Office of Technology Development

Chimeric Antigen Receptors for Adoptive Cell Therapy

SK1036/SK1276

Summary of Invention

Enlarge Image Immunotherapy is an attractive approach for systemic eradication of malignancies. Immunotherapeutic approaches are hindered, however, by the poor immunogenicity of tumors and by a tumor microenvironment hostile to invading immune cells. Michel Sadelain and his colleagues have overcome these barriers through the development of chimeric antigen receptors (CARs). CARs are engineered fusion proteins comprising of a non-HLA restricted antigen recognition and binding domain (i.e., the antigen-binding domain of an antibody) and T-cell intracellular signaling domains. When expressed in T-cells, alone or in conjunction with co-stimulatory molecules, CARs direct the specificity and cytotoxicity of the T-cells toward tumor cells expressing the targeted antigen.

The inventors have employed these CAR constructs for adoptive cell therapy. A patient’s own T-cells are harvested, transduced with a CAR construct that recognizes and binds to the patient’s tumor, activated, expanded, and infused back into the patient. These CAR-expressing T-cells then home to tumor sites that express the target antigen, destroying such tumors and conferring long-term, anti-tumor immunity. This autologous cell therapy approach has been fully validated in animal models, and phase I clinical studies have demonstrated that the approach is safe and potentially efficacious. In addition, the inventors have pioneered a scalable process for the manufacture of activated, autologous, CAR-transduced T-cells, and the MSKCC manufacturing facility can provide GMP manufacture for multi-center phase II trials.

Advantages

  • Persistent and self-replicating immunotherapy offers greater potential for long-term systemic cure;
  • Autologous approach eliminates potential for complications associated with allogenic transplants;
  • Non-HLA restricted antigen recognition allows the use of universal “off-the-shelf” CAR constructs for all patients and permits targeting of tumors that fail to express MHC:peptide complexes;
  • Single infusion reduces complexity and cost of treatment in comparison to competing technologies;
  • Platform technology expandable to multiple malignancies as well as to other disease indications, which represents a multi-product opportunity and significant market potential

Areas of Application

  • Adoptive immunotherapy for eradication of tumors expressing a tumor-specific antigen:
    • B-cell malignancies (CD19-targeted CARs):
      • Leukemias (CLL, ALL)
      • Lymphomas (NHL)
    • Prostate Cancer (PSMA-targeted CARs)
    • Mesothelioma, Pancreatic Cancer, Lung Cancer (Mesothelin-targeted CARs)
    • Ovarian Cancer (Muc16-targeted CARs)
    • Neuroblastoma (GD2-targeted CARs)
    • Myeloma (CD56-targeted CARs)
  • Applicable to adoptive immunotherapy in other indications, such as auto-immune disease and HIV-infection

Development Status

  • Phase I clinical trial successfully completed in CD19+ chronic lymphocytic leukemia (CLL);
  • Phase II clinical trial planned in CD19+ chronic lymphocytic leukemia (CLL);
  • Phase I clinical trials ongoing in CD19+ acute lymphoblastic leukemia (ALL) and PSMA+ metastatic prostate cancer;
  • Pre-clinical and pre-IND work currently underway with CARs targeting Mesothelin (Mesothelioma) and Muc 16 (Ovarian Cancer);
  • Fully optimized, scalable, closed-system manufacturing process for production and expansion of clinical-grade, autologous T-cells expressing CARs sufficient for supply of phase II clinical trials;
  • Scalable gamma-retroviral vector production system utilizing packaging cell lines grown in suspension with serum-free media under development for phase II clinical trials.

Lead Investigators

Renier Brentjens, MD, PhD
Isabelle Rivière, PhD
Michel Sadelain, MD, PhD

Publications

Intellectual Property Status

SK1036: United States Patent 7,446,190 Issued

SK1276: PCT Application published WO 2008/121420

Contact Information

Yashodhara Dash, MBBS, PhD, MBA
Senior Licensing Manager
dashy@mskcc.org
Tel: 646-888-0577; Fax:212-717-3439

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