Journal Article

Combining mTor Inhibitors With Rapamycin-resistant T Cells: A Two-pronged Approach to Tumor Elimination

Huye, Leslie E, Nakazawa, Yozo, Sun, Jiali, Rooney, Cliona M, Patel, Mayuri P, Savoldo, Barbara, Wilson, Matthew H, Yvon, Eric, Dotti, Gianpietro

2011

Overview

Despite activity as single agent cancer therapies, Rapamycin (rapa) and its rapalogs may have their greatest effects when combined with other therapeutic modalities. In addition to direct antitumor activity, rapalogs reverse multiple tumor-intrinsic immune evasion mechanisms. These should facilitate tumor-specific T cell activity, but since rapa directly inhibits effector T cells, this potential immune enhancement is lost. We hypothesized that if T cells were rendered resistant to rapa they could capitalize on its downregulation of tumor immune evasion. We therefore modified T cells with a rapa-resistant mutant of mTor, mTorRR, and directed them to B lymphomas by coexpressing a chimeric antigen receptor (CAR) for CD19 (CAR.CD19-28ζ). T cells expressing transgenic mTorRR from a piggyBac transposon maintain mTor signaling, proliferate in the presence of rapa and retain their cytotoxic function and ability to secrete interferon-γ (IFNγ) after stimulation, effector functions that were inhibited by rapa in control T cells. In combination, rapa and rapa-resistant-CAR.CD19-28ζ-expressing T cells produced greater antitumor activity against Burkitt's lymphoma and pre-B ALL cell lines in vitro than CAR.CD19-28ζ T cells or rapa alone. In conclusion, the combination of rapa and rapa-resistant, CAR.CD19-28ζ-expressing T cells may provide a novel therapy for the treatment of B cell malignancies and other cancers.

• Publisher: Elsevier Inc,Elsevier Limited,Nature Publishing Group
• Subject: Animals / Antigens / Antigens, CD19 - genetics / Antigens, CD19 - metabolism / Apoptosis - drug effects / B-Lymphocytes - drug effects / B-Lymphocytes - metabolism / Blotting, Western / Burkitt Lymphoma - genetics / Burkitt Lymphoma - immunology / Burkitt Lymphoma - prevention & control / Cancer / Cell growth / Cell Proliferation - drug effects / Cells, Cultured / Combined Modality Therapy / Cytotoxicity / Drug Resistance, Neoplasm / Female / Flow Cytometry / Gene therapy / Genetic engineering / Humans / Immunosuppressive Agents - pharmacology / Interferon-gamma - metabolism / Ligands / Lymphocyte Activation - drug effects / Lymphocytes / Lymphoma / Medical schools / Medicine / Mice / Mice, Inbred NOD / Mice, SCID / Original / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - immunology / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - prevention & control / Proteins / Receptors, Antigen - genetics / Receptors, Antigen - metabolism / Sirolimus - pharmacology / T-Lymphocytes - drug effects / T-Lymphocytes - metabolism / TOR Serine-Threonine Kinases - antagonists & inhibitors / TOR Serine-Threonine Kinases - metabolism / Tumors / Vectors (Biology)