T-cell Homing Therapy for Reducing Regulatory T Cells and Preserving Effector T-cell Function in Large Solid Tumors

Abstract

Infused autologous tumor-infiltrating lymphocytes (TIL) 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. We tested the effects of 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). 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 immunosuppressive 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 NKG2DCD8 T cells to tumors, and this effect was boosted by IL12-induced IFNγ accumulation in tumors, promoting the penetration of NKG2DCD8 T cells. The deep penetration of infused T cells associated with combined 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..

Anin vitroquantitative systems pharmacology approach for deconvolving mechanisms of drug-induced, multilineage cytopenias

“…(Table 1 and full data in Supplemental Table 2 ). The estimated anti-proliferative and cell-killing effects of palbociclib and dinaciclib are consistent with published mechanisms(10, 16).…”

Intra-Tumoral Delivery of IL-27 Using Adeno-Associated Virus Stimulates Anti-tumor Immunity and Enhances the Efficacy of Immunotherapy

“…For instance, IL-2 is the first effective immunotherapy of human cancer but it is also known to be very toxic (Rosenberg, 2014). IL-12 exhibits potent anti-tumor activity (Colombo and Trinchieri, 2002) via promoting Th1/Tc1 response (Colombo and Trinchieri, 2002;Del Vecchio et al, 2007) and enhancing T cell trafficking to tumors through induction of chemokines (Hu et al, 2018). However, systemically delivered IL-12 causes fatal toxicity (Car et al, 1995;Ryffel, 1997).…”

Targeting cytokines secreted by CD4+CD25highCD127low regulatory T cells inhibits ovarian cancer progression

“…It has been well established that Tregs contribute to inhibition of the anti‐tumour immune response . The efficacy of many immunotherapeutic approaches that target T cell co‐inhibitory and co‐stimulatory receptors correlate with an altered balance in the ratio of effector T cells to Tregs in favour of the effector cells . Despite the evidence that Tregs inhibit tumour immunity, the question remains as to where and through what mechanism do Tregs inhibit the anti‐tumour immune response .…”

“…20 The efficacy of many immunotherapeutic approaches that target T cell co-inhibitory and co-stimulatory receptors correlate with an altered balance in the ratio of effector T cells to Tregs in favour of the effector cells. 21 Despite the evidence that Tregs inhibit tumour immunity, the question remains as to where and through what mechanism do Tregs inhibit the anti-tumour immune response. 8 Notably, we identified that the percentage of CD4 + CD25 + CD127 low Tregs was significantly increased and was related to lymphatic invasion in EOC.…”