Science

Engineered T cell Therapies

Engineered T cell therapy is a type of immunotherapy treatment consisting of genetic modification of human T cells to express specific receptors, enabling the T cells to efficiently recognize and destroy target disease-causing cells. Current methods are primarily autologous, whereby T cells are removed from an individual patient, modified to express the desired receptor, and infused back into the same patient to take effect. Future research may enable allogeneic approaches that would be ‘off-the-shelf’ with one product being used in all patients or multiple HLA-matched patients.

Current Paradigm: Chimeric Antigen Receptors (CARs)

A key application of engineered cell therapy involves the use of chimeric antigen receptors, or CARs, which are engineered molecules that enable the T cells to identify specific proteins or antigens present on the surface of other cells. This technology has been employed to develop potent and durable therapies for the treatment of patients suffering from B cell-mediated cancers with remarkable clinical success. Two CD19-specific CAR T cell products have achieved regulatory approval for acute lymphoblastic leukemia (ALL) and diffuse large B cell lymphoma (DLBCL) in 2017. CAR-enabled targeting is a key technology for the development of oncology therapeutic programs across the biotechnology industry.

Most CARs adhere to a similar basic framework that incorporates an:

  • Extracellular Target Binding Domain: The extracellular end of the CAR molecule in most oncology applications consists of an antibody-derived domain, most commonly a single chain variable fragment (scFv), that binds specifically to a target antigen on cancer cells such as CD19.
  •  Intracellular Signaling Domain: The intracellular domain of the CAR is responsible for stimulating the T cell to carry out its immune functions when the CAR engages its target molecule on the surface of a cell. Most CARs in active clinical trials incorporate the intracellular domain of CD3 ζ, a primary component of the natural T cell receptor complex.  The CD3 ζ domain initiates an essential primary signal for T cells that is required for triggering the release of cytotoxic granules that contain proteins that kill a target-molecule-expressing cell.  Additional costimulatory domains such as the cytoplasmic domain of 4-1BB (CD137) are generally included to produce what have been termed 2nd generation CARs. These latter costimulatory domains enhance both cytokine production and the replication of the CAR T cells, which is central to the unique, self-renewing nature of this living therapy.
Chimeric Autoantibody Receptors (CAARs)

Building upon the design of traditional CARs, our scientific founders have developed a variation termed chimeric autoantibody receptors, or CAARs, which permits the creation of engineered T cells that can target and kill disease-causing autoimmune B cells, sparing normal B cells that are needed for protection from infection. The Cabaletta CAARs differ from the CD19-specific CAR (tisagenlecleucel) that was developed at the University of Pennsylvania solely within the extracellular domain. Our CAAR incorporates the antigen that is being attacked in a B-cell mediated autoimmune disease as part of the extracellular domain of the CAAR. The extracellular antigen programs the CAAR T cell to detect only the disease-causing B cells, engage them, and destroy them while sparing the normal B cells.  This is in contrast to currently approved CAR T products, which destroy all B cells, including the normal and the leukemic or cancer-causing B cells. Because CAAR T cells are designed to kill only a small fraction of all B cells, in contrast to currently approved CAR T cell products which are designed to kill 100% of healthy and disease-causing B cells, CAAR T cells products may have a substantially lower risk of serious side effects that are commonly observed with CAR T cell therapy today.

Publication Highlight
July 8, 2016
Science
Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease
Christoph T. Ellebrecht, Vijay G. Bhoj, Arben Nace, Eun Jung Choi, Xuming Mao, Michael Jeffrey Cho,Giovanni Di Zenzo, Antonio Lanzavecchia, John T. Seykora, George Cotsarelis, Michael C. Milone, Aimee S. Payne

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