Method of reducing mesothelin-expressing tumor burden by administration of T cells comprising mesothelin-targeted chimeric antigen receptors
Inventors
Adusumilli, Prasad S. • Sadelain, Michel • Dimitrov, Dimiter S. • Feng, Yang
Assignees
Memorial Sloan Kettering Cancer Center • US Department of Health and Human Services
Publication Number
US-11702472-B2
Publication Date
2023-07-18
Expiration Date
2035-06-05
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Abstract
The presently disclosed subject matter provides for methods and compositions for enhancing the immune response toward cancers and pathogens. It relates to chimeric antigen receptors (CARs) that specifically target human mesothelin, and immunoresponsive cells comprising such CARs. The presently disclosed mesothelin-targeted CARs have enhanced immune-activating properties, including anti-tumor activity.
Core Innovation
The presently disclosed subject matter provides methods and compositions for enhancing the immune response toward cancers and pathogens. Specifically, it relates to chimeric antigen receptors (CARs) that specifically target human mesothelin, and immunoresponsive cells comprising such CARs. The mesothelin-targeted CARs have enhanced immune-activating properties, including anti-tumor activity, while minimizing CAR-induced toxicity and immunogenicity.
The invention addresses the challenge of treating solid tumors, which pose obstacles such as generating an immunosuppressive microenvironment, restricted anatomical compartments impeding T cell trafficking, lack of agonistic costimulatory ligands, and expression of negative regulators of T cell function. These barriers limit the efficacy of targeted T cell therapies, necessitating effective tumor infiltration and overcoming tumor-induced immunosuppression.
To overcome these issues, the invention provides CARs comprising an extracellular antigen-binding domain that specifically binds human mesothelin with high affinity (e.g., Kd about 1 nM to about 25 nM), linked to various transmembrane and intracellular domains including co-stimulatory signaling regions such as CD28 or 4-1BB. Immunoresponsive cells (e.g., T cells) expressing these CARs demonstrate antigen-specific cytotoxicity, enhanced cytokine secretion, proliferation, and persistent anti-tumor responses, in vitro and in vivo. The methods include regional administration (e.g., intrapleural) of these CAR T cells, which results in superior tumor infiltration, tumor eradication, systemic trafficking including to metastatic sites, and long-term persistence. This approach effectively activates both CD4+ and CD8+ T cell subsets and can induce tumor regression with minimal toxicity to normal tissues.
Claims Coverage
The patent includes one independent method claim that encompasses administering T cells expressing mesothelin-targeted chimeric antigen receptors (CARs) with specific structural features to reduce tumor burden or increase survival in subjects with mesothelin-expressing neoplasms.
Specific mesothelin-targeted CAR composition
The CAR comprises an extracellular antigen-binding domain that specifically binds to human mesothelin composed of a heavy chain variable region including CDR1-3 with amino acid sequences SEQ ID NOS: 11-13, and a light chain variable region including CDR1-3 with amino acid sequences SEQ ID NOS: 14-16.
Recognition of mesothelin with defined expression level
The extracellular antigen-binding domain recognizes human mesothelin with an expression level of about 1,000 or more mesothelin binding sites per cell.
Defined heavy and light chain variable regions
The heavy chain variable region comprises amino acids at least 95% identical to amino acids 1-119 of SEQ ID NO:1, and the light chain variable region comprises amino acids at least 95% identical to amino acids 1-107 of SEQ ID NO:3, with CDR sequences invariable.
Structural composition of the antigen binding domain
The antigen-binding domain can comprise the heavy and light chain variable region sequences of an scFv as set forth in SEQ ID NO:7, optionally with a linker (e.g., the peptide of SEQ ID NO:17) between them.
Varied transmembrane and intracellular domains
The transmembrane domain comprises polypeptides selected from CD8, CD28, CD3ζ, CD4, 4-1BB, OX40, ICOS, CTLA-4, PD-1, LAG-3, 2B4, BTLA, or combinations thereof. The intracellular domain comprises CD3ζ polypeptide and optionally at least one co-stimulatory signaling region, such as CD28 or 4-1BB.
Cell and therapeutic method features
The CAR is expressed in T cells including CD4+ or CD8+ subsets or regulatory T cells, to reduce tumor cell number, tumor size, or eradicate tumor, particularly solid tumors such as mesothelioma, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, and others, administered intrapleurally or otherwise, alone or with immunomodulatory agents including IL-12 and checkpoint blockade antibodies.
The claims cover a method of treating mesothelin-expressing tumors using immunoresponsive T cells engineered with CARs having defined heavy and light chain variable regions targeting human mesothelin, with specific transmembrane and intracellular domain compositions, and details on administration routes and combination therapies. The invention emphasizes targeting tumors with defined mesothelin expression levels and co-stimulatory signaling to enhance efficacy and persistence.
Stated Advantages
The mesothelin-targeted CARs provide enhanced immune-activating properties including potent anti-tumor activity.
Strategies capable of inducing potent tumor eradication with minimal toxicity and immunogenicity.
Regional (e.g., intrapleural) administration leads to superior T cell accumulation in tumor sites and enhanced therapeutic efficacy compared to systemic delivery.
CD28 co-stimulation enhances CAR T cell cytokine secretion, proliferation, persistence, and anti-tumor efficacy.
CD4+ CAR T cells demonstrate multifunctional roles with cytotoxicity and helper functions, supporting sustained tumor clearance and long-term immunity.
4-1BB co-stimulation in CAR T cells can overcome tumor-mediated immunoinhibition more effectively than CD28 co-stimulation under certain conditions.
Documented Applications
Treatment of neoplasia, including solid tumors such as mesothelioma, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, colon cancer, pleural tumor, glioblastoma, esophageal cancer, gastric cancer, synovial sarcoma, thymic carcinoma, endometrial carcinoma, stomach cancer, cholangiocarcinoma, and combinations thereof.
Treatment or prevention of pathogen infections including cytomegalovirus (CMV), Epstein Barr Virus (EBV), Human Immunodeficiency Virus (HIV), and influenza virus infections.
Application in immunomodulation for autoimmune disorders, inflammatory diseases such as pancreatitis, and organ transplant recipients to prevent graft rejection.
Combination with immunomodulatory agents including IL-12, checkpoint immune blockade antibodies (e.g., anti-PD-L1), radiation therapy, and chemotherapy agents to enhance efficacy.
Use in methods for reducing tumor burden, increasing survival, increasing immune-activating cytokine production, and establishing systemic tumor immunity including in metastatic disease.
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