A Phase I Trial of Human Gamma Interferon Transduced Autologous Tumor Cells in Patients with Disseminated Malignant Melanoma. Duke University Medical Center, Durham, North Carolina
This discussion was moderated by Victor Tapson, MD, Editor-in-Chief of Advances in Pulmonary Hypertension and Associate Professor, Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina. The participants included Robert Frantz, MD, Assistant Professor of Medicine, Cardiovascular Division, Mayo Clinic, Rochester, Minnesota; and John Conte, MD, Associate Professor of Surgery and Director of Heart and Lung Transplantation, Johns Hopkins University, Baltimore, MD.
Controversy still exists as to the best laboratory method to use to screen newborns for sickle cell disease and other hemoglobinopathies. The proposed methods include hemoglobin electrophoresis, column chromatography, isoelectric focusing, and high performance liquid chromatography. There is also debate concerning the preferred method of sample collection. The proposed methods of sample collection include cord blood or blood obtained from the infant collected in a tube with anticoagulant or on filter paper.
We compared hemoglobin electrophoresis patterns from infant blood samples collected in heparinized capillary tubes and on filter paper. This comparison was performed because hemoglobin electrophoresis of dried blood samples collected on filter paper has been advocated as a practical, reliable, and inexpensive method for mass screening programs, although the limitations of this technique have not been explored fully. We also summarize data from the North Carolina Newborn Hemoglobinopathy Screening Program, which relates to the advantages and limitations of hemoglobin electrophoresis from filter paper blood specimens.
MATERIALS AND METHODS
Specimens
Four sets of specimens were used for this study: (1) specimens collected at Duke University Medical Center to compare hemoglobin electrophoresis patterns of hemolysates from filter paper and heparinized capillary tubes, (2) specimens collected by the North Carolina program for hemoglobinopathy screening, (3) specimens routinely collected at Duke University in heparinized capillary tubes for newborn hemoglobinopathy screening, and (4) samples for retesting to examine the error rate of the state program and to confirm screening results compatible with a hemoglobinopathy.
Samples for Direct Comparison Between Filter Paper and Heparinized Specimens
Here, we report on the results of a phase I/II trial (NCT00490529) for patients with mantle cell lymphoma who, having achieved remission after immunochemotherapy, were vaccinated with irradiated, CpG-activated tumor cells. Subsequently, vaccine-primed lymphocytes were collected and reinfused after a standard autologous stem cell transplantation (ASCT). The primary endpoint was detection of minimal residual disease (MRD) within 1 yr after ASCT at the previously validated threshold of ≥1 malignant cell per 10,000 leukocyte equivalents. Of 45 evaluable patients, 40 (89%) were found to be MRD negative, and the MRD-positive patients experienced early subsequent relapse. The vaccination induced antitumor CD8 T cell immune responses in 40% of patients, and these were associated with favorable clinical outcomes. Patients with high tumor PD-L1 expression after in vitro exposure to CpG had inferior outcomes. Vaccination with CpG-stimulated autologous tumor cells followed by the adoptive transfer of vaccine-primed lymphocytes after ASCT is feasible and safe.
Podoplanin (PDPN), a small transmembrane mucin-like glycoprotein, is ectopically expressed on tumor cells. PDPN is known to be linked with several aspects of tumor malignancies in certain types of human and canine tumors. Therefore, it is considered to be a novel therapeutic target. Monoclonal antibodies targeting PDPN expressed in human tumor cells showed obvious anti-tumor effects in preclinical studies using mouse models. Previously, we generated a cancer-specific mouse–dog chimeric anti-PDPN antibody, P38Bf, which specifically recognizes PDPN expressed in canine tumor cells. In this study, we investigated the safety and anti-tumor effects of P38Bf in preclinical and clinical trials. P38Bf showed dose-dependent antibody-dependent cellular cytotoxicity against canine malignant melanoma cells. In a preclinical trial with one healthy dog, P38Bf administration did not induce adverse effects over approximately 2 months. In phase I/II clinical trials of three dogs with malignant melanoma, one dog vomited, and all dogs had increased serum levels of C-reactive protein, although all adverse effects were grade 1 or 2. Severe adverse effects leading to withdrawal of the clinical trial were not observed. Furthermore, one dog had stable disease with P38Bf injections. This is the first reported clinical trial of anti-PDPN antibody therapy using spontaneously occurring canine tumor models.
A Phase I Trial of Bortezomib and Sorafenib in Advanced Malignant Melanoma