Treating cancer with genetically engineered T cells

Abstract

Administration of ex vivo cultured, naturally occurring tumor-infiltrating lymphocytes (TILs) has been shown to mediate durable regression of melanoma tumors. However, the generation of TILs is not possible in all patients and there has been limited success in generating TIL in other cancers. Advances in genetic engineering have overcome these limitations by introducing tumor-antigen-targeting receptors into human T lymphocytes. Physicians can now genetically engineer lymphocytes to express highly active T-cell receptors (TCRs) or chimeric antigen receptors (CARs) targeting a variety of tumor antigens expressed in cancer patients. In this review, we discuss the development of TCR and CAR gene transfer technology and the expansion of these therapies into different cancers with the recent demonstration of the clinical efficacy of these treatments.

Published by Elsevier Ltd.

Figures

Figure 1

Clinical application of gene-modified T cells. Shown is a diagram of the use of both natural (top) and gene modified T cells (bottom) for treatment of cancer.

Figure 2

Producing anti-tumor T cells. Shown is the general schema for the construction of gene transfer reagents for the engineering of T cells with anti-tumor receptors. Step 1. Anti-tumor antigen receptor can be isolated as natural TCRs (left) or an antibody can be turned into a chimeric antigen receptor (right). Step 2. Both TCR and CARs are produced as fusion proteins to facilitate insertion into gene transfer vectors. Step 3. Gene transfer vector that afford the possibility for stable gene transfer include transposons, gamma-retroviral vectors, and lentiviral vectors. Abbreviations: VH and VL, immunoglobulin variable regions; 2A and G4S, linker peptides; Exo, extracellular domain; TM, transmembrane domain; IR/DR, inverted/direct repeat; pA, polyadenylation signal; LTR, long terminal repeat; SD, splice donor; SA, splice acceptor, ψ, packaging signal; sinLTR, self-inactivating LTR; RRE, rev responsive element; cPPT, central polypurine tract; WPRE, woodchuck hepatitis virus post-translation regulator element.

Figure 3

Cancer regression using TCR gene-modified T cells. Shown is an X-ray computed tomography (CT) scan of the abdomen of a patient with metastatic melanoma before and >2 years after administration of anti-gp100 TCR gene transduced autologous T cells. The dashed circle indicates the position of one of the patients’ metastatic tumors in a pelvic lymph node. The long line-like element in the pre-treatment image is a biopsy needle. The patient continues to be disease free four years post-treatment.