This article is more than 5 years old. Information may no longer be current.
‘Smarter and stronger’ T cells offer hope for more effective, less toxic cancer therapy
Click Here to Manage Email Alerts
Editor’s note: This is the first in a series of articles that spotlight research efforts supported through Cancer Research Institute’s Lloyd J. Old STAR program. The program provides up to $1.25 million over a 5-year period to mid-career scientists who pursue high-risk, high-reward research in cancer immunotherapy.
By Yvonne Y. Chen, PhD
Immunotherapy has emerged as a pillar of cancer treatment, offering new strategies to treat diseases that not long ago had been considered incurable.
In particular, adoptive T-cell therapy — the infusion of tumor-targeting T cells into patients with cancer — has shown remarkable clinical efficacy against advanced B-cell malignancies, and CD19-specific chimeric antigen receptor (CAR) T cells became the first genetically modified cell therapy to receive FDA approval in 2017.
Despite these encouraging developments, T-cell therapy remains vulnerable to several safety and efficacy concerns, including antigen escape, off-tumor toxicity and failure to achieve efficient infiltration into solid tumor masses.
These challenges have thus far prevented the effective application of T-cell therapy against solid tumors, which account for 90% of cancer diagnoses and deaths in the United States each year.
Variegated approaches are being developed to address these obstacles, and overviews of these strategies can be found in several recent review articles (see references).
‘Smarter and stronger’
My laboratory focuses on applying biomolecular engineering and synthetic biology techniques to develop “smarter and stronger” T cells that can precisely and efficiently kill tumor cells by overcoming defense mechanisms that cancers have developed against the immune system.
For example, we have been engineering T cells to overcome antigen escape, the process through which tumor cells escape from therapy by losing the antigen targeted by engineered T cells.
Despite the high initial response rate of patients with B-cell leukemia and lymphoma to CD19 CAR-T cell therapy, a large percentage of these patients eventually relapse with tumor cells that no longer express CD19.
In response, we developed a single-chain, bispecific CAR that triggers robust T-cell activation and antitumor effector functions as long as the target cell presents either CD19 or CD20 on the cell surface, and the loss of one antigen does not reduce the activity of the engineered T cells. This strategy reduces the probability of tumor cells evading detection, as the tumor now has to lose two antigens instead of one in order to escape.
We demonstrated that the CD19/CD20 OR-gate CAR is not only able to capture preexisting CD19 tumor cells, but also can prevent tumor relapse resulting from spontaneous antigen loss in a mouse model bearing human lymphoma xenografts.
A phase 1 clinical trial designed to treat patients with non-Hodgkin lymphoma or chronic lymphocytic leukemia with CD19/CD20 bispecific CAR-T cell therapy is scheduled to open enrollment at my institution this fall.
Our research also has focused on engineering stronger T cells to overcome immunosuppression.
A major obstacle of adoptive T-cell therapy for solid tumors is the highly immunosuppressive microenvironment that surrounds tumor masses. In particular, transforming growth factor (TGF) beta is a potent T-cell suppressor associated with poor disease prognosis, and it has been identified as a critical barrier to effective immunotherapy against solid tumors.
Our laboratory developed TGF beta-targeting CARs that not only inhibit endogenous TGF beta signaling but also trigger robust T-cell activation, proliferation, cytokine production and protection over nearby tumor-specific immune cells in response to TGF beta stimulation.
In other words, the TGF beta CAR effectively converts TGF beta from an immunosuppressant to a T-cell stimulant. The TGF beta CAR can be modularly combined with tumor-specific receptor targeting, and we are evaluating the use of TGF beta CAR T cells for the treatment of various solid tumors known to overproduce TGF beta as a defense mechanism against immune infiltration.
Our laboratory also has been developing strategies to regulate gene expression in T cells to better control T-cell behavior, and to increase tumor-targeting specificity by engineering T cells that can interrogate not only surface antigens but also intracellular tumor markers prior to killing a target cell.
A three-tiered approach
Looking ahead, we will continue to take a systematic approach to developing next-generation T cells with robust, programmable and regulatable therapeutic activities.
With critical support from the Lloyd J. Old STAR award from the Cancer Research Institute (CRI), my laboratory will pursue a three-tiered approach to systematically optimize T-cell therapy at molecular, cellular and physiological levels.
At the molecular level, we aim to gain an in-depth understanding of the relationship among CAR sequence, structure and function, and to apply this knowledge to the engineering of novel receptors with predictable function.
At the cellular level, we hope to deepen our understanding of T-cell biology and apply synthetic-biology approaches to engineer genetic circuitry that enhances T-cell performance while preventing premature exhaustion.
Finally, we will focus on optimizing the interaction between T cells and the often-hostile tumor microenvironment, with the goal of maintaining robust T-cell function at and recruiting endogenous immune responses to tumor sites.
Immunotherapy has been hailed as a new pillar in cancer therapy, and adoptive T-cell therapy plays a prominent role in this promise.
However, the efficacy of T-cell therapy against solid tumors and the overall durability of therapeutic response continue to leave substantial room for improvement.
Funding support from grants, such as through the CRI’s STAR program, plays an indispensable role in enabling high-risk, high-reward research that takes aim at seemingly intractable problems.
Armed with such critical funding support, we and others in the field strive to address the challenges that limit the safety and/or efficacy of cell-based immunotherapy. These efforts will lead to more robust, less toxic and more scalable therapies that can be offered to a wider population of patients in need.
References:
Chang ZL and Chen YY. Trends Mol Med. 2017;doi:10.1016/j.molmed.2017.03.002.
Chen LC and Chen YY. Curr Opin Biotechnol. 2019;doi:10.1016/j.copbio.2019.01.016.
For more information:
Yvonne Y. Chen, PhD, is associate professor in the department of microbiology, immunology and molecular genetics, and the department of chemical and biomolecular engineering, at University of California, Los Angeles. She also is co-director of Jonsson Comprehensive Cancer Center’s tumor immunology program and a member researcher of Parker Institute for Cancer Immunotherapy. She can be reached at yvonne.chen@ucla.edu.
Disclosure: Chen reports no relevant financial disclosures.