2020
DOI: 10.1084/jem.20191166
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A Fas-4-1BB fusion protein converts a death to a pro-survival signal and enhances T cell therapy

Abstract: Adoptive T cell therapy (ACT) with genetically modified T cells has shown impressive results against some hematologic cancers, but efficacy in solid tumors can be limited by restrictive tumor microenvironments (TMEs). For example, Fas ligand is commonly overexpressed in TMEs and induces apoptosis in tumor-infiltrating, Fas receptor–positive lymphocytes. We engineered immunomodulatory fusion proteins (IFPs) to enhance ACT efficacy, combining an inhibitory receptor ectodomain with a costimulatory endodomain to c… Show more

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Cited by 44 publications
(53 citation statements)
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“…In this study, 4-1BB has been discovered as a new target of CADA. Recently, the role of 4-1BB agonistic signaling in cancer immunotherapy has received great attention: the effect of 4-1BB stimulation by means of agonistic monoclonal anti-4-1BB antibodies on cytolytic T-cell responses has been used to increase the potency of vaccines against cancers (58)(59)(60). Therapeutic use of CADA would imply depletion of 4-1BB in order to attenuate cytotoxic T cell activity.…”
Section: Discussionmentioning
confidence: 99%
“…In this study, 4-1BB has been discovered as a new target of CADA. Recently, the role of 4-1BB agonistic signaling in cancer immunotherapy has received great attention: the effect of 4-1BB stimulation by means of agonistic monoclonal anti-4-1BB antibodies on cytolytic T-cell responses has been used to increase the potency of vaccines against cancers (58)(59)(60). Therapeutic use of CADA would imply depletion of 4-1BB in order to attenuate cytotoxic T cell activity.…”
Section: Discussionmentioning
confidence: 99%
“…In this study, 4-1BB has been discovered as a new target of CADA. Recently, the role of 4-1BB agonistic signaling in cancer immunotherapy has received great attention: the effect of 4-1BB stimulation by means of agonistic monoclonal anti-4-1BB antibodies on cytolytic T-cell responses has been used to increase the potency of vaccines against cancers (Bartkowiak et al, 2015;Chester et al, 2016;Oda et al, 2020). Therapeutic use of CADA would imply depletion of 4-1BB in order to attenuate cytotoxic T cell activity.…”
Section: Discussionmentioning
confidence: 99%
“…Fas is expressed on antigenexperienced T cells, and FasL expression in the tumor vasculature of human and murine ovarian cancer can induce apoptosis of these Fas-expressing T cells 11,12 . To overcome this mechanism facilitating evasion from T cell responses, we generated a panel of immunomodulatory fusion proteins (IFP) containing the Fas receptor (Fas) extracellular binding domain fused to a 4-1BB co-stimulatory domain rather than the natural death domain 13 . Our prior results demonstrated this IFP can improve therapeutic efficacy of engineered T cells in mouse models of pancreatic cancer and acute myeloid leukemia 13 , but the mechanism of in vivo action and broader generalization of this strategy remained undefined.…”
Section: Introductionmentioning
confidence: 99%