ABSTRACT
OBJECTIVE: We conducted a phase 1 study of a conditioning regimen with or without total marrow irradiation (TMI) before allogeneic hematopoietic stem cell transplantation for patients with high-risk or refractory multiple myeloma. METHODS: Eighteen patients were enrolled on one of 2 strata. Patients with no prior radiation received TMI (900 cGy), fludarabine (FLU), and melphalan (MEL) conditioning, with bortezomib added in the second cohort (stratum I). Patients with prior radiation received FLU, MEL, and bortezomib, without TMI (stratum II). RESULTS: Eight patients were enrolled in the TMI arm (stratum I). One of 3 patients in cohort 1 experienced dose-limiting toxicity (DLT), which led to the expansion to 3 more patients with no DLT. Cohort 2 enrolled only 2 patients due to low accrual, with bortezomib, added at 0.5 mg/m 2 ; neither experienced DLT. Nine patients were enrolled in the non-TMI arm (stratum II). Three patients were enrolled in cohort 1 (bortezomib 0.5 mg/m 2 ) and none experienced DLT. Three were enrolled in cohort 2 (bortezomib 0.7 mg/m 2 ), and 1 experienced DLT; therefore, the cohort expanded to 3 more patients. One more patient experienced DLT. Median overall survival on strata I and II was 44.5 months (95% CI: 1.73-not reached) and 21.6 months (95% CI: 4.1-72.7), respectively. Median progression-free survival on strata I and II was 18.1 months (95% CI: 1.73-not reached) and 8.9 months (95% CI: 2.7-24.4), respectively. CONCLUSION: TMI 900 cGy, FLU, and MEL are considered feasible as conditioning for allogeneic stem cell transplantation and may warrant further investigation due to favorable response rates and survival.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Bortezomib , Hematopoietic Stem Cell Transplantation , Melphalan , Multiple Myeloma , Transplantation Conditioning , Vidarabine , Humans , Multiple Myeloma/therapy , Multiple Myeloma/mortality , Multiple Myeloma/pathology , Bortezomib/administration & dosage , Bortezomib/therapeutic use , Male , Middle Aged , Melphalan/administration & dosage , Melphalan/therapeutic use , Vidarabine/analogs & derivatives , Vidarabine/administration & dosage , Vidarabine/therapeutic use , Female , Hematopoietic Stem Cell Transplantation/methods , Transplantation Conditioning/methods , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Adult , Transplantation, Homologous , Neoplasm Recurrence, Local/therapy , Neoplasm Recurrence, Local/pathology , Survival Rate , Bone Marrow/radiation effectsABSTRACT
Plant-based oral vaccines are a promising emergent technology that could help alleviate disease burden worldwide by providing a low-cost, heat-stable, oral alternative to parenterally administered commercial vaccines. Here, we describe high-level accumulation of the hepatitis B surface antigen (HBsAg) at a mean concentration of 0.51%TSP in maize T1 seeds using an improved version of the globulin1 promoter. This concentration is more than fourfold higher than any previously reported lines. HBsAg expressed in maize seeds was extremely heat stable, tolerating temperatures up to 55 °C for 1 month without degradation. Optimal heat stability was achieved after oil extraction of ground maize material, either by supercritical fluid extraction or hexane treatment. The contributions of this material towards the development of a practical oral vaccine delivery system are discussed.
Subject(s)
Hepatitis B Surface Antigens/biosynthesis , Hepatitis B Vaccines/biosynthesis , Plants, Genetically Modified/metabolism , Seeds/chemistry , Zea mays/immunology , Hepatitis B Surface Antigens/analysis , Plant Extracts/analysis , Plant Extracts/immunology , Plant Oils/analysisABSTRACT
The hepatitis B virus continues to be a major pathogen worldwide despite the availability of an effective parenteral vaccine for over 20 years. Orally-delivered subunit vaccines produced in maize may help to alleviate the disease burden by providing a low-cost, heat-stable alternative to the parenteral vaccine. Oral subunit vaccination has been an elusive goal due to the large amounts of antigen required to induce an immunologic response when administered through the digestive tract. Here we show that high levels of HBsAg were obtained in maize grain, the grain was formed into edible wafers, and wafers were fed to mice at a concentration of approximately 300 µg/g. When these wafers were made with supercritical fluid extraction (SFE)-treated maize material, robust IgG and IgA responses in sera were observed that were comparable to the injected commercial vaccine (Recombivax(®)). In addition, all mice administered SFE wafers showed high secretory IgA titers in fecal material whereas Recombivax(®) treated mice showed no detectable titer. Increased salivary IgA titers were also detected in SFE-fed mice but not in Recombivax(®) treated mice. Wafers made from hexane-treated or full fat maize material induced immunologic responses, but fecal titers were attenuated relative to those produced by SFE-treated wafers. These responses demonstrate the feasibility of using a two-dose oral vaccine booster in the absence of an adjuvant to induce immunologic responses in both sera and at mucosal surfaces, and highlight the potential limitations of using an exclusively parenteral dosing regime.
Subject(s)
Hepatitis B Surface Antigens/immunology , Hepatitis B Vaccines/immunology , Immunity, Mucosal , Plants, Genetically Modified/metabolism , Administration, Oral , Animals , Chromatography, Supercritical Fluid , Hepatitis Antibodies/blood , Hepatitis B Surface Antigens/biosynthesis , Immunoglobulin A/blood , Immunoglobulin A, Secretory/immunology , Immunoglobulin G/blood , Mice , Mice, Inbred BALB C , Vaccines, Subunit/immunology , Vaccines, Synthetic/immunology , Zea mays/genetics , Zea mays/metabolismSubject(s)
Radiopharmaceuticals/therapeutic use , Antibodies, Monoclonal/therapeutic use , Ascites/radiotherapy , Bone Neoplasms/radiotherapy , Bone Neoplasms/secondary , Chromium Compounds/therapeutic use , Humans , Hyperthyroidism/radiotherapy , Iodine Radioisotopes/therapeutic use , Lymphoma, Non-Hodgkin/radiotherapy , Organometallic Compounds/therapeutic use , Organophosphorus Compounds/therapeutic use , Pain/etiology , Pain/radiotherapy , Patient Isolation/standards , Phosphates/therapeutic use , Pleural Effusion, Malignant/radiotherapy , Polycythemia Vera/radiotherapy , Radiation Protection/standards , Radiopharmaceuticals/adverse effects , Sodium Iodide/therapeutic use , Strontium Radioisotopes/therapeutic use , Thrombocytopenia/radiotherapy , Thyroid Neoplasms/radiotherapy , Yttrium Radioisotopes/therapeutic useABSTRACT
Vitamin E is the common name that describes eight naturally occurring compounds possessing alpha-tocopherol activity. These eight vitamin E compounds are collectively termed tocols, and all have antioxidant activity. There is natural variation among different corn breeding lines for levels of tocols. The two predominant isomers present in corn grain are gamma-tocopherol and alpha-tocopherol. Alpha-tocopherol is considered more desirable for human and animal consumption because it has higher biological activity than gamma-tocopherol. Most corn breeding lines naturally have much more gamma-tocopherol than alpha-tocopherol. Therefore a breeding goal is to increase levels of alpha-tocopherol relative to gamma-tocopherol. However, recent research suggests that gamma-tocopherol and compounds metabolized from it have properties important to human health that are unique from properties of alpha-tocopherol. Therefore it may be desirable to not only increase levels of alpha-tocopherol in corn grain, but also levels of gamma-tocopherol. Determination of levels of tocopherols in corn grain is very laborious, requires HPLC analysis and is too time consuming for use in routine commercial corn breeding programs. Therefore we are performing biotechnology enabled molecular marker mapping of chromosomal regions with genes that control levels and ratios of alpha- and gamma-tocopherol. Breeders can use molecular markers we have identified to expediently select for desirable alleles of genes that will improve levels of alpha- and gamma-tocopherol in corn grain, without having to perform laborious HPLC assays. Another biotechnology strategy we have initiated is genetic transformation of corn with the gamma-tocopherol methyl transferase gene to enhance conversion of gamma-tocopherol to alpha-tocopherol and thus increase levels of alpha-tocopherol. This transgenic strategy has been demonstrated in the model plant Arabidopsis, and we are now applying this approach to corn.