The molecular biology and immunology of glioblastoma multiforme (GBM) with the presentation of an immunotherapy protocol for a clinical trial.

After a short explanatory Introduction, an immunotherapy protocol is presented for glioblastoma multiforme (GBM). GBM is considered to be an incurable tumor; tumor-free survival over 2 to 3 years is so rare that when it happens the original diagnosis is questioned. It is known that the type of the genetic mutation that a given GBM tumor harbors strongly influences the length of survival. However, most patients with GBM are receiving treatment without the preparation of a microarray gene map of their tumors. It is possible that the reason for a rare and exceptional long survival was not the treatment that the patient received, but the type of gene mutations that the tumor was exposed to. It is recognized that any therapeutic approach should ideally be evaluated against the background of all prognostic factors of each individual case, prominent among them the microarray gene map of the tumor. In practice, this is not easily achieved, while the patient is in need of, and is expecting, prompt therapy. Insurance companies do not reimburse the patient, or the clinical investigators, or their institutions for investigational diagnostic tests, or such treatment modalities. A temporary compromise is possible. The emergence of empirically administered treatment modalities with extraordinary efficacy has occasionally been recorded in the history of medical oncology. In some of these rare clinical trials, the control groups were discontinued (to the dismay of the statisticians), and the control patients were enrolled in the treatment groups so to escape doom and share the benefit of the unfolding high remission inductions experienced in the treatment group. Chemo-radiotherapy of Hodgkin's disease and cisplatin therapy of certain testicular carcinomas provided the first éclat examples. More recently, the rapidly approved and marketed imitanib mesylate for Ph-chromosome-positive chronic myelogenous leukemia and the anti-HER2/neu monoclonal antibody trastuzumab, and the not yet marketed double tyrosine kinase (ErbB1/2) inhibitor lapatinib (Tykerb, GlaxoSmithKline) for a subgroup of breast carcinoma patients excelled. Thus, a clinical trial for GBM, but without precise pre-identification of all its prognostic factors, however with a great deal of evidence-based empirical expectations of benefits, for patients with rapid advarcement toward a fatal outcome, implying an element of urgency, appears to be justified.

Virological and immunological connotations of apoptotic and anti-apoptotic forces in neoplasia.

Against the background of its earliest recognition, programmed cell death (PCD) or apoptosis (A) is presented in its fundamental biological contexts. Techniques of its demonstration are listed. Former original works of the authors encompass designs for genetically engineered oncolytic viruses. Presented here are observations on mesenchymal stromal cells of the bone marrow serving as feeder layers to chronic lymphocytic leukemia (CLL) cells (recently rediscovered elsewhere as subverted "nurse cells" protecting CLL cells from A). A-resistant human melanoma cells are shown to expropriate the Fas ligand to Fas receptor (CD95; APO-1) (FasL-->FasR) system for their autocrine growth loop not only in melanoma cells coexpressing CD95 and its ligand but also in CD95-positive melanoma cells undergoing divisions when exposed to CD95 ligand. Bi-directional A-induction is demonstrated upon the encounter of cytotoxic lymphocytes and targeted tumor cells as exemplified with lymphomas; and chemotherapy-induced A of malignant cells as exemplified by paclitaxel-induced PCD of Reed-Sternberg (RS) cells in a case of chemotherapy-resistant Hodgkin's disease (HD). A list of interventions capable of inducing A in tumor cells is provided. These interventions are of potential therapeutic value. The balance of apoptotic and anti-apoptotic forces in virally infected normal and malignant cells is discussed.

Newcastle disease virus (NDV): brief history of its oncolytic strains.

BACKGROUND: While genetically engineered viruses are now being tested for the virus therapy of human cancers, some naturally occurring viruses display unmatched oncolytic activity. Newcastle disease virus (NDV) excels as an oncolytic agent. OBJECTIVES: As its virulence versus attenuation can be explained on molecular biological bases, it may be possible to develop or select highly oncolytic strains of NDV without adverse toxicity. STUDY DESIGN: Questions are posed as to the mechanisms of viral oncolysis, the appropriateness of tests to predict oncolytic activity of a given NDV strain and the best modes of administration for oncolytic effects. Answers are provided based on specific data or on considerations drawn from experience (the authors use NDV oncolysates to immunize against melanoma and kidney carcinoma) or from analogous clinical situations (therapeutic use of mumps or measles viruses). RESULTS AND CONCLUSIONS: NDV oncolysates probably suit better for immunotherapy (providing also active tumor-specific immunization) than massive repeated inoculations of NDV strains, especially when the NDV strain used is not proven to be oncolytic by appropriate pre-clinical tests.

Vaccination against human cancers (review).

Classical and molecular immunological means of active tumor-specific immunization against human cancers yielded whole cell or tumor cell lysate vaccines of preventive value (reduced relapse rates) and dendritic cell-peptide or genetically engineered vaccines that may induce remissions even in metastatic disease. Active tumor-specific immunization was often successful in the past 50 years against experimental tumors maintained in the laboratory. During the epochs of classical and molecular immunology several vaccines were generated and used for the reduction of relapse rates of human cancer after surgical removal of the primary or metastatic tumors. Whole cell vaccines consist of X-irradiated autologous or allogeneic tumor cells coadministered with immunostimulants (BCG, Detox). Tumor cells haptenized biologically (as in viral oncolysates) or chemically were also used. Dendritic cell vaccines are prepared by transfection or transduction with tumor antigen-encoding DNA or by pulsing the cells with antigenic peptides in vitro; or collecting dendritic cells that engulfed apoptotic tumor cell DNA and/or peptide antigens in vivo for reinjection into the patient. Genetically engineered tumor cells are prepared in vitro to express MHC and peptides, costimulatory molecules (B7.1) and cyto- or lymphokines (interferons, interleukins, hematopoietic growth factors) for vaccination of patients. Antibody- and immune T cell-mediated immune reactions to autologous tumor cells are newly generated and/or quantitatively increased in immunized patients but do not always correlate with clinical response. Most vaccines are claimed to have reduced relapse rates presumably by inducing effective host immunity against micrometastases. Dendritic cell-peptide vaccines could induce partial or occasionally complete remissions in metastatic disease. The wrong antigenic presentation may result in tolerance induction toward the tumor; occasionally tumor enhancement may occur. Human tumor antigens when presented appropriately (with costimulatory molecules and with IL-2, IL-12) break the host's natural tolerance toward its tumor and induce rejection strength immune reactions even in patients with metastatic disease. Immune T cells thus generated could be collected for adoptive immunotherapy. For successful active specific immunization against human cancers the understanding of the immunoevasive maneuvers of the tumor cell (through FasL --> Fas; TRAIL; CD40L --> CD40; TGFbeta etc. systems) is essential.

Cancer vaccines with emphasis on a viral oncolysate melanoma vaccine.

Biotherapy of malignant diseases has become the fourth treatment modality besides surgery, chemo- and radiotherapy. Whole cell melanoma vaccines with or without BCG and other adjuvants, purified ganglioside and shed antigens, recombinant viruses carrying tumor antigens, dendritic cells pulsed with antigenic peptides etc. are in clinical trials. Efficacious viral oncolysate vaccines induce the host to mount tumor-specific cytotoxic T-cell response and prevention of relapses is supported by clinical trials. The use of "polyvalent" whole cell vaccines vs. purified or genetically engineered single antigen vaccines is justified as i. only very few single tumor antigens are present in all tumors of a given histological type; and ii. antigen modulation occurs in tumors rendering them resistant to immune attack generated by vaccine against a single antigen. Thus polyvalent vaccines immunize against several antigens vs. against a selected antigen.

Kaposi's sarcoma: breeding ground of herpesviridae - A tour de force over viral evolution (review).

After reviewing the molecular biological basis of prominent theories for the integration of viruses into the earliest forms of living matter, an account is given on the immunoevasive strategies viruses have had to acquire in order to secure their existence against the most sophisticated anti-viral defensive mechanisms evolving in their hosts. Herpes-viridae and Kaposi's sarcoma illustrate the complexity of host-virus relationship. In following the evolutionary steps of simians and hominoids to Homo, it becomes evident that: a) Epstein-Barr virus evolved in Africa and its ancestral viruses are present in cercopithecines and hominoids; b) human herpes-virus-8-related viruses are present in macaques, in S. American primates and in Homo but such isolates from the great apes are missing. Thus interspecies transfer occurred from lower monkeys to Homo but when and at what geographical location? The human retrolentiviruses also jumped species barriers: this occurred recently in Africa, from great apes (chimpanzee and bonobo) to Homo sapiens (except when HIV-2 was transferred to mankind from sooty mangabeys). The matter is further complicated by the long coevolutionary cooperative interactions between herpes- and retrolentiviruses. Of pathological entities suspected to be etiologically affected by such complex viral cooperation, the origin of Reed-Sternberg cells of Hodgkin's disease is singled out for critical analysis. In this article the senior author summarizes his own 52 years of studentship in virology.