Journal
CANCER RESEARCH
Volume 77, Issue 6, Pages 1296-1309Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-16-1831
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Funding
- National Health and Medical Research Council (NHMRC) [1062580]
- Cancer Council Victoria project [APP1084420]
- National Breast Cancer Foundation fellowships [PF-14-008, ECF-16-005]
- NHMRC senior research fellowships [APP1041828, APP1058388]
- National Breast Cancer Foundation [IN-16-005, ECF-17-005, ECF-16-005] Funding Source: researchfish
- National Health and Medical Research Council of Australia [1062580] Funding Source: NHMRC
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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 a-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-41BB significantly enhanced CAR T-cell efficacy directed against the Her2 antigen in two different established solid tumor settings. Treatment also increased the expression of IFN gamma 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 a-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. (C)2017 AACR.
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