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Review
. 2016 Sep 6:7:345.
doi: 10.3389/fimmu.2016.00345. eCollection 2016.

Improving Adoptive T Cell Therapy: The Particular Role of T Cell Costimulation, Cytokines, and Post-Transfer Vaccination

Anke Redeker  1 , Ramon Arens  1
Affiliations
Review

Improving Adoptive T Cell Therapy: The Particular Role of T Cell Costimulation, Cytokines, and Post-Transfer Vaccination

Anke Redeker et al. Front Immunol. .

Abstract

Adoptive cellular therapy (ACT) is a form of immunotherapy whereby antigen-specific T cells are isolated or engineered, expanded ex vivo, and transferred back to patients. Clinical benefit after ACT has been obtained in treatment of infection, various hematological malignancies, and some solid tumors; however, due to poor functionality and persistence of the transferred T cells, the efficacy of ACT in the treatment of most solid tumors is often marginal. Hence, much effort is undertaken to improve T cell function and persistence in ACT and significant progress is being made. Herein, we will review strategies to improve ACT success rates in the treatment of cancer and infection. We will deliberate on the most favorable phenotype for the tumor-specific T cells that are infused into patients and on how to obtain T cells bearing this phenotype by applying novel ex vivo culture methods. Moreover, we will discuss T cell function and persistence after transfer into patients and how these factors can be manipulated by means of providing costimulatory signals, cytokines, blocking antibodies to inhibitory molecules, and vaccination. Incorporation of these T cell stimulation strategies and combinations of the different treatment modalities are likely to improve clinical response rates further.

Keywords: T cells; adoptive cell therapy; costimulation; cytokines; vaccination.

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Figures

Figure 1
Figure 1
A T cell centric view of improving adoptive T cell therapy by provision of T cell stimulation signals. Upon transfer of ex vivo-expanded disease-specific T cells into the host, these cells recognize their cognate antigen in the context of MHC molecules via their TCR. Amplification of costimulatory signals (e.g., via agonistic antibodies) can be used to additionally stimulate T cells. Antibodies against CD28, CD27, 4-1BB, OX40, and GITR have been evaluated in preclinical models and clinical trials for their capacity to enhance T cell function. Targeting of costimulatory receptors can also be used during the ex vivo expansion of the T cells. In case of CAR T cells, recognition occurs via the CAR, a chimeric TCR that already provides a certain degree of costimulation. Blockade of inhibitory molecules, such as CTLA-4 and PD-1 by antibodies after transfer, counteracts suppressed T cells thereby improving T cell activity. In addition, inflammatory cytokines are able to provide signals for enhancing expansion, differentiation, and migration. Cytokines, such as IFN-α, IL-2, IL-7, IL-12, IL-15, and IL-21, have shown to have the capacity to enhance T cell efficacy either during ex vivo culturing or after adoptive transfer. Autocrine production of IL-2 is a vital property for secondary population expansion, and enhancing autocrine IL-2 is a promising way to improve T cell therapies. The + and − symbols indicate positive and negative signaling, respectively.
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