Elsevier

Cytotherapy

Volume 15, Issue 6, June 2013, Pages 632-640
Cytotherapy

Review
Biomarkers in T-cell therapy clinical trials

https://doi.org/10.1016/j.jcyt.2013.01.002Get rights and content

Abstract

T-cell therapy represents an emerging and promising modality for the treatment of disease. Data from recent clinical trials of genetically modified T cells, most notably chimeric antigen receptor (CAR) T cells, have yielded dramatic clinical results and highlighted the potential for this approach to mediate anti-tumor activity. Continued progress in the development of such T-cell therapies will require the identification of the relevant biomarker strategies to support and guide clinical development of the candidate products. In this review, we review and discuss (i) principles for development and use of biomarkers in clinical research, (ii) the rationale and a strategy for the integration of biomarker data at all stages of the product development process, from preclinical studies through product manufacture and during the clinical trial and (iii) the different classes of biomarkers that are relevant to T-cell therapy trials. Throughout this review, we discuss how biomarkers can play a central role in the development of novel T-cell therapeutic agents and highlight how appropriately designed biomarker studies can provide critical insights to this process. Finally, we discuss future directions and challenges for the appropriate development of biomarkers to evaluate product bioactivity and treatment efficacy.

Section snippets

Principles for development and use of biomarkers in clinical research

The primary objectives of clinical trials are the evaluation of the safety and clinical efficacy of novel therapeutic agents. Although the first of these goals is generally straightforward, measuring clinical efficacy of adoptive T-cell treatments targeting cancer is often challenging for a variety of reasons that relate to heterogeneity in patient clinical and immune status, as well as to the biological nature and intrinsic variability of the therapeutic modality. With these considerations in

Integration of biomarkers from preclinical studies to clinical application

Early evidence for product efficacy and bioactivity in clinical trials is of critical importance to guide the further development of the candidate product. Accordingly, there is growing interest to identify sensitive, robust and meaningful biomarkers that may provide relevant insights into the clinical development process 8, 9. In addition to informing decisions on whether to advance new agents into clinical trials, preclinical biomarker studies commonly evaluate mechanistic aspects of the

T-cell therapy clinical trials

The essential objectives of immunotherapy as a treatment for cancer are (i) to mediate potent anti-tumor immunity leading to disease remission and (ii) to establish long-lasting immunity to target antigens and tumor. For the past 20 years, immunotherapy approaches have principally focused on the evaluation of therapeutic vaccine-based approaches to target cancer (10). In the vast majority of cases, such approaches have not been successful, with reviews of the many clinical trials indicating

Biomarkers in T-cell therapy trials

Unlike the majority of anti-cancer therapeutics in clinical trials, adoptive T-cell therapy is unique in that the therapeutic is a biological entity whose physiological status is critical to mediate the desired therapeutic effect. Thus, for treatment to be efficacious, the transferred T cells must be present and functional. Furthermore, to protect the patient against recurrent disease, the infused cells and their progeny probably must be capable of long-term functional persistence.

Classes of biomarkers for T-cell trials

We may classify biological parameters that are likely to be important for T-cell bioactivity as follows: (i) presence, (ii) relevant phenotypes and functional competence, (iii) systemic impact on patient biology and (iv) patient immune responses to the infused product.

Flow cytometry-based approaches

The antigenic specificity of T cells is associated with the α/β heterodimer, which is part of the TcR complex. Thus, assays to detect specific TcR α/β pairs present on infused cells can be used to quantify infused T-cell products. For products that are composed of CD8 T cells with a defined antigenic specificity, MHC (major histocompatibility complex) class I and class II multimers (tetramers, pentamers, dextramers) have been used to detect and quantify infused cells with a defined antigenic

Conclusions

Promising results from recent clinical trials suggest that the potential of T-cell immunotherapy as an effective approach to target cancer is finally beginning to be realized 18, 46, 47. As discussed above, a wide variety of biomarkers have been developed and are available to evaluate T-cell presence, persistence, phenotype and function as well as the impact of the treatment on the patient biology, disease status and immune function. Because it is unlikely that clinical efficacy of T-cell

Acknowledgments

Effort and publication costs for this work were supported in part by the human Immunology Core (HIC) of the University of Pennsylvania.

Disclosure of interests: MK has patents and potential royalties based on commercialization of CAR-based technologies; he is a member scientific advisory board for Adaptive Biotechnologies. SFL reports no commercial, proprietary or financial interest in the products or companies described in this article.

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