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

Abstract

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.

Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer

“…The clinical benefits of this approach have been validated using CAR-CD19 T cells to treat a range of CD19 + hematological malignancies including B cell chronic lymphocytic leukemia (B-CLL) and acute lymphoblastic leukemia (ALL). [29][30][31][32] For example, Grupp and colleagues 30 recently reported a complete remission rate of 92% in pediatric patients with relapsed/refractory CD19 + ALL, while Davila et al 3 achieved an overall complete remission rate of 88% in adults with B-ALL. In many cases, clinical benefit correlated with the ability of infused cells to expand and persist in vivo.…”

Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors

“…Chimeric antigen receptor (CAR)-redirected T cells have seen success in CD19 + hematological malignancies, leading to cure of acute lymphoid leukemia (ALL) and lymphoma of B-cell origin (1)(2)(3)(4)(5). The success of T-cell based CAR strategies depends on distinct T-cell subsets (6).…”

Recent advances in T‐cell immunotherapy for haematological malignancies

“…Investigators at the University of Pennsylvania reported three patients with advanced CLL who received T-cells modified with a second-generation lentiviral vector 4-1BB-CD19-CAR after receiving lymphodepletion. (Kalos et al 2011) Impressive expansion and anti-tumour activity were seen, with two CRs and one prolonged PR. However, adverse effects, including cytokine release syndrome (CRS) and B cell aplasia with hypogammaglobulinemia, were also observed (see the section on Safety below).…”