Therapeutic Efficacy of Adoptive Cell Transfer on Survival of Patients with Glioblastoma Multiforme: Case Reports.

Glioblastoma multiforme (GBM), which occurs mostly in individuals over the age of 40, accounts for 12-15% of all primary brain tumors. Patients with GBM have a poor prognosis, even after aggressive upfront therapies. The present study documents that in 5 of these patients, the use of a novel immunotherapeutic approach combined with standard initial therapies resulted in a prolonged survival of over 3 years, which is significantly longer than the expected survival time with conventional therapies. During the course of intravenous cell-transfer immunotherapy, axial magnetic resonance images of the tumor region were monitored for over 5 years. The discontinuation of adoptive transfer regimens resulted in the rapid deterioration of patients with development of Gd-enhancing regions, indicating the initiation of tumor recurrence. Among patients with recurrence, the reinstatement of adoptive cell regimens with more frequent cell-transfers resulted in an apparent re-regression of tumors. Significantly longer survival times were seen in patients receiving transferred autologous lymphoid cells which were expanded in vitro, and which had a considerable proportion of gammadeltaT cells. We conclude that immunotherapy, combined with standard treatment, plays a significant role in the management of GBM patients and provides patients with a better prognosis.

Tumoricidal effects of beta-glucans: mechanisms include both antioxidant activity plus enhanced systemic and topical immunity.

A study to evaluate the mechanisms of tumoricidal activity resulting from orally administered extract of Agaricus blazei Murill (A. blazei) was performed in mice bearing syngeneic and xenogeneic tumors. Tumor regression was comparably seen in both syngeneic and xenogeneic tumor-bearing mice when administered oral extract preparations. In addition, in a murine syngeneic tumor model, oral administration of water-soluble extracts of A. blazei resulted in significant production of cytokines such as IFN-gamma, and TNF-alpha in peritoneal exudate cells, in parallel with the marked regression of tumor development. The water-soluble extracts also induced pronounced antioxidant activity in in vitro and in vivo assays using two different methods. These results indicate the A. blazei extract may enhance not only the immnunomodulatory effects that promote activity of peritoneal exudate cells for tumor regression but also potentially result in the direct destruction of tumor cells through its antioxidant activity.

Cell transfer regimens in patients with highly advanced surgically unresectable non-small cell lung cancer: significantly improved overall survival in patients with lower levels of serum immunosuppressive acidic protein.

Sixty-one non-small cell lung cancer (NSCLC) patients with stage II and III/IV were enrolled and 49 completed immunotherapy. Patients were grouped based on immunosuppressive acidic protein (IAP). All patients received monthly intravenous infusions containing 1 x 10(10) (mean cell number per patient) ex vivo expanded and IFN-alpha-treated peripheral blood mononuclear cells. No patients had grade 2 or greater adverse events. The patients with < or = 580microg/ml of serum IAP levels (n=33) had significantly longer recurrence-free survival than those with > 580microg/ml of serum IAP levels (n=16). Patients with lower IAP levels are still under immunotherapeutic control after 27 months free of recurrence. The IAP levels may be a prognostic marker for treatment efficacy in NSCLC. This immunotherapeutic regimen was feasible and well tolerated in patients with advanced NSCLC in terms of prolongation of survival.

Occult lymphoma cells prevalent in autologous marrow from non-Hodgkin's diffuse lymphoma.

The most effective treatment for recurrent non-Hodgkin's lymphoma (NHL) appears to be a high-dose cytotoxic chemotherapy (HDC) followed by autologous bone marrow transplantation (ABMT). However, it has been suggested that the presence of occult lymphoma cells in harvested marrow may be responsible for a significant fraction of treatment failures after HDC/ABMT. The present study examined randomly accrued NHL patients, independent of their cytogenic grades, for the presence of cells bearing bcl-2/immunoglobulin heavy chain (IgH) gene rearrangements in lymph node (LN) biopsies and the bone marrow by polymerase chain reaction (PCR) and Southern blot hybridization combined with a classical culturing technique. Among 41 NHL patients examined, bcl-2/IgH translocations were evident in LN biopsies and marrow from each of 10 follicular lymphoma patients, but not in any samples from 31 newly diagnosed diffuse lymphoma patients. Marrow aspirates from several patients that were cultured using a one-week "triggering culture" followed by an extended period of conventional culture resulted in emergence of a monoclonal, IgH-rearranged, bcl-2-normal lymphoid cell population. Such outgrowth was specifically seen in cultures of diffuse lymphoma marrow (7 of 28 evaluable patients). Southern analysis for IgH rearrangement within LN biopsies and of cells cultured from marrow of individual diffuse lymphoma patients produced identical patterns, suggesting that the occult lymphoma cells present in harvested marrow were derived from the predominant lymphoma cell population represented within involved lymph nodes. The culture of histologically occult lymphoma from diagnostic marrow and analysis of the derived cells by Southern blot hybridization can be used to detect potentially aggressive lymphoma cells within harvested marrow, despite their lack of bcl-2 gene rearrangement.

Antitumor and anticytopenic effects of aqueous extracts of propolis in combination with chemotherapeutic agents.

Using an ICR mouse model bearing a syngeneic Ehrlich ascitis carcinoma, the present study was undertaken to examine the effects of crude, water-soluble propolis (CWSP) on tumor progression, chemotherapeutic efficacy, and hematopoiesis in the peripheral blood. It was demonstrated that CWSP, administered subcutaneously, resulted in marked regression of tumor growth in mice, at the early phase after tumor inoculation (CWSP, p < 0.05 vs. saline control). Molecular analysis indicated that the CWSP is composed of 8.4% protein, 4.2% quercetin plus a variety of saccharides with a molecular weight of 29 kDa. Orally administered CWSP did not produce any regression for the observation period (oral CWSP, p > 0.05 vs. saline control). Peritoneal injection of CWSP into neonatal mice resulted in an increased lymphocyte/polymorphonuclear leukocyte ratio activity, indicating the potential activation of lymphoid cell lineages. These observations suggest that subcutaneously injected CWSP could regulate the development of tumors by possibly stimulating multicellular immunity. In addition, oral administration of CWSP concurrently with 5-fluorouracil (5-FU) or mitomycin C (MMC), significantly increased tumor regression as compared with the respective chemotherapy alone, illustrating the adjuvant effect of orally administered CWSP for tumor regression when combined with chemotherapeutic agents. To examine further the potential usefulness of CWSP for chemotherapeutic regimens, which induce profound multilineage hematopoietic suppression, mice that received CWSP orally in addition to a 5-FU or MMC were followed for absolute numbers of platelets and white and red blood cells. The oral administration of CWSP significantly ameliorated the cytopenia induced by 5-FU, resulting in recovery of white as well as red blood cell counts (5-FU plus CWSP, p < 0.05 vs. 5-FU alone or water control; white blood cells on day 15, red blood cells on day 25), but no marked effects on platelet counts was observed (5-FU plus CWSP, p > 0.05 vs. 5-FU alone or water control). On the other hand, CWSP significantly reduced all three MMC-induced cytopenias, especially at the later stage of the chemotherapeutic course (after day 30), suggesting repetitive requirements of oral administration of CWSP. In summary, subcutaneous administration of an aqueous CWSP resulted in marked regression of transplanted tumors. Orally administered CWSP combined with chemotherapeutic agents significantly increased tumor regression and ameliorated the cytopenia induced by the chemotherapeutic agents alone. These results suggest the benefits of potential clinical trials using CWSP combined with chemotherapeutic agents in order to maximize enhanced immunity while potentially minimizing postchemotherapeutic deteriorated reactions.

Suppression of NO production in activated macrophages in vitro and ex vivo by neoandrographolide isolated from Andrographis paniculata.

In this study, we investigated the in vitro and ex vivo suppressive effects of Andrographis paniculata on nitric oxide (NO) production in mouse peritoneal macrophages elicited by bacillus Calmette-Guéin (BCG) and stimulated by lipopolysaccharide (LPS). Incubation of BCG-induced macrophages with the methanol extract of A. paniculata reduced LPS stimulated NO production. The diterpene lactones andrographolide and neoandrographolide were isolated as active components from the extract. These compounds suppressed NO production in a concentration-dependent manner in the concentration range from 0.1 to 100 microM and their IC50 values were 7.9 and 35.5 microM. Neoandrographolide also suppressed NO production by 35 and 40% when the macrophages were collected after oral administration of neoandrographolide at doses of 5 and 25 mg/kg/d and LPS stimulated NO production was examined. However, andrographolide did not reduce NO production on oral administration at the same doses. These results indicate that neoandrographolide, which inhibited NO production both in vitro and ex vivo may play an important role in the use of A. paniculata as an anti-inflammatory crude drug.

Orally administered beta-1,6-D-polyglucose extracted from Agaricus blazei results in tumor regression in tumor-bearing mice.

There is an increasing demand from both patients and practicing oncologists for orally formulated chemotherapy. The present study focused on the oral formulation for natural products that may be effectively used in oncologic treatment regimens. Tumor-bearing mice treated with intratumoral administration of aqueous ammonium oxalate-soluble and ethanol-insoluble derivatives of Agaricus blazei showed marked tumor regression at doses ranging from 0.1 to 2.5 mg (p < 0.05 vs. saline control; n = 7). However, oral administration of this same fraction, either prior to, simultaneously with, or after, tumor cell inoculation did not result in tumor regression (p > 0.05 vs. control). When this fraction was treated with hydrochloric acid (acid-treated fraction; ATF), intratumoral administration resulted in a marked regression of tumor growth comparable to that of the acid-untreated fraction. More importantly, parenteral administration of ATF resulted in a significantly greater regression of tumor growth than that produced by the untreated fraction (p < 0.05 vs. untreated; n = 7). When a total of 4.5 mg of ATF was given orally at varying schedules prior to, simultaneously with, or after, tumor inoculation, a significant regression was seen using a schedule starting 4 days prior to inoculation (p < 0.05 vs. all other treatments; n = 7). NMR and molecular analyses showed that the ATF fraction had a molecular weight of approximately 10 kDa and consisted mainly of only (1,6)-beta- D-polyglucose. These results suggest that the oral administration of simple acid-treated ATF results in a remarkable tumor regression. Thus, simple acid hydrolysis of natural products may not only bring measurable benefits in oncological practice, but may also be a useful general formulation for natural products for oral chemotherapy.