T-cell based immunotherapy is a promising therapeutic modality for cancer. We and others have developed therapies to treat human melanomas by isolating and expanding autologous tumor infiltrating lymphocytes (TILs), followed by reinfusion into patients. Although tumor regression can be dramatic in some patients, in other patients we see no clinical response. We hypothesize that inefficient migration of T cells to tumors is one of the rate limiting steps in the generation of an effective anti-tumor response. Therefore, we are investigating methods to improve T-cell trafficking to tumors through the introduction of specific receptor genes that can enhance migration to tumor sites. Melanomas specifically express the chemokines CXCL1 and CXCL8, which are thought to promote autocrine growth and angiogenesis. However, we have found that tumor antigen-specific T-cells fail to express the chemokine receptors specific for these ligands, including CXCR2. In a strategy designed to direct T cells toward chemokines expressed by tumors, we have developed a system to genetically modify T cells using retroviral vectors encoding CXCR2. We show that murine T-cells transduced to express CXCR2 demonstrated enhanced trafficking to CXCL1 expressing tumors and this led to improved anti-tumor responses and survival. We have established an adoptive T-cell therapy program at our institution to treat melanoma patients with tumor-reactive T-cells and have extensive expertise in genetic manipulation of T cells, so we now propose to translate our findings from our mouse models to humans by treating melanoma patients with autologous tumor-reactive TILs genetically modified to express CXCR2.The following three specific aims will be pursued to address the hypothesis in this clinical trial: 1) Generate clinical grade high titer retroviral supernatants capable of transducing T-cells with the CXCR2 gene and optimize large-scale transduction and in vitro expansion of melanoma-specific T-cells, 2) Perform a clinical trial using adoptive transfer of CXCR2-transduced TILs, and determine the objective clinical response rates in treated metastatic melanoma patients, and 3) Assess the ability of CXCR2-transduced T-cells to traffic to tumor sites, and determine whether T-cell migration correlates with chemokine expression in the tumor microenvironment and clinical response. Results from this study may improve clinical responses in melanoma patients receiving adoptive T cell therapy, and may provide a new paradigm in personalizing cancer treatments based on chemokine expression profile.
Immune cells called T-cells are capable of recognizing a patient's own tumor and can be expanded to large numbers in the laboratory followed by reinfusion resulting in dramatic tumor regressions in some patients. However, some do not respond to this approach and this project is aimed at improving the ability of these T-cells to migrate to the tumor in the body so they can destroy the cancer cells. This may enable improved immune therapies for melanoma and other cancers.
|Huang, L; Wang, Z; Liu, C et al. (2017) CpG-based immunotherapy impairs antitumor activity of BRAF inhibitors in a B-cell-dependent manner. Oncogene 36:4081-4086|
|Peng, Weiyi; Chen, Jie Qing; Liu, Chengwen et al. (2016) Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy. Cancer Discov 6:202-16|
|Forget, Marie-Andrée; Malu, Shruti; Liu, Hui et al. (2014) Activation and propagation of tumor-infiltrating lymphocytes on clinical-grade designer artificial antigen-presenting cells for adoptive immunotherapy of melanoma. J Immunother 37:448-60|
|Liu, Chengwen; Peng, Weiyi; Xu, Chunyu et al. (2013) BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clin Cancer Res 19:393-403|
|Gao, Jianjun; Bernatchez, Chantale; Sharma, Padmanee et al. (2013) Advances in the development of cancer immunotherapies. Trends Immunol 34:90-8|
|Radvanyi, Laszlo; Pilon-Thomas, Shari; Peng, Weiyi et al. (2013) Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer--letter. Clin Cancer Res 19:5541|
|Liu, Chengwen; Lewis, Carol M; Lou, Yanyan et al. (2012) Agonistic antibody to CD40 boosts the antitumor activity of adoptively transferred T cells in vivo. J Immunother 35:276-82|
|Peng, Weiyi; Liu, Chengwen; Xu, Chunyu et al. (2012) PD-1 blockade enhances T-cell migration to tumors by elevating IFN-ýý inducible chemokines. Cancer Res 72:5209-18|
|Bernatchez, Chantale; Radvanyi, Laszlo G; Hwu, Patrick (2012) Advances in the treatment of metastatic melanoma: adoptive T-cell therapy. Semin Oncol 39:215-26|
|Lou, Yanyan; Liu, Chengwen; Lizée, Gregory et al. (2011) Antitumor activity mediated by CpG: the route of administration is critical. J Immunother 34:279-88|
Showing the most recent 10 out of 12 publications