Oxford BioMedica PLC (OXBDF)

[georgejjl]

CART 5T4 combined with IL-12 plus doxorubicinn could be extremely potent.

T cell homing therapy for reducing regulatory T cells and preserving effector T cell function in large solid tumors
Jiemiao Hu, Chuang Sun, Chantale Bernatchez, Xueqing Xia, Patrick Hwu, Gianpietro Dotti and Shulin Li
DOI: 10.1158/1078-0432.CCR-17-1365

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Abstract
Purpose: Infused autologous tumor-infiltrating lymphocytes (TILs) and tumor-targeted chimeric antigen receptor (CAR)-T cells typically surround malignant lesions or penetrate small tumor nodules, but fail to penetrate large solid tumors, significantly compromising their antitumor impact. Strategies to overcome this primary challenge are largely required. Experimental Design: We tested the effects of IL-12 plus doxorubicin on T cell penetration and efficacy in solid tumors in a murine lung cancer model, a murine breast carcinoma lung metastasis model and two human xenograft tumor models bearing large tumors (>10 mm). Results: Intriguingly, this simple approach increased the numbers, the distribution, and the depth of penetration of infused CD8+ T cells in these tumors, including both TILs and CAR-T cells. This combined treatment halted tumor progression, and significantly extended survival time. Studies of the underlying mechanism revealed multiple effects. First, the combined treatment maintained the high ratios of immune-stimulatory receptors to immune-inhibitory receptors on infiltrated CD8+ T cells, reduced the accumulation of immune-suppressive regulatory T cells, and enhanced the numbers of T-bet+ effector T cells in the tumors. Second, doxorubicin induced chemokines CXCL9 and CXCL10, which may attract NKG2D+CD8+ T cells to tumors, and this effect was boosted by IL-12-induced IFN? accumulation in tumors, promoting the penetration of NKG2D+CD8+ T cells. Conclusions: The deep penetration of infused T cells associated with combined IL-12 plus doxorubicin yielded striking therapeutic effects in murine and human xenograft solid tumors. This approach might broaden the application of T cell therapy to a wider range of solid tumors.

http://clincancerres.aacrjournals.org/content/early/2018/02/01/1078-0432.CCR-17-1365

Good luck and GOD bless,

George