University of Pennsylvania

Novartis Ag

Wayne State University

Yangbing Zhao

Carl H June

Andreas Loew

Xiaojun Liu

Jiangtao Ren

Matthew J Frigault

Sonia Guedan Carrio

Michael C Milone

Daniel J Powell

John Scholler

Devon Shedlock

Lawrence G Lum

Anne Chew

Archana Thakur

Wei Pan

Szu Hua Sharon Lin

Devon J Shedlock

Xiaojun Lui

The present invention relates generally to a fusion protein that when displayed on a cell can convert a negative signal into a positive signal in the cell. The fusion protein is a chimeric protein in that the protein comprises at least two domains, wherein the first domain is a polypeptide that is associated with a negative signal and the second domain is a polypeptide that is associated with a positive signal. Thus, the invention encompasses switch receptors that are able to switch negative signals to positive signals for enhancement of an immune response.

Switch costimulatory receptors

The present invention provides compositions and methods for generating a genetically modified T cells comprising a chimeric antigen receptor (CAR) having an antigen binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain, wherein the T cell exhibits prolonged exponential expansion in culture that is ligand independent and independent of the addition of exogenous cytokines or feeder cells.

Compositions and methods for generating a persisting population of T cells useful for the treatment of cancer

The present invention relates to compositions and methods for generating a modified T cell with a nucleic acid capable of downregulating endogenous gene expression selected from the group consisting of TCR α chain, TCR β chain, beta-2 microglobulin, a HLA molecule, CTLA-4, PD1, and FAS and further comprising a nucleic acid encoding a modified T cell receptor (TCR) comprising affinity for a surface antigen on a target cell or an electroporated nucleic acid encoding a chimeric antigen receptor (CAR). Also included are methods and pharmaceutical compositions comprising the modified T cell for adoptive therapy and treating a condition, such as an autoimmune disease.

Altering gene expression in cart cells and uses thereof

The present disclosure provides gene edited modified immune cells or precursors thereof (e.g., gene edited modified T cells) comprising an exogenous T cell receptor (TCR) and/or a chimeric antigen receptor (CAR) having specificity for a target antigen, and an insertion and/or deletion in one or more endogenous gene loci, wherein the endogenous gene loci encode regulators of T cell function, thereby resulting in immune cells having enhanced function. Compositions and methods of treatment are also provided. The present invention provides methods of screening for TCR- or CAR-T cells with enhanced immune function (e.g., T cell efficacy, T cell memory, and/or T cell persistence).

Modified immune cells having enhanced function and methods for screening the same

The present invention includes compositions and methods for a modified immune cell or precursor cell thereof comprising an inducible expression system. Also provided are gene edited modified immune cells suitable for T cell therapy. Methods of treatment using modified immune cells of the present invention are also provided.

Use of gene editing to generate universal TCR re-directed t cells for adoptive immunotherapy

The present invention includes compositions and methods for modifying a T cell with a nucleic acid encoding a switch molecule comprising an extracellular domain comprising a membrane receptor or fragment thereof and an intracellular domain comprising a signaling receptor or fragment thereof. In one aspect, a method comprises introducing a nucleic acid encoding a switch molecule and a nucleic acid encoding a soluble fusion protein and/or a nucleic acid encoding a bispecific antibody into a population of cells comprising T cells, wherein the T cells transiently expresses the switch molecule and soluble fusion protein or bispecific antibody. In other aspect, compositions of T cells and methods of treating a disease or condition, such as cancer or an autoimmune disease, are also included.

Compositions and methods for T cell delivery of therapeutic molecules

The invention provides T cells comprising nucleic acid sequence encoding a chimeric antigen receptor and a nucleic acid sequence encoding an enhancer of T cell priming, compositions including the T cells, and methods of using the T cells to treat diseases associated with the expression of disease-associated antigens.

Enhanced antigen presenting ability of RNA car T cells by co-introduction of costimulatory molecules

The present invention includes compositions and methods for modifying primary T cells. In one aspect, the invention comprises administering to a cell a stem-loop Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) RNA (st-crRNA) and a Cpf1 enzyme.

Compositions and methods for gene editing in T cells using CRISPR/Cpf1

The present disclosure provides modified immune cells (e.g., modified T cells) comprising a chimeric antigen receptor (CAR) having affinity for a prostate-specific membrane antigen (PSMA) (e.g., human PSMA). The present disclosure provides modified immune cells (e.g., modified T cells) comprising a CAR having affinity for PSMA and a dominant negative receptor and/or a switch receptor. The present disclosure provides modified immune cells (e.g., modified T cells) comprising a CAR having affinity for PSMA and a dominant negative receptor and/or a switch receptor, wherein the modified cell is capable of expressing and secreting a bispecific antibody.

Prostate-specific membrane antigen cars and methods of use thereof

The present invention provides compositions and methods for treating cancer in a human. The invention includes administering a genetically modified Th17 cell to express a CAR having an antigen binding domain, a transmembrane domain, and an ICOS intracellular signaling domain.

Use of ICOS-based cars to enhance antitumor activity and car persistence

Modified immune cells having enhanced function and methods for screening for same

The present invention relates to compositions and methods for enhancing T cell metabolism and activity for more effective adoptive T cell therapy. By expressing an chimeric antigen receptor and bispecific antibodies in T cells, the T cells are metabolically enhanced with improved cytotoxicity and resistance to immunosuppression imposed by tumor microenvironments. Certain aspects include modified T cells and pharmaceutical compositions comprising the modified cells for adoptive cell therapy and treating a disease or condition associated with enhanced immunity.

Methods and compositions for cells expressing a chimeric intracellular signaling molecule

The present invention provides compositions and methods for treating cancer in a human. The invention includes administering a T cell, genetically modified to express a chimeric antigen receptor (CAR), a bispecific antibody, or a combination thereof to a subject. The CAR and bispecific antibody of the invention can comprise a human antibody, a humanized antibody, or antigen-binding fragments thereof.

Enhancing activity of CAR T cells by co-introducing a bispecific antibody

The present disclosure provides modified immune cells or precursors thereof (e.g. T cells) comprising a chimeric antigen receptor (CAR) capable of binding human PSCA. CARs capable of binding human PSCA, and nucleic acids encoding the same are also provided. Provided herein are bispecific CARs capable of binding human PSCA and human PSMA, nucleic acids encoding the same, and modified immune cells comprising the same. Modified immune cells comprising a PSMA CAR and a PSCA CAR are also provided. Compositions and methods of treatment are also provided.

Compositions and methods comprising prostate stem cell antigen (PSCA) chimeric antigen receptors (CARs)

The present disclosure provides modified immune cell (e.g., modified T cell) comprising an exogenous T cell receptor (TCR) having specificity for NY-ESO-1. The present disclosure provides modified immune cells or precursors thereof (e.g., modified T cells) comprising an exogenous TCR and a switch receptor. Gene edited modified cells are also provided, such that the expression of one or more of an endogenous T-cell receptor gene (e.g., TRAC, TRBC) or an endogenous immune checkpoint gene (e.g., PD-1 or TIM-3) is downregulated.

Growing community of inventors

Lumberton, NJ, United States of America

Yangbing Zhao