Other

Baxter Travenol Laboratories, Inc.

Pharmacia Ab

Jenomic

Jenquest

David Stephen Terman

Herbert M Cullis

Jay L Stone

Joseph P Balint

David Elliott Bradley

Mirza A Khoja

Michael Sulliva

John J Langone

Raoul F Reiser

Michael R Sullivan

Resistance of randomly dispersed and oxygen-starved lung tumor cells to chemo- and radiotherapy constitutes the vast majority recurrences and death from lung cancer. We use sickle cells derived from humans with sickle cell anemia to target oxygen-deprived tumor cells that persist and multiply after conventional treatment. Transfused sickle cells selectively occluded tumor microvessels and shut down blood flow to these oxygen-deprived pockets leading to tumor cell death and complete shrinkage of aggressive lung tumors. Combining the sickle cells with a vascular disrupting agents and radiation injure and narrow tumor blood vessels, amplified the scale of sickle cell-induced blood vessel closure and tumor cell killing. The strength of the tumor killing produced by this combination exceeded that of either agent alone or combined with conventional anti-angiogenics, chemotherapy or radiation. Combinatorial sickle cells-Combretastatin treatment thereby constitutes a major advance toward eradicating treatment-resistant tumor cells and reducing the frequency of lung cancer recurrence.

Compositions and methods for treatment of cancer

Here we show that SEG/SEI presented from a HLA-DQ8 (HLA-DQB*0302 and HLA-DQA*0301) platform prevent the de novo outgrowth (vaccination) of Lewis lung carcinoma (LLC) and B16-F10 melanoma and retard the growth of established tumors with no significant toxicity. Vaccination of DQ8 tg mice with irradiated LLC or B16-F10 melanoma followed by SEG/SEI immunization and live tumor challenge resulted in 100 and 66% survival respectively for 200 days compared to a median survival of 20 days for untreated controls (p&#x3c;0.001). In vaccination studies, DQ8 tg mice showed a surge in IFN&#x3b3; serum levels reaching 3000 fold above baseline devoid of a parallel spike in TNF&#x3b1; levels above baseline levels. Presentation of the SEG/SEI superantigen from a MHC-DQ8 platform, therefore, augments the therapeutic index of these SAgs inducing a tumoricidal response against Lewis lung carcinoma and B16 melanoma accompanied by a sharp increase of therapeutic IFN&#x3b3; levels absent toxic levels of TNF&#x3b1;.

Herein we provide cDNA extracted from tumor cells, normal cells or treatment resistant tumor cells that have been transduced with virus capable of altering self and/or tumor associated antigens (VASTA) fused recombinantly to nucleic acids encoding wild type superantigens, superantigens, superantigen homologues and superantigen-tumor specific targeting molecules and further linked to a costimulatory molecule. The extracted cDNA is linked to a VASTA and delivered to tumor bearing hosts parenterally wherein they induce a tumoricidal response. These agents are also incorporated into a tumor tropic cell carrier for protected delivery to tumor.

Compositions and methods for treatment of neoplastic disease

The present invention comprises the use of sickle cells or sickle cell precursors loaded with a therapeutic agent that localize in tumors and induce a tumoricidal response.

Described herein is an interactive digital software program and hardware that enables rapid acquisition of textual or audio subject matter, its conversion to editable text and immediate compression into a user understandable summary. The software program maximizes 'time on task' while minimizing the time-consuming steps of 'concept capture' and &#x201c;compression&#x201d;. The instant invention provides an accurate condensate of textual subject matter in a fraction of the time it would take to prepare such a document by manual note taking. In a single step, mobile devices such as cameras, camera phones, tablets, iPODs&#x2122;, scanners and the like rapidly capture textual images convert them to OCR and to a user understandable summary in a fraction of the time it takes to process such a document by manual note taking. With more study time available for repetitious practice of the lesson, the user improves preparedness and performance on tests and presentations.

Knowledge acquisition nexus for facilitating concept capture and promoting time on task

The present invention provides erythrocytes or nucleated erythrocyte precursors from animals or patients with at least one S hemoglobin allele which are capable of selectively localizing in tumor vasculature resulting in vaso-occlusion, hemolysis and heme release. A tumoricidal effect is achieved when these cells are administered in before during or after administration of (i) an agent(s) that interferes with degradation of reactive oxygen species, (ii) impairs glucose uptake and/or (iii) chemotherapy. These cells also carry oncolytic viruses, antitumor proteins, multidrug resistant proteins, chemotherapy, monoclonal antibodies, superantigens, superantigen conjugates and fusion proteins, siRNAs, plasmids and non-protein toxins and attenuated tumoricidal bacterial cells specifically into the tumors and induce a tumoricidal effect.

Sickled erythrocytes with anti-tumor agents induce tumor vaso-occlusion and tumoricidal effects

The presence of tumor nodules in organs often results in serious clinical manifestations and the permeation by cancer cells of sheaths surrounding organs often produces clinical manifestations of pleural effusion, ascites or cerebral edema. The present invention addresses this problem by providing a method for treating minors comprising (a) intratumoral administration of a superantigen and/or (b) intrathecal or intracavitary administration of a superantigen directly into the sheath. Intratumoral superantigen results in significant and sustained reduction of the tumor size. Intrathecal administration produces significant sustained reduction of the fluid accumulation associated with clinical improvement and prolonged survival. Useful superantigen compositions for intrathecal and intratumoral injection include tumoricidally effective homologues, fragments and fusion proteins of native superantigens. Also disclosed is combined therapy that includes intratumoral or intrathecal superantigen compositions in combination with (i) intratumoral low, non-toxic doses of one or more chemotherapeutic drugs or (ii) systemic chemotherapy at reduced and non-toxic doses of chemotherapeutic drugs.

Intrathecal and intratumoral superantigens to treat malignant disease

The present invention comprises the use of sickle cells or sickle cell precursors loaded with a therapeutic agent that localizes in tumors and induces a tumoricidal response.

The presence of tumor nodules in organs often results in serious clinical manifestations and the permeation by cancer cells of sheaths surrounding organs often produces clinical manifestations of pleural effusion, ascites or cerebral edema. The present invention addresses this problem by providing a method for treating tumors comprising (a) intratumoral administration of a superantigen and/or (b) intrathecal or intracavitary administration of a superantigen directly into the sheath. Intratumoral superantigen results in significant and sustained reduction of the tumor size. Intrathecal administration produces significant sustained reduction of the fluid accumulation associated with clinical improvement and prolonged survival. Useful superantigen compositions for intrathecal and intratumoral injection include tumoricidally effective homologues, fragments and fusion proteins of native superantigens. Also disclosed is combined therapy that includes intratumoral or intrathecal superantigen compositions in combination with (i) intratumoral low, non-toxic doses of one or more chemotherapeutic drugs or (ii) systemic chemotherapy at reduced and non-toxic doses of chemotherapeutic drugs.

Superantigens, including Staphylococcal enterotoxins streptococcal pyrogenic exotoxins (SpE's), biologically active fragments and homologues thereof and fission proteins of the native superantigens, homologues and fragments, are useful agents for killing tumor cells, enhancing antitumor immunity and for treating tumors in a tumor-bearing subject. In particular, a subject having a tumor is treated with a tumoricidally effective amount of a superantigen, such as a SE or SpE, or a biologically active homologue thereof, fusion protein thereof or a fusion protein of the homologue. These agents stimulate T cells, leading to increased antitumor immunity and killing of tumor cells.

Tumor killing effects of enterotoxins, superantigens, and related compounds

Polymers and polymer conjugates comprising crosslinked Staphylococcal protein A, or crosslinked protein A-superantigen, or crosslinked functional derivatives thereof ranging in size from 12kDa to 1O,OOOkDa are useful in the treatment of autoimmune diseases, such as rheumatoid arthritis and ITP as well as neoplastic diseases. Compositions and pharmaceutical composition comprising chemically crosslinked polymers of protein A alone or protein A and bacterial enterotoxins, optionally further complexed with immunoglobulins and complement components, are disclosed, as are methods for making and using these compositions in the treatment of diseases. Plasma perfusates of protein A immunadsorbent columns in clinical use are shown to act through the leaching of polymers of protein A and protein A-Staphylococcal enterotoxin B having a broad range of molecular masses. Methods of treating patients by monitoring column plasma perfusates for either of these chemical entities and appropriately adjusting doses of perfusate are also disclosed.

Polymerized staphylococcal protein a for treatment of diseases

The present invention relates to therapeutic methods and compositions employing superantigens. Methods and compositions employing superantigens and immunotherapeutic proteins in combination with one another have been found to provide more effective treatment than either component used alone. Superantigens, in conjunction with one or more additional immunotherapeutic antigens, may be used to either induce a therapeutic immune response directed against a target or to inhibit a disease causing immune response. Specific combinations of superantigens and immunotherapeutic antigens are used to treat specific diseases. The induction (or augmentation) of a desired immune against a target may be used, for example, to kill cancer cells or kill the cells or an infectious agent. The inhibition of an immune response, e.g., through the induction of T cell anergy, may be used to reduce the symptoms of an autoimmune disease. Diseases that may be treated by the methods and compositions of the invention include neoplastic diseases, infectious diseases, and autoimmune diseases. One aspect of the invention is to provide methods for the treatment of diseases comprising the steps of administering an effective amount of a superantigen and an immunotherapeutic so as to have the desired therapeutic effect. The superantigen and immunotherapeutic antigen may be administered together as a mixture. Alternatively, the superantigen and immunotherapeutic antigen may be administered separately. In one embodiment of the invention, the superantigen and immunotherapeutic antigen are administered to the patient in the form of a immunotherapeutic antigen-superantigen polymer of the invention. Another aspect of the invention is to provide methods for the treatment of diseases comprising the steps of incubating a lymphocyte population ex vivo a superantigen and an immunotherapeutic protein so as to either activate or anergize T cells within the selected population.

Superantigen based methods and compositions for treatment of diseases

Superantigens, including staphylococcal enterotoxins, are useful agents for killing tumor cells, enhancing antitumor immunity and treating cancer in a tumor-bearing host. Other useful superantigens include Streptococcal pyrogenic exotoxin, toxic shock syndrome toxins, mycoplasma antigens, mycobacteria antigens, minor lymphocyte stimulating antigens, heat shock proteins, stress peptides and derivatives thereof. The immune system of a subject with cancer is contacted with tumor cells that have been transfected with a nucleic acid encoding a superantigen or biologically active polypeptide of a superantigen. Alternatively, transfected accessory cells, inmunocytes or fibroblasts are used. Expression of the superantigen in the host induces T cell proliferation leading to increased antitumor immunity and tumor cell killing. The superantigen encoding nucleic acid may be administered to the tumor in vivo to transfect tumor cells, wherein superantigen expression induces a tumoricidal immune response. Furthermore, transfected cells incubated ex vivo with an immunocyte population, particularly T lymphocytes, tumoricidally activate the population; such activated cells are then administered to the tumor-bearing host.

Treatment of solid tumors, including their metastases, without radiation, surgery or standard chemotherapeutic agents is described. Ex vivo stimulation of cells, selection of specific V&bgr; subsets of stimulated cells and reinfusion of the V&bgr; subsets of stimulated cells is employed for cancer therapy.

Method of cancer treatment

Superantigens, including staphylococcal enterotoxins, are useful agents in the killing of tumor cells, the enhancement of antitumor immunity and in the treatment of cancer in a tumor-bearing host. In particular, the immune system of a subject with cancer is contacted with tumor cells that have been transfected with nucleic acid encoding a superantigen or biologically active polypeptide of a superantigen. Alternatively, transfected accessory cells, immunocytes or fibroblasts are used. When the superantigen is expressed in the host, T cell proliferation is induced leading to increased antitumor immunity and tumor cell killing. The nucleic acid encoding a superantigen may be administered to the tumor in vivo to transfect tumor cells wherein superantigen expression induces a similar tumoricidal immune response. Also disclosed are methods for treating a tumor wherein the transfected cells described above are incubated ex vivo with an immunocyte population, particularly T lymphocytes, to tumoricidally activate the population, followed by administering the activated population to the tumor-bearing host. Superantigens useful in these methods also include Streptococcal pyrogenic exotoxin, toxic shock syndrome toxins, mycoplasma antigens, mycobacteria antigens, minor lymphocyte stimulating antigens, heat shock proteins, stress peptides and derivatives thereof.

Growing community of inventors

Pebble Beach, CA, United States of America

David Stephen Terman