Despite myriad challenges, clinicians see room for progress.
Image credit: Shutterstock/David Tadevosian.
New Research In
Physical Sciences
Featured Portals
Articles by Topic
Biological Sciences
Featured Portals
Articles by Topic
The field of cancer immunotherapy has seen several recent successes as a result of an improved understanding of T-cell regulation and responses. The foundation for these successes existed in earlier work consisting of the identification of tumor antigens that could be recognized by cytotoxic T cells with the eventual elimination of tumor cells (1, 2). On the basis of these early studies, initial clinical trials focused on antigen-specific methods (e.g., peptide, protein, and DNA vaccines) to expand T cells in an attempt to generate antitumor responses. Unfortunately, many of these vaccine trials failed to demonstrate clinical efficacy (3). Investigations as to why these initial trials failed led to the identification of a complex system that includes intrinsic mechanisms that control T-cell responses [cytotoxic lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1)], extrinsic mechanisms that control T-cell responses (regulatory T cells), cytokine pathways that act to regulate T-cell responses [granulocyte macrophage colony-stimulating factor (GM-CSF), TGF-β], and lack of sufficient quantities of T cells with high-affinity T-cell receptors against tumor antigens. Immunotherapy strategies are now addressing these complex systems with subsequent clinical efficacy, including a significant survival benefit in patients with metastatic melanoma as a result of anti–CTLA-4 therapy (4), improved survival of patients with metastatic prostate cancer after transfer of autologous peripheral blood mononuclear cells pulsed ex vivo with a fusion protein consisting of the prostatic acid phosphatase antigen and GM-CSF cytokine (5), and elimination of tumors in patients after adoptive transfer of T cells bearing engineered T-cell receptors with high affinity for a specific tumor antigen (6).
Tumor Eradication with Adoptive T-Cell Therapy
The article by Koya et al. in PNAS (7) addresses one of the important questions that has arisen as a result of adoptive T-cell therapies: what happens to the T cells after they are transferred? It was previously shown that autologous adoptive T-cell therapy, consisting of T cells reactive against a selected antigen that are isolated from the patient and expanded to large numbers in vitro before reinfusion to the patient, can lead to potent antitumor responses (8–10). However, several factors limit the efficacy and clinical application of adoptive T-cell immunotherapy, including the inability of transferred T cells to persist at high levels in vivo after infusion and the difficulty of reproducibly isolating high-affinity T cells that recognize relevant tumor antigens. To address the latter problem, researchers have relied onAdoptive T-cell therapy with an engineered TCR provides exquisite specificity against tumors.
transfer of T-cell receptor (TCR) genes into primary T cells to generate high-affinity T cells specific for a given tumor antigen. The transfer of TCRα and TCRβ genes into T cells was first shown in vitro (11–13) and then in animal models (14–19), followed by a subsequent clinical trial demonstrating tumor regression in 2 of 17 patients (6). The clinical trial used a MART-1–specific TCR, and at the time of infusion of the engineered T cells into patients, 42% of the CD8+ T cells expressed the MART-1–specific TCRβ chain; however, 1 mo after infusion, expression of the MART-1–specific TCRβ chain was detected on only 8% of patients’ peripheral T cells, which may explain the limited responses observed with this immunotherapy strategy.
Tracking Adoptively Transferred T Cells
Understanding what happens within the host after adoptive transfer of T cells is an important step in improving this immunotherapy approach. The article by Koya et al. reports on molecular imaging techniques with reporter gene labeling of cells to allow noninvasive detection of adoptively transferred TCR transgenic cell populations in recipient immunocompetent transgenic HLA-A2/Kb mice. Splenocytes from the transgenic mice were transduced with tyrosinase-specific TCR, with proximal constant TCR subunits being murine and distal variable subunits being human restricted to HLA-A2.1. The α and β TCR chains were linked to molecular imaging reporter genes consisting of luciferase for bioluminescence imaging and herpes simplex virus 1 thymidine kinase for microPET imaging. Transgenic mice bearing tumors that had been engineered to express a chimeric/human MHC molecule (HLA-A2.1/Kb) underwent whole-body myelodepleting irradiation followed by adoptive T-cell transfer of the engineered T cells and studied. This unique system allowed the authors to track the T cells by both bioluminescence and microPET for in vivo trafficking, persistence, and localization to tumor and other tissues. The authors showed that there was peak accumulation of the transferred T cells into tumors at day 5. After day 5, there was decreased signal on imaging studies that correlated with tumor shrinkage as a result of therapy. These studies demonstrate the feasibility of in vivo tracking of adoptively transferred T cells in an immunocompetent animal and provide a preclinical model to further evaluate and develop future immunotherapy strategies with adoptive T-cell therapies consisting of HLA-A2–restricted T cells before clinical trial implementation.
Building on Current Successes
Adoptive T-cell therapy with an engineered TCR provides exquisite specificity against tumors and can potentially be combined with other immunotherapy strategies, such as cytokine therapy, anti–CTLA-4 therapy, or anti–PD-1 therapy, which may lead to increased persistence and antitumor activity of transferred cells. These combination therapies hold great promise for enhanced therapeutic efficacy. The article by Koya et al. provides a feasible method to test these combinations to develop the best strategies for clinical trial implementation and eventual patient benefit.
Footnotes
- 1E-mail: padsharma{at}mdanderson.org.
Author contributions: P.S. wrote the paper.
The author declares no conflict of interest.
See companion article on page 14286.
References
Cancer immunotherapy: In vivo imaging of adoptively transferred T cells in an immunocompetent host
Sign up for Article Alerts
Jump to section
You May Also be Interested in
Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
Using CRISPR, researchers showed that a region some used to label “junk DNA” has a major role in a rare genetic disorder.
Image credit: Nathan Devery.
Mara Reed and Michael Manga explore why Yellowstone's Steamboat Geyser resumed erupting in 2018.
A study demonstrates how two enzymes—MHETase and PETase—work synergistically to depolymerize the plastic pollutant PET.
Image credit: Aaron McGeehan (artist).