| First Author | Mardiana S | Year | 2017 |
| Journal | Cancer Res | Volume | 77 |
| Issue | 6 | Pages | 1296-1309 |
| PubMed ID | 28082401 | Mgi Jnum | J:239738 |
| Mgi Id | MGI:5829590 | Doi | 10.1158/0008-5472.CAN-16-1831 |
| Citation | Mardiana S, et al. (2017) A Multifunctional Role for Adjuvant Anti-4-1BB Therapy in Augmenting Antitumor Response by Chimeric Antigen Receptor T Cells. Cancer Res 77(6):1296-1309 |
| abstractText | Adoptive immunotherapy utilizing chimeric antigen receptor (CAR) T cells has demonstrated high success rates in hematologic cancers, but results against solid malignancies have been limited to date, due in part to the immunosuppressive tumor microenvironment. Activation of the 4-1BB (CD137) pathway using an agonistic alpha-4-1BB antibody is known to provide strong costimulatory signals for augmenting and diversifying T-cell responses. We therefore hypothesized that a combination of alpha-4-1BB and CAR T-cell therapy would result in improved antitumor responses. Using a human-Her2 self-antigen mouse model, we report here that alpha-4-1BB significantly enhanced CAR T-cell efficacy directed against the Her2 antigen in two different established solid tumor settings. Treatment also increased the expression of IFNgamma and the proliferation marker Ki67 in tumor-infiltrating CAR T cells when combined with alpha-4-1BB. Strikingly, alpha-4-1BB significantly reduced host immunosuppressive cells at the tumor site, including regulatory T cells and myeloid-derived suppressor cells, correlating with an increased therapeutic response. We conclude that alpha-4-1BB has a multifunctional role for enhancing CAR T-cell responses and that this combination therapy has high translational potential, given current phase I/II clinical trials with alpha-4-1BB against various types of cancer. Cancer Res; 77(6); 1296-309. (c)2017 AACR. |
