Gene Therapy Modified T Cells Show Strong Response to Chronic Lymphocytic Leukemia Cells

by Dr Sam Girgis on August 11, 2011

The immune system functions to protect the normal tissues of the body from cells that are viewed as being foreign.  Foreign invaders can take the form of infectious organisms such as bacteria or viruses, or can be cancer cells.  For many years, researchers have attempted to harness the immune system’s ability to defend the body from harmful foreign invaders such as cancer cells.  There have been several attempts to develop a cancer vaccine but past attempts have met several obstacles.  Recently, a prostate cancer vaccine was developed by Dendreon Corporation and has been termed Provenge.  Additional methods of harnessing the power of the immune system to attack cancer cells have been attempted.  Researchers from the University of Pennsylvania have recently developed a gene therapy modification of T cells that has shown early promise in the treatment of chronic lymphocytic leukemia (CLL) and could possibly be more broadly applicable to other B cell malignancies.  The researchers used a lentiviral vector to induce T cell express of a chimeric antigen receptor (CAR) with specificity for CD19, coupled with CD137, and CD3 zeta.  The antigen receptor consisted of an antibody binding domain that binds to CD19 attached to a T cell specific costimulatory domain and a T cell specific intracellular signaling domain.  The resulting gene therapy modified cells were termed CAR T cells and specifically targeted CLL cells and other B cell derived cell lines.  The in vitro modified CAR T cells were transferred into 3 patients with CLL and showed a marked antitumor response with resulting tumor lysis syndrome.  The CAR T cells expanded in vivo by more than 1000 fold, and exhibited a strong targeted attack against CD19 expressing CLL cells, as well as plasma cells, and other B cells.  The CAR T cells persisted for at least a 6 month period in vivo and continued to express chimeric antigen receptor and serve as anti-CD19 effector memory cells.  An expected side effect which was observed was hypogammaglobulinemia.    Two of the three treated patients with CLL had a complete remission, and the third had a strong response and has continued to improve.  Although it is very early in this phase I trial, this gene therapy modification of T cells has the potential of being able to treat other B cell malignancies and further investigation will focus of targeting other types of cancers such as pancreatic, ovarian, breast, and colon cancer cells.  The authors wrote, “These CART19 cells tracked efficiently to sites of tumor and became established as de facto “tumor-infiltrating lymphocytes” that exhibited CD19 specificity and retained effector function in vivo in patient blood and marrow specimens for months”.  In an accompanying editorial to the New England Journal of Medicine article it was cautioned, “Only with the more widespread clinical use of chimeric antigen–receptor T cells will we learn whether the results reported by Porter et al. reflect an authentic advance toward a clinically applicable and effective therapy or yet another promising lead that runs into a barrier that cannot be easily overcome”.

References:

David L. Porter et al. “Chimeric Antigen Receptor-Modified T Cells in Chronic Lymphoid LeukemiaNEJM published August 10, 2011 doi: 10.1056/NEJMoa1103849

Michael Kalos et al. “T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced LeukemiaSci Transl Med published August 10, 2011 Vol. 3, Issue 95, p. 95ra73 DOI: 10.1126/scitranslmed.3002842

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