The United States of America As Represented by the Department of Health

University of Minnesota

National Institutes of Health, a Component of the US Dept. of Health & Human Services

The Johns Hopkins University

The United States of America As Represented by the Secretary of

Immunex Corporation

National Institutes of Health

The United States of America As Represented by the Secretary, Department

Biomira USA Inc.

Biormia USA Inc.

Dan L Longo

Augusto C Ochoa

Paritosh Ghosh

Howard A Young

Cynthia M Loeffler

Bira Arya

John J O'Shea

Richard Jeffrey Armitage

William Christian Fanslow, Iii

Andrew P Feinberg

William J Murphy

Andre Levchenko

Richard J Robb

Christine A Iacobuzio-Donahue

Hiromoto Mizuguchi

Minoru Ko

Mary Neville

Igor Espinoza-Delgardo

Mark L Saxton

Larry W Kwak

Igor Espinoza

Walter Urba

Hiromoto Mizoguchi

Minoru Sh Ko

The instant invention provides compositions for the treatment of cancer. Specifically, the invention provides polypeptides and nucleic acid molecules comprising tumor-associated embryonic antigens, e.g., OFA-iLRP, and chemoattractant ligands, e.g., a proinflammatory chemokine such as MIP3&#x3b1;/CCL20 or &#x3b2;-defensin mDF2&#x3b2;. The invention further provides cancer vaccines and methods for treating subjects having, or at risk of developing, cancer.

Methods and compositions for the treatment and prevention of cancer

The invention relates to methods and compositions for identifying subjects having, or predisposed to having, a neoplastic or cell proliferation or neoplastic disorder. The methods are applicable to any type of tissue sample and can be conducted on otherwise normal tissue.

Methods of screening for cell proliferation or neoplastic disorders

Methods of identifying a patient having an altered immune status involve determining an immune status index for the patient and comparing it to the immune status index in healthy individuals. In general, an immune status index is the ratio of the amount of a protein that varies significantly in a patient with an altered immune status to the amount of another protein that is substantially invariant in both healthy and immune-altered individuals. Variable proteins can be TCR subunit proteins, T lymphocyte signal transduction pathway proteins, polynucleotide binding proteins or biological response modifiers (BRM). In addition, the ratio of a TH-1-type BRM to a TH-2-type BRM, the ratio of cytoplasmic to nuclear levels of polynucleotide binding proteins, the pattern of protein binding to an oligonucleotide probe that comprises the protein binding region of a gene for a BRM, or the pattern of distribution of T lymphocytes in a density gradient following density gradient centrifugation are also suitable as an immune status index. The methods are useful in identifying patients exhibiting immunosuppression, hyperimmunity and autoimmunity, as well as in assessing the immune status of a patient undergoing organ transplant.

Methods of identifying patients having an altered immune status

A soluble immunosuppressive factor present in serum derived from tumor-bearing mammals, is associated with changes in TCR protein subunit levels, T lymphocyte signal transduction pathway proteins. These changes provide a method of determining the level of immunosuppression in a mammal by determining the level of expression of at least one selected TCR subunit protein, a protein in the T lymphocyte signal transduction pathway, or of the NF-.kappa.B/rel family and comparing the level and pattern to that found in non-immunosuppressed individuals. The method is useful to identify patients having T lymphocytes capable of activation for immunotherapy and for identifying agents which cause or reverse immunosuppression. An isolated immunosuppressive factor associated with the level of expression of the proteins is useful for suppressing the immune response, for example, in organ transplantation.

Evaluation and treatment of patients with progressive immunosuppression

This invention provides a method of improving a transplantation of hematopoietic cells from a donor to a recipient to treat a hematopoietic cell tumor in the recipient comprising immunizing the donor's hematopoietic cells with an antigen specific for the recipient's hematopoietic cell tumor, and transplanting the donor's immunized hematopoietic cells to the recipient. Also provided is a composition comprising purified hematopoietic cells primed to produce an immunological response to foreign tumor specific antigen. Also provided is a method of treating a tumor by the transplantation of hematopoietic cells from a donor to a recipient to treat the tumor in the recipient comprising immunizing the donor's hematopoietic cells with an antigen specific for the recipient's tumor, and transplanting the donor's immunized hematopoietic cells to the recipient.

Method and composition for transfer of active tumor-specific

The present invention provides a method for enhancing the immunotherapeutic activity, e.g., antitumor activity, of immune cells by depleting immune cells of a cell subset that down-regulates the immune response, such as either CD4.sup.+ or CD8.sup.+ lymphocytes. The remaining depleted immune cell population or the separated immune cell subsets then are cultured in the presence of an antibody to a lymphocyte surface receptor, preferably an anti-CD3 monoclonal antibody (MoAb), optionally in the presence of a relatively minor amount of interleukin-2 (IL-2). These stimulated cells then are optionally additionally cultured in the presence of IL-2 without an antibody to a lymphocyte surface receptor. The present invention also provides a method of treating a mammal having tumors or immunizing a mammal against tumors by administering the stimulated depleted immune cell population or a stimulated immune cell subset to a mammal, advantageously together with an immunosuppressant, and with liposomal IL-2. The invention further provides a method of transferring the immunity of mammals that are treated or immunized in accordance with the invention by extracting splenocytes from these mammals and administering these splenocytes to a second mammal.

Method of treating tumors with CD8.sup.+ -depleted or CD4.sup.+ T cell

There is disclosed a method of treating a mammal afflicted with a disease characterized by neoplastic cells that express CD40, comprising administering a therapeutically effective amount of a CD40 binding protein in a pharmaceutically acceptable buffer. CD40 binding proteins include monoclonal antibodies to CD40, and CD40 ligand. CD40 binding proteins may also be used to prevent disease characterized by neoplastic cells that express CD40, in individuals at risk for such disease.

Method of preventing or treating disease characterized by neoplastic

A soluble immunosuppressive factor present in serum derived from tumor-bearing mammals, is associated with changes in TCR protein subunit levels and T-lymphocyte signal transduction pathway proteins. These changes provide a method of determining the level of immunosuppression in a mammal by determining the level of expression of at least one selected TCR subunit protein, or a protein in the T lymphocyte signal transduction pathway, and comparing the level to that found in non-immunosuppressed individuals. The method is useful to identify patients having T lymphocytes capable of activation for immunotherapy and for identifying agents which cause or reverse immunosuppression. An isolated immunosuppressive factor associated with the level of expression of the proteins is useful for suppressing the immune response, for example, in organ transplantation.

The present invention is directed to a method of increasing the in vivo immune response of lymphocytes by stimulating the lymphocytes in vitro in the presence of an anti-CD3 monoclonal antibody for less than about 24 hours to form stimulated lymphocytes; infusing the stimulated lymphocytes into a tumor-bearing mammal; and administering IL-2 to the mammal. As a result of this method, the anti-CD3 stimulated lymphocytes display enhanced immunotherapeutic, e.g., cytotoxicity or lymphokine production, in vivo as represented by a decrease in the number of tumors by at least about 20%.

Short-term anti-CD3 stimulation of lymphocytes to increase their in vivo

A method of determining the level of immunosuppression in a mammal involves determining the level of expression of at least one selected TCR subunit protein, or protein in the T lymphocyte signal transduction pathway, and comparing the level to that found in healthy individuals. The method is useful to identify patients having T lymphocytes capable of activation for autologous adoptive immunotherapy and for identifying agents which cause or reverse immunosuppression.

Evaluation and treatment of patients with progessive immunosuppression

Growing community of inventors

Kensington, MD, United States of America

Dan L Longo