Use of inhibitory chimeric receptors to prevent t cell-induced blood brain barrier damage
AssigneesThe Trustees of the University of Pennsylvania, The Board of Trustees of the Leland Stanford Junior University
InventorsAvery Posey, Carl H. June, Denis Migliorini, Howard Chang, Ansuman Satpathy, Kevin Parker
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Abstract
Neurotoxicity associated with CD19-targeted CAR-T therapy is reduced by including an inhibitory CAR (iCAR) in the CAR-T cell, wherein the iCAR specifically recognizes an antigen specific for or associated with neurovascular mural cells (e.g. pericytes or vSMC).
Claims98
A modified immune cell comprising a chimeric antigen receptor (CAR) and an inhibitory CAR (iCAR),
- wherein the CAR comprises an antigen-binding domain capable of binding CD19, a transmembrane domain, and an intracellular domain, and
- wherein the iCAR comprises an antigen-binding domain capable of binding a pericyte-associated or pericyte-specific antigen, and an inhibitory signaling domain.
A nucleic acid encoding an inhibitory chimeric antigen receptor (iCAR), wherein the iCAR comprises an antigen-binding domain capable of binding a pericyte-associated or pericyte-specific antigen, and an inhibitory signaling domain.
An inhibitory chimeric antigen receptor (iCAR) comprising an antigen-binding domain capable of binding a pericyte-associated or a pericyte-specific antigen, and an inhibitory signaling domain.
A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a modified T cell comprising a CAR and an iCAR,
- wherein the CAR comprises an antigen-binding domain capable of binding CD19, a transmembrane domain, and an intracellular domain, and
- wherein the iCAR comprises an antigen-binding domain capable of binding a pericyte-associated or pericyte-specific antigen, and an inhibitory signaling domain.
A method of inhibiting CAR T cell-induced neurotoxicity, the method comprising administering to the subject an effective amount of a modified T cell comprising a CAR and an iCAR,
- wherein the CAR comprises an antigen-binding domain capable of binding CD19, a transmembrane domain, and an intracellular domain, and
- wherein the iCAR comprises an antigen-binding domain capable of binding a pericyte-associated or pericyte-specific antigen, and an inhibitory signaling domain.
A modified immune cell comprising a chimeric antigen receptor (CAR) and an inhibitory CAR (iCAR),
- wherein the CAR comprises an antigen-binding domain capable of binding CD19, a transmembrane domain, and an intracellular domain, and
- wherein the iCAR comprises an antigen-binding domain capable of binding a mural cell-associated or mural cell-specific antigen, and an inhibitory signaling domain.
A nucleic acid encoding an inhibitory chimeric antigen receptor (iCAR), wherein the iCAR comprises an antigen-binding domain capable of binding a mural cell-associated or mural cell-specific antigen, and an inhibitory signaling domain.
An inhibitory chimeric antigen receptor (iCAR) comprising an antigen-binding domain capable of binding a mural cell-associated or a mural cell-specific antigen, and an inhibitory signaling domain.
A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a modified T cell comprising a CAR and an iCAR,
- wherein the CAR comprises an antigen-binding domain capable of binding CD19, a transmembrane domain, and an intracellular domain, and
- wherein the iCAR comprises an antigen-binding domain capable of binding a mural cell-associated or mural cell-specific antigen, and an inhibitory signaling domain.
A method of inhibiting CAR T cell-induced neurotoxicity, the method comprising administering to the subject an effective amount of a modified T cell comprising a CAR and an iCAR,
- wherein the CAR comprises an antigen-binding domain capable of binding CD19, a transmembrane domain, and an intracellular domain, and
- wherein the iCAR comprises an antigen-binding domain capable of binding a mural cell-associated or mural cell-specific antigen, and an inhibitory signaling domain.
A bi-specific iCAR comprising:
- a) a CAR comprising an antigen-binding domain capable of binding CD19, a transmembrane domain, an intracellular domain, and a CD3zeta domain, and
- b) an iCAR comprising an antigen-binding domain capable of binding a mural cell, a transmembrane domain, and an inhibitory signaling domain.
Dependencies are inferred from the claim text.