City of Hope

Leland Stanford Junior University

Umamaheswararao Jonnalagadda

Armen Mardiros

Christine E. Brown

Stephen J. Forman

Jonnalagadda, Umamaheswararao

Mardiros, Armen

Forman, Stephen J.

Brown, Christine E.

Christine E Brown

Stephen J Forman

John C Williams

Don Jeffrey Diamond

Saul J Priceman

Xiuli Wang

Uma Maheswara Rao Jonnalagadda

Lawrence Stern

Ignacio Moraga Gonzalez

K Christopher Garcia

Bart Otto Roep

Michael Barish

Jose Enrique Montero Casemiro

Xin Yang

Joseph Cohen

Dongrui Wang

Jose Enrique Montero Casimiro

Stephen J Foreman

Benham Badie

Chimeric antigen receptor molecules that include a variant IL-13. The variant IL-13 are more selective for IL13Rα2 than IL13Rα1 by virtue of weaker binding to IL13Rα1. The chimeric antigen receptors can be used to treat IL13Rα2 expressing cancers.

Targeted chimeric antigen receptor modified T cells for treatment of IL13Rα2 positive malignancies

Provided herein are, inter alia, CD6 targeting CAR-T cell compositions and methods useful for treating autoimmune diseases (e.g., Type I diabetes).

CD6 targeted chimeric antigen receptors for treatment of certain autoimmune disorders

Provided herein are, inter alia, methods and compositions including T cells expressing (i) a recombinant CAR protein which includes a peptide binding site and is capable of specifically binding cancer-specific antigens and (ii) a T cell receptor specific for a viral antigen (e.g., a CMV pp65 protein). The engineered T cells provided herein may be used in combination with a viral vaccine (e.g. cytomegalovirus (CMV) Triplex Vaccine) to treat a variety of cancers. The methods described herein also permit in vivo expansion of CMV-specific CAR T cells, instead of or in addition to ex vivo expansion, avoiding excessive T cell exhaustion that results in some cases from ex vivo manufacturing.

Use of endogenous viral vaccine in chimeric antigen receptor T cell therapy

Methods for preparing T cell populations useful for a variety of purposes requiring a highly active, long-lived T cell population. The T cell populations are enriched for: naive T cells (TN), memory stem cells (TSCM) and central memory T cells (TCM). These cell populations can be derived from peripheral blood mononuclear cells (PBMC) by both: 1) depleting unwanted cell populations such as CD14 expressing myeloid cells and CD25 expressing cells; and 2) enriching for CD62L expressing memory and naive T cells.

T cells for expression of chimeric antigen receptors and other receptors

A family of chimeric antigen receptors (CARs) containing a CD123 specific scFv was developed to target different epitopes on CD123. In some embodiments, such a CD123 chimeric antigen receptor (CD123CAR) gene includes an anti-CD123 scFv region fused in frame to a modified IgG4 hinge region comprising an S228P substitution, an L235E substitution, and optionally an N297Q substitution; a costimulatory signaling domain; and a T cell receptor (TCR) zeta chain signaling domain. When expressed in healthy donor T cells (CD4/CD8), the CD123CARs redirect T cell specificity and mediated potent effector activity against CD123+ cell lines as well as primary AML patient samples. Further, T cells obtained from patients with active AML can be modified to express CD123CAR genes and are able to lyse autologous AML blasts in vitro. Finally, a single dose of 5.0×10CAR123 T cells results in significantly delayed leukemic progression in mice. These results suggest that CD123CAR-transduced T cells may be used as an immunotherapy for the treatment of high risk AML.

CD123-specific chimeric antigen receptor redirected t cells and methods of their use

Nucleic acid molecules that include a nucleotide sequence encoding a chimeric antigen receptor (CAR) and a nucleotide sequence encoding a protease sensitive scFv, wherein the chimeric antigen receptor comprises: an scFv targeting a tumor antigen, a spacer, a transmembrane domain, a co-stimulatory domain, and a CD3&#x3b6; signaling domain; and the protease-sensitive scFv and the scFv target the same tumor antigen are described.

Chimeric antigen receptors and methods for reducing toxicity

Chimeric transmembrane immunoreceptors (CAR) targeted to PSCA are described.

Chimeric antigen receptors targeted to PSCA

Chimeric transmembrane immunoreceptors (CAR) which include an extracellular domain that includes chlorotoxin or a related toxin, or a variant of chlorotoxin or a related toxin, that binds to human glioma or other human tumor cells, a transmembrane region, a costimulatory domain and an intracellular signaling domain are described.

Chimeric antigen receptors containing a chlorotoxin domain

Chimeric transmembrane immunoreceptors (CAR) which include an extracellular domain targeted to HER2, a transmembrane region, a costimulatory domain and an intracellular signaling domain are described.

Chimeric antigen receptors targeting HER2

Provided herein are, inter alia, methods and compositions including T cells expressing (i) a recombinant CAR protein which includes a peptide binding site and is capable of specifically binding cancer-specific antigens and (ii) a T cell receptor specific for a viral antigen (e.g., a CMV pp65 protein). The engineered T cells provided herein may be used in combination with a viral vaccine (e.g. cytomegalovirus (CMV) Triplex Vaccine) to treat a variety of cancers. The methods described herein also permit in viva expansion of CMV-specific CAR T cells, instead of or in addition to ex vivo expansion, avoiding excessive T cell exhaustion that results in some cases from ex vivo manufacturing.

Chimeric transmembrane immunoreceptors (CAR) which include an extracellular domain that includes IL-13 or a variant thereof that binds interleukin-13R&#x3b1;2 (IL13R&#x3b1;2), a transmembrane region, a costimulatory domain and an intracellular signaling domain are described.

Costimulatory chimeric antigen receptor T cells targeting IL13R&#x3b1;2

A family of chimeric antigen receptors (CARs) containing a CD123 specific scFv was developed to target different epitopes on CD123. In some embodiments, such a CD123 chimeric antigen receptor (CD123CAR) gene includes an anti-CD123 scFv region fused in frame to a modified IgG4 hinge region comprising an S228P substitution, an L235E substitution, and optionally an N297Q substitution; a costimulatory signaling domain; and a T cell receptor (TCR) zeta chain signaling domain. When expressed in healthy donor T cells (CD4/CD8), the CD123CARs redirect T cell specificity and mediated potent effector activity against CD123+ cell lines as well as primary AML patient samples. Further, T cells obtained from patients with active AML can be modified to express CD123CAR genes and are able to lyse autologous AML blasts in vitro. Finally, a single dose of 5.0&#xd7;10CAR123 T cells results in significantly delayed leukemic progression in mice. These results suggest that CD123CAR-transduced T cells may be used as an immunotherapy for the treatment of high risk AML.

CD123-specific chimeric antigen receptor redirected T cells and methods of their use

Provided herein are compositions, which exhibit diagnostic capabilities and allow to rapidly add functionality to adoptive immunotherapy. The compositions include isolated nucleic acids encoding proteins including antibody regions capable of binding compounds including a peptidyl moiety (e.g., a meditope). The recombinant proteins provided herein are useful, inter alia, for a broad variety of therapeutic and diagnostic purposes. For example, the recombinant proteins provided herein including embodiments thereof may be used as non-invasive means to characterize chimeric antigen receptor (CAR) T cells before and/or during treatment of diseases (e.g., cancer).

Growing community of inventors

Duarte, CA, United States of America

Christine E Brown