Compositions and methods for treating cancer with anti-ROR1 immunotherapy
Inventors
Orentas, Rimas J. • Schneider, Dina • Dropulic , Boro • Dimitrov, Dimiter S. • Zhu, Zhongyu
Assignees
Lentigen Technology Inc • US Department of Health and Human Services
Publication Number
US-10428141-B2
Publication Date
2019-10-01
Expiration Date
2038-11-02
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Abstract
Chimeric antigen receptors containing ROR1 antigen binding domains are disclosed. Nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions, relating to the chimeric antigen receptors are also disclosed. Methods of treating or preventing cancer in a subject, and methods of making chimeric antigen receptor T cells are also disclosed.
Core Innovation
The present invention provides chimeric antigen receptors (CARs) containing ROR1 antigen binding domains derived from fully human antibodies or fragments thereof. These CARs are designed to achieve high surface expression on transduced T cells, exhibit a high degree of cytolysis of ROR1-expressing cells, and demonstrate in vivo expansion and persistence of the CAR-transduced T cells. The invention further provides isolated polynucleotides encoding these CARs, recombinant expression vectors, host cells expressing the CARs (especially human T cells), and pharmaceutical compositions containing such CAR-expressing cells. Also included are methods of making these CAR T cells and methods of using the CARs and CAR T cells to treat or prevent cancers expressing ROR1.
The problem being addressed stems from limited effectiveness and specificity of current cancer therapies targeting ROR1. Although ROR1 is highly expressed in many cancer types including hematologic and solid tumors and generally absent in normal tissues, previous therapies often used murine antibody-derived CARs that can induce anti-mouse immune responses leading to CAR T cell elimination and limited persistence. There is a need for improved CARs with human antigen binding domains that avoid immune rejection, have improved functional activity, and specific targeting to ROR1-expressing cancer cells to enhance treatment efficacy and reduce off-target toxicity.
Claims Coverage
The patent includes one independent claim directed to an isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR) comprising specific domains, supported by related claims to vectors, cells, pharmaceutical compositions, and methods of treatment. The main inventive features focus on the structural components of the CAR and its therapeutic use.
Chimeric antigen receptor comprising a fully human ROR1 antigen binding domain with specific transmembrane and intracellular signaling domains
An isolated nucleic acid molecule encoding a CAR comprising at least one extracellular antigen binding domain that binds ROR1 encoded by nucleotide sequence SEQ ID NO: 1 or SEQ ID NO: 7, a CD8 transmembrane domain, and intracellular signaling domains including functional signaling domains of 4-1BB and CD3 zeta.
Use of vectors and host cells for CAR expression
Vectors comprising the nucleic acid encoding the CAR can be DNA, RNA, plasmid, cosmid, herpes virus, measles virus, lentivirus, adenoviral, retrovirus or combinations thereof. Host cells, such as human T cells, can be genetically modified with these vectors to express the ROR1-targeting CAR on the cell surface.
Pharmaceutical compositions comprising CAR-expressing T cells for treatment of ROR1-expressing cancers
Pharmaceutical compositions comprising an anti-cancer effective amount of human T cells genetically modified to express the disclosed CAR comprising a human ROR1 antigen binding domain (SEQ ID NO: 2 or 8), linker domain derived from IgG4 or CD8 extracellular domain, CD8 transmembrane domain, and intracellular 4-1BB and CD3 zeta signaling domains, for use in treating ROR1-expressing cancer.
Methods of treating ROR1-expressing cancer via administration of CAR T cells
Methods of treating ROR1-expressing cancer in a subject comprising administering a pharmaceutical composition of genetically modified human T cells expressing the disclosed CAR with the specified domains and human ROR1 antigen binding domain, wherein the CAR T cells specifically target ROR1-positive cancers including hematological cancers and various carcinomas.
The claims are focused on CARs incorporating fully human ROR1 antigen binding domains linked to CD8 transmembrane and intracellular 4-1BB and CD3 zeta signaling domains, their genetic constructs, host cells expressing these CARs, pharmaceutical compositions containing such modified T cells, and their therapeutic applications in treating ROR1-expressing cancers.
Stated Advantages
The use of fully human antigen binding domains in the CARs reduces the risk of anti-mouse immune responses seen with murine-derived CARs, improving CAR T cell persistence and function in vivo.
The disclosed CAR T cells show high surface expression, potent and specific cytotoxic activity against ROR1-expressing tumor cells, and ability to produce high levels of cytokines upon antigen engagement.
The CAR design allows tuning of CAR activity and specificity based on antigen binding domain affinity, potentially reducing on-target off-tumor toxicity by differentiating cancerous from normal tissues expressing low levels of ROR1.
The CAR constructs lack basal or antigen-independent cytokine production, indicating an absence of auto-activation, important for safety and controlled therapeutic action.
Documented Applications
Therapeutic treatment or prevention of cancers expressing ROR1, including hematological cancers such as chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), mantle cell lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, multiple myeloma, as well as solid tumors including ovarian, breast, lung adenocarcinoma, glioblastoma, sarcomas, and other adult carcinomas.
Diagnostic use to detect ROR1 expression in cells for diagnosing diseases or cancers associated with ROR1 expression by contacting cells or samples with human anti-ROR1 antibodies or antigen binding fragments.
Methods of generating CAR T cells by genetically modifying T cells with vectors encoding the disclosed CARs for adoptive cellular immunotherapy.
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