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence.
PURPOSEThe purpose of this study was to explore whether methods adapted from oncology pharmacological trials have utility in reporting adherence (tolerability) of exercise treatment in cancer.
...METHODSUsing a retrospective analysis of a randomized trial, 25 prostate cancer patients received an aerobic training regimen of 72 supervised treadmill walking sessions delivered thrice weekly between 55% and 100% of exercise capacity for 24 consecutive weeks. Treatment adherence (tolerability) was assessed using conventional (lost to follow-up and attendance) and exploratory (e.g., permanent discontinuation, dose modification, and relative dose intensity) outcomes.
RESULTSThe mean total cumulative “planned” and “completed” dose was 200.7 ± 47.6 and 153.8 ± 68.8 MET·h, respectively, equating to a mean relative dose intensity of 77% ± 24%. Two patients (8%) were lost to follow-up, and mean attendance was 79%. A total of 6 (24%) of 25 patients permanently discontinued aerobic training before week 24. Aerobic training was interrupted (missing ≥3 consecutive sessions) or dose reduced in a total of 11 (44%) and 24 (96%) patients, respectively; a total 185 (10%) of 1800 training sessions required dose reduction owing to both health-related (all nonserious) and non–health-related adverse events. Eighteen (72%) patients required at least one session to be terminated early; a total of 59 (3%) sessions required early termination.
CONCLUSIONSNovel methods for the conduct and reporting of exercise treatment adherence and tolerability may provide important information beyond conventional metrics in patients with cancer.
T cell dysfunction contributes to tumor immune escape in patients with cancer and is particularly severe amidst glioblastoma (GBM). Among other defects, T cell lymphopenia is characteristic, yet ...often attributed to treatment. We reveal that even treatment-naïve subjects and mice with GBM can harbor AIDS-level CD4 counts, as well as contracted, T cell-deficient lymphoid organs. Missing naïve T cells are instead found sequestered in large numbers in the bone marrow. This phenomenon characterizes not only GBM but a variety of other cancers, although only when tumors are introduced into the intracranial compartment. T cell sequestration is accompanied by tumor-imposed loss of S1P1 from the T cell surface and is reversible upon precluding S1P1 internalization. In murine models of GBM, hindering S1P1 internalization and reversing sequestration licenses T cell-activating therapies that were previously ineffective. Sequestration of T cells in bone marrow is therefore a tumor-adaptive mode of T cell dysfunction, whose reversal may constitute a promising immunotherapeutic adjunct.
Abstract
Background. To evaluate the safety and efficacy of moderate-to-high intensity aerobic training in breast cancer patients receiving neoadjuvant chemotherapy. Methods. Twenty patients with ...stage IIB-IIIC operable breast cancer were randomly assigned to receive doxorubicin plus cyclophosphamide (AC) or AC in combination with aerobic training (AC + AET) (n = 10/group) for 12 weeks. The AC+ AET group performed three supervised aerobic cycle ergometry sessions per week at 60%-100% of exercise capacity (VO2peak). Safety outcomes included exercise testing as well as treatment- and exercise training-related adverse events (AEs), whereas efficacy outcomes included cardiopulmonary function and patient-reported outcomes (PROs) as measured by a cardiopulmonary exercise test (CPET) and Functional Assessment of Cancer Therapy-Breast (FACT-B) scale. Results. Twelve non-significant ECG abnormalities and three non-life threatening events occurred during CPET procedures. One AE was reported during aerobic training. There were no significant between group differences for clinician-documented events (e.g. pain, nausea) or hematological parameters (p's > 0.05). Attendance and adherence rates to aerobic training were 82% and 66%, respectively. Intention-to-treat analysis indicated that VO2peak increased by 2.6 ± 3.5 ml/kg/min (+ 13.3%) in the AC + AET group and decreased by 1.5 ± 2.2 ml/kg/min (−8.6%) in the AC group (between group difference, p = 0.001). FACT-B increased 11.1 points in the AC + AET group compared to a 1.5 point decrease in the AC group (between group difference, p = 0.685). Conclusion. Moderate-to-high intensity aerobic training when conducted with one-on-one supervision is a safe adjunct therapy associated with improvements in cardiopulmonary function and select PROs during neoadjuvant chemotherapy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Virtually all patients with malignant glioma (MG) eventually recur. This study evaluates the safety of concurrent stereotactic radiosurgery (SRS) and bevacizumab (BVZ), an antiangiogenic agent, in ...treatment of recurrent MG.
Fifteen patients with recurrent MG, treated at initial diagnosis with surgery and adjuvant radiation therapy/temozolomide and then at least 1 salvage chemotherapy regimen, were enrolled in this prospective trial. Lesions <3 cm in diameter were treated in a single fraction, whereas those 3 to 5 cm in diameter received 5 5-Gy fractions. BVZ was administered immediately before SRS and 2 weeks later. Neurocognitive testing (Mini-Mental Status Exam, Trail Making Test A/B), Functional Assessment of Cancer Therapy-Brain (FACT-Br) quality-of-life assessment, physical exam, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed immediately before SRS and 1 week and 2 months following completion of SRS. The primary endpoint was central nervous system (CNS) toxicity. Secondary endpoints included survival, quality of life, microvascular properties as measured by DCE-MRI, steroid usage, and performance status.
One grade 3 (severe headache) and 2 grade 2 CNS toxicities were observed. No patients experienced grade 4 to 5 toxicity or intracranial hemorrhage. Neurocognition, quality of life, and Karnofsky performance status did not change significantly with treatment. DCE-MRI results suggest a significant decline in tumor perfusion and permeability 1 week after SRS and further decline by 2 months.
Treatment of recurrent MG with concurrent SRS and BVZ was not associated with excessive toxicity in this prospective trial. A randomized trial of concurrent SRS/BVZ versus conventional salvage therapy is needed to establish the efficacy of this approach.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Currently, a blood test for lung cancer does not exist. Serum biomarkers that could aid clinicians in making case management decisions would be enormously valuable. We used two proteomic platforms ...and a literature search to select candidate serum markers for the diagnosis of lung cancer.
We initially assayed six serum proteins, four discovered by proteomics and two previously known to be cancer associated, on a training set of sera from 100 patients (50 with a new diagnosis of lung cancer and 50 age- and sex-matched controls). Classification and Regression Tree (CART) analysis selected a panel of four markers that most efficiently predicted which patients had lung cancer. An independent, blinded validation set of sera from 97 patients (49 lung cancer patients and 48 matched controls) determined the accuracy of the four markers to predict which patients had lung cancer.
Four serum proteins-carcinoembryonic antigen, retinol binding protein, alpha1-antitrypsin, and squamous cell carcinoma antigen-were collectively found to correctly classify the majority of lung cancer and control patients in the training set (sensitivity, 89.3%; specificity, 84.7%). These markers also accurately classified patients in the independent validation set (sensitivity, 77.8%; specificity, 75.4%). Remarkably, 90% of patients who fell into any one of three groupings in the CART analysis had lung cancer.
This panel of four serum proteins is valuable in suggesting the diagnosis of lung cancer. These data may be useful for treating patients with an indeterminate pulmonary lesion, and potentially in predicting individuals at high risk for lung cancer.
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