Compositions and methods for treating cancer with self-driving chimeric antigen receptors
Inventors
Schneider, Dina • Dropulic , Boro • Webster, Brian Robert
Assignees
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Publication Number
US-11969443-B2
Publication Date
2024-04-30
Expiration Date
Abstract
Self-driving surface antigen-regulated promoter-therapeutic payload constructs containing antigen binding domains are disclosed. Nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions, relating to the surface antigen-regulated promoter-therapeutic payload constructs are also disclosed. Methods of treating or preventing cancer in a subject, and methods of making self-driving surface antigen-regulated promoter-therapeutic payload constructs in T-cells are also disclosed.
Core Innovation
The invention provides CAR T therapy constructs in which a surface antigen-regulated inducible promoter controls transcription of an anti-tumor chimeric antigen receptor (CAR) payload. The promoter adjusts transcription dependent upon the level of expression of surface antigen on a target cell, thereby enabling CAR expression to increase in response to target surface antigen levels rather than relying on constitutive expression.
The constructs have low basal CAR payload expression without antigen and upregulate CAR in proportion to target surface antigen levels. This antigen-dependent control creates a positive feedback loop for improved timing and magnitude of antitumor activity while aiming to reduce overactivation and toxicity, including cytokine release syndrome (CRS) and neurotoxicity.
In disclosed embodiments, autologous T cells are transduced with nucleic acids encoding a CAR comprising the amino acid sequence of SEQ ID NO: 78. The nucleic acid includes a surface antigen-regulated inducible promoter comprising the nucleotide sequence of SEQ ID NO: 138 or a sequence with specified identity to SEQ ID NO: 138, operably linked to the CAR encoding sequence, so that CAR transcription is adjusted based on surface antigen levels on target cells.
The constructs further enable co-expression of CAR LTG1563 with dominant-negative inhibitory payloads, including dominant negative inhibitory TGF-beta receptor (TGFBRIIdn) and dominant negative PD1 (PD1dn). Transcriptional control is provided using response elements such as STAT5_RE or inducible/cytokine-regulated AP1/NFkB response elements, or using constitutive EF1 promoters, and these payloads are used to address immunosuppression associated with TGF/PD-L1 conditions.
Claims Coverage
The independent claims require autologous anti-tumor T-cell therapy for hematological cancer, a CAR defined by SEQ ID NO: 78, and a surface antigen-regulated inducible promoter comprising SEQ ID NO: 138 or specified identity variants that adjusts transcription according to target-cell surface antigen expression. Additional claim language supports related promoter specifications, hematological cancer types, and co-expression embodiments.
Autologous CAR T treatment with SEQ ID NO: 78 CAR
Administering a pharmaceutical composition comprising an anti-tumor effective amount of a population of autologous T cells, wherein each cell comprises a nucleic acid sequence encoding a chimeric antigen receptor (CAR) comprising the amino acid sequence of SEQ ID NO: 78.
Surface antigen-regulated inducible promoter controlling CAR transcription
A nucleic acid comprising a surface antigen-regulated inducible promoter comprising the nucleotide sequence of SEQ ID NO: 138 or a sequence with 85%, 90%, 95%, 96%, 97%, 98% or 99% identity, operably linked to the CAR encoding sequence, wherein the promoter adjusts its level of transcription dependent upon the level of expression of surface antigen on a target cell.
Autologous anti-tumor T-cell treatment of hematological cancer
Treating a hematological cancer in a human subject by administering an anti-tumor effective amount of a population of autologous T cells.
Overall claim coverage centers on antigen-level-dependent transcriptional control of CAR payload expression in autologous T cells using a surface antigen-regulated inducible promoter specified as SEQ ID NO: 138 or identity variants linked to a CAR encoding sequence defined by SEQ ID NO: 78, for treating hematological cancer in a human subject.
Stated Advantages
Adjusts CAR transcription based on the level of surface antigen expression on a target cell.
Low basal CAR payload expression without antigen.
Upregulation of CAR in proportion to target surface antigen levels.
Improved timing and magnitude of antitumor activity via antigen-dependent positive feedback.
Reduction of overactivation and toxicity, including cytokine release syndrome (CRS) and neurotoxicity.
Restores cytotoxicity under TGF/PD-L1 conditions.
Documented Applications
Treating a hematological cancer in a human subject by administering an autologous T-cell pharmaceutical composition comprising CAR-expressing cells regulated by a surface antigen-regulated inducible promoter.
Treating leukemia, including acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), acute lymphoblastic T cell leukemia (T-ALL), or acute lymphoblastic B cell leukemia (B-ALL).
Treating mantle cell lymphoma, non-Hodgkin's lymphoma, or Hodgkin's lymphoma.
Addressing immunosuppression associated with TGF/PD-L1 by co-expressing CAR LTG1563 with dominant-negative inhibitory payloads (TGFBRIIdn and PD1dn) using specified regulatory elements (STAT5_RE, AP1/NFkB response elements) or constitutive EF1 promoters.
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