Augmenting adoptive T cell therapy through universal chimeric costimulators
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* Ken-ichi Hanada
* Prachi Bagadia
* Qiong Wang
* Kayla Griffith
* James Yang

*   Melanoma
*   Adoptive Transfer
*   Tumor Infiltrate Lymphocyte
*   Chimeric Antigen Receptor
*   Melanoma Tumor

Meeting abstracts

Adoptive transfer of Tumor Infiltrating Lymphocytes (TIL), T-cell receptor (TCR)-transduced PBL and Chimeric Antigen Receptor (CAR)-transduced PBL have proven to be clinically effective. CARs have evolved by introducing cytoplastic costimulatory domains. Higher cytokine secretion and longer persistence of CAR-transduced T-cells in vivo imply important roles of costimulatory signals. In contrast, costimulation of TIL or TCR-transduced PBL in vivo relies on the expression of costimulatory receptors on T-cells and ligands on tumor cells or antigen presenting cells (APCs). One way to give T-cells their desired costimulation signal independent of the endogenous receptor/ligand expression would be to introduce a fusion molecule that is comprised of a receptor whose ligand is frequently expressed on tumor cells and an intra-cellular costimulatory domain. In a pursuit for a “universal costimulator” that is applicable to various tumors, we produced fusions of CD2 and various costimulators such as CD28, 4-1BB, ICOS, CD27 and OX-40 (Figure 1). CD2 is the receptor for CD58 that is expressed on various tumor cells. Since CD2-CD58 complex localizes to the Supramolecular Activation Complex (SMAC) on activation of TCR, CD2-costimulators may signal in a TCR-activation dependent manner. Human PBL were retrovirally transduced with genes that encode NY-ESO-1-reactive TCR and each CD2-costimulator. In vitro co-culture assay showed higher IFN-γ and IL-2 secretion by CD2-CD28 and higher IFN-γ by CD2-OX40. To examine the in vivo effect of these fusion costimulators, vascularized SK23 melanoma tumor was established in NOD scid gamma (NSG) immunodeficient mice and human CD8+ T-cells transduced with anti-NY-ESO1 TCR and each fusion costimulator were injected. Out of five costimulators tested, CD2-CD28 showed a significant enhancement of anti-tumor effect. These results suggest that the CD2-CD28 costimulator may improve TIL and TCR-transduced PBL therapy.

![Figure1](http://jitc.bmj.com/https://jitc.bmj.com/content/jitc/1/Suppl_1/P14/F1.medium.jpg)

[Figure1](http://jitc.bmj.com/content/1/Suppl_1/P14/F1)

Figure 1

*   © The Author(s). 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ([http://creativecommons.org/licenses/by/2.0](http://creativecommons.org/licenses/by/2.0)), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.