Trends in Biotechnology
ReviewTreating cancer with genetically engineered T cells
Introduction
The ability of lymphocytes to eradicate tumor cells in cancer patients has been demonstrated in metastatic melanoma for which the T cell cytokine interleukin (IL)-2 (aldesleukin), now an FDA-approved therapy, can mediate measurable responses in 15% of patients treated 1, 2. The immunogenic nature of melanoma tumors has served as the foundation for the development of other immune-based therapies for the treatment of this and other cancers. Nonspecific immune stimulation with IL-2 and anti-cytotoxic T-lymphocyte antigen-4 (Ipilimumab) antibody leads to activation of antitumor lymphocytes in vivo, and has been shown to mediate tumor regression in metastatic melanoma and renal cell cancer [3]. Currently, the most effective immune-based therapy for melanoma is adoptive cell therapy involving the generation of T lymphocytes with antitumor activity. When these TILs are infused into patients along with IL-2 and reduced-intensity chemotherapy to knock down temporarily the patient's circulating immune cells, TILs can mediate tumor responses in up to 70% of patients, with a significant portion of these being durable complete responses (defined as the disappearance of all target lesions) [4].
The protein that T cells utilize to identify foreign epitopes (or in the case of TILs, tumor antigens) is the T-cell receptor (TCR). The TCR is a member of the immunoglobulin gene super family and is a heterodimer composed of an α and a β chain. TCR genes can be isolated from tumor-reactive T cell clones (clones that mediate clinical responses), inserted into gene transfer vectors, and used to genetically engineer normal T lymphocytes to redirect them with antitumor specificity. These genetically engineered T cells were shown to result in objective responses in a small number of metastatic melanoma patients in 2006 [5]. Progress in the ability to mediate responses with the above immune-based therapies in metastatic melanoma has prompted the translation of these therapies to treat cancers of other tissues and organs. Recently, a series of new clinical trials have shown that measurable responses can be achieved using gene-modified T cells in cancers other than melanoma, including colorectal cancer, lymphoma, neuroblastoma, and synovial sarcoma 6, 7, 8, 9, 10. In this review, we discuss the development of T cell genetic engineering, two specific gene modifications, and the clinical applications of these biotechnologies.
Section snippets
Initial studies using natural antitumor T-cell therapy
Adoptive immunotherapy using the transfer of viral-antigen-specific T cells is now a well-established procedure that results in effective treatment of transplant-associated viral infections and rare viral-related malignancies. In these approaches, allogeneic peripheral blood lymphocytes (PBLs) are first isolated from the bone marrow donor. PBLs with reactivity to human cytomegalovirus (CMV) or Epstein–Barr virus (EBV) are isolated and expanded, and then intravenously infused into patients
Development of engineered T cells: TCR gene transfer
As an alternative to TIL therapy, highly avid TCRs can be cloned from naturally occurring T cells and, by using gene transfer vectors, introduced into patient's lymphocytes, thus creating the opportunity to generate large quantities of antigen-specific T cells for treatment (Figure 1) 14, 15. The first step in TCR gene therapy is to isolate a high-affinity T-cell clone for a defined target antigen. These TCRs can be isolated from patients with rare, highly reactive T-cell clones that recognize
Development of engineered T cells: chimeric antigen receptors
Redirection of T-cell specificity by TCRs is constrained by HLA restriction, which limits the applicability of TCR therapy to patients who express the particular HLA type (similar to organ or bone marrow transplantation). In addition, tumors can lose their antigen expression by downregulation of HLA [38]. CARs can avoid these limitations because they can confer non-HLA restricted specificity to T cells based on antibody recognition. CARs consist of a tumor-antigen-binding domain of a
Clinical trials using engineered T cells
As first documented in melanoma, genetically engineered T cells can recognize and destroy large established tumors in cancer patients; an example of this is shown in Figure 3 (this particular patient had complete elimination of melanoma tumors and remained disease free >4 years post-treatment). Recently, several clinical trials have been reported documenting the clinical efficacy of gene-modified T cells for treatment of other cancers (Table 1). These trials used both TCR- and CAR-engineered T
Future directions
Active efforts are being made in the basic research arena to improve TCR and CAR function. For TCRs, site-directed mutagenesis in the CDR region to improve antigen affinity and manipulations to improve TCR chain pairing are active areas of research. For CARs, second and third generation CARs with additional co-stimulatory signaling domains are being investigated for their ability to improve cell signaling, survival, and proliferation. Lessons learned from the clinical responses in patients
Acknowledgements
All of the clinical trials results reported from the Surgery Branch of the National Cancer Institute were performed by principal investigator and Branch Chief, Steve A. Rosenberg, MD, PhD. We thank Nicholas Restifo for the creation of Figure 1 in this review and James Kochenderfer for helpful discussions.
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