T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia

By M. Kalos, B. Levine, D. Porter, Sharyn I. Katz, S. Grupp, A. Bagg, C. June. Science Translational Medicine, 2011

2,431 citations recorded by the source corpus.

Adoptively transferred gene-modified T cells expand in vivo, eliminate leukemic cells, and form functional memory cells in patients. Go CAR-Ts in the Fast Lane As members of the body’s police force, cells of the immune system vigilantly pursue bad actors that harm healthy tissues, such as infection or cancer, and then try to deter dangerous activity. Researchers have long sought to harness the power of the immune system to fight cancers such as leukemia; however, targeting functional immune T cells to the tumor and maintaining these cells in patients remains challenging. Now, Kalos et al. have genetically modified T cells to express a chimeric antigen receptor (CAR) to yield so-called CAR T cells that specifically target chronic lymphocytic leukemia (CLL) (a B cell cancer). The designer T cells not only expanded, persisted, and attacked tumor cells after transfer into patients; they also mediated cancer remission. Innocent bystanders were also targeted, as reflected by decreased numbers of B cells and plasma cells and the development of hypogammaglobulinemia. The CAR T cells used in this study expressed an antigen receptor that consists of antibody binding domains that bind in a restricted manner to the CD19 protein (which is found solely on normal B cells and plasma cells) attached to both a T cell–specific costimulatory domain and a T cell–specific intracellular signaling domain. The resulting chimeric receptor could activate T cells in response to CD19 in the absence of major histocompatibility complex restriction, allowing for much broader cellular targeting than is obtained with normal T cells. After transfer into three CLL patients, these CAR T cells expanded >1000-fold, persisted for more than 6 months, and eradicated CLL cells. Some of these CAR T cells persisted with a memory phenotype, which would allow them to respond more quickly and on a larger scale with a second exposure to CLL cells. Indeed, two of the three CLL patients who underwent the CAR T cell treatment had complete remission of their leukemia. Although this is early in the clinical study, these results highlight the potential for CAR-modified T cells to bring cancer therapy up to speed. Tumor immunotherapy with T lymphocytes, which can recognize and destroy malignant cells, has been limited by the ability to isolate and expand T cells restricted to tumor-associated antigens. Chimeric antigen receptors (CARs) composed of antibody binding domains connected to domains that activate T cells could overcome tolerance by allowing T cells to respond to cell surface antigens; however, to date, lymphocytes engineered to express CARs have demonstrated minimal in vivo expansion and antitumor effects in clinical trials. We report that CAR T cells that target CD19 and contain a costimulatory domain from CD137 and the T cell receptor ζ chain have potent non–cross-resistant clinical activity after infusion in three of three patients treated with advanced chronic lymphocytic leukemia (CLL). The engineered T cells expanded >1000-fold in vivo, trafficked to bone marrow, and continued to express functional CARs at high levels for at least 6 months. Evidence for on-target toxicity included B cell aplasia as well as decreased numbers of plasma cells and hypogammaglobulinemia. On average, each infused CAR-expressing T cell was calculated to eradicate at least 1000 CLL cells. Furthermore, a CD19-specific immune response was demonstrated in the blood and bone marrow, accompanied by complete remission, in two of three patients. Moreover, a portion of these cells persisted as memory CAR+ T cells and retained anti-CD19 effector functionality, indicating the potential of this major histocompatibility complex–independent approach for the effective treatment of B cell malignancies.

Subfields: Genetics, Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/b2bff1a2bab8b47ed85eafe41340f83fc1babbbd

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Citations in the corpus

CD22-CAR T Cells Induce Remissions in CD19-CAR Naïve and Resistant B-ALL (2017, positive): “CD22-CAR T cell expansion was measured by quantitative PCR (qPCR) (Life Technologies, Grand Island, NY, USA), and adapted from published methods 55 .”
Managing Cytokine Release Syndrome Associated With Novel T Cell-Engaging Therapies (2014, background): “In addition to elevations in IL-10, IL-6, and IFN-γ, elevated IL-2R, MCP-1, and MIP1B are reported in patients treated with CART-19 and blinatumomab, with normal levels of IL-1B, IL-4, IL-5, IL-7, IL-12, IL-13, IL-17, tumor necrosis factor (TNF)-α, and granulocyte macrophage colonystimulating factor”
B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. (2019, methodology): “gene sequence as per Supplemental Methods and described (35).”
Global Manufacturing of CAR T Cell Therapy (2016, background): “As more experience is gained and these data begin to be made public, fair comparisons on the utility and appropriate ranges may be assessed.(51,52)”
TRUCKs: the fourth generation of CARs (2015, background): “Second-generation CARs with a CD28 or 4-1BB costimulatory domain are currently entering clinical practice [11-17].”
Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy (2015, background): “One of the most innovative approaches involves the use of adoptive T cells expressing chimeric antigen receptors (CAR-T) against CD19 (2, 3).”