Hypoxia-inducible CAR expression: An answer to the on-target/off-tumor dilemma?

Prinzing, Brooke L.; Krenciute, Giedre

doi:10.1016/j.xcrm.2021.100244

Cited by 7 publications

(5 citation statements)

References 11 publications

(13 reference statements)

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“…Conditional or inducible gene engineering in CAR T cells is a major advancement in the field, with the potential to greatly improve the safety and overall efficacy of solid tumor-directed CAR T cells 3,53 . Various spatially and temporally activated gene promoters which drive the expression of CAR or other genes have been widely explored, ranging from heat-, light-, and hypoxia-inducible promoters, as well as synthetic Notch and drug-induced circuits [54][55][56][57][58][59] . While many of these approaches have not yet been investigated clinically, previous attempts to regulate gene expression by linking to conditionallyactivated promoters, including the NFAT promoter 50 , have been clinically tested.…”

Section: Discussionmentioning

confidence: 99%

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting

et al. 2023

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Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumors. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies. Here, we describe CAR T cells targeting tumor-associated glycoprotein-72 (TAG72), utilizing the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFNγ secretion. CAR T cell-mediated IFNγ production facilitated by IL-12 signaling is required for tumor cell killing, which is recapitulated by engineering an optimized membrane-bound IL-12 (mbIL12) molecule in CAR T cells. These T cells show improved antigen-dependent T cell proliferation and recursive tumor cell killing in vitro, with robust in vivo efficacy in human ovarian cancer xenograft models. Locoregional administration of mbIL12-engineered CAR T cells promotes durable anti-tumor responses against both regional and systemic disease in mice. Safety and efficacy of mbIL12-engineered CAR T cells is demonstrated using an immunocompetent mouse model, with beneficial effects on the immunosuppressive tumor microenvironment. Collectively, our study features a clinically-applicable strategy to improve the efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting regional and systemic disease.

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Section: Discussionmentioning

confidence: 99%

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting

et al. 2023

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“…Conditional or inducible gene engineering in CAR T cells is a major advancement to the field, with the potential to greatly improve safety and overall efficacy of solid tumor-directed CAR T cells 3,47 . Various spatially and temporally activated gene promoters which drive expression of CAR or other genes have been widely explored, ranging from heat-, light-, and hypoxiainducible promoters, as well as synthetic Notch and drug-induced circuits [48][49][50][51][52][53] . While many of these approaches have not yet been investigated clinically, previous attempts to regulate gene expression by linking to conditionally-activated promoters, including the NFAT promoter 54 , have been clinically tested.…”

Section: Discussionmentioning

confidence: 99%

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting

Lee

Cullen

Murad

et al. 2023

Preprint

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Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumor microenvironments. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies, which are being harnessed to improve solid tumor CAR T cell therapies. Here, we describe fully optimized CAR T cells targeting tumor-associated glycoprotein-72 (TAG72) for the treatment of solid tumors, identifying the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFNγ secretion. These findings have culminated into a phase 1 trial evaluating safety, feasibility, and bioactivity of TAG72-CAR T cells for the treatment of patients with advanced ovarian cancer (NCT05225363). Preclinically, we found that CAR T cell-mediated IFNγ production facilitated by IL-12 signaling was required for tumor cell killing, which was recapitulated by expressing an optimized membrane-bound IL-12 (mbIL12) molecule on CAR T cells. Critically, mbIL12 cell surface expression and downstream signaling was induced and sustained only following CAR T cell activation. CAR T cells with mbIL12 demonstrated improved antigen-dependent T cell proliferation and potent cytotoxicity in recursive tumor cell killing assays in vitro and showed robust in vivo anti-tumor efficacy in human xenograft models of ovarian cancer peritoneal metastasis. Further, locoregional administration of TAG72-CAR T cells with antigen-dependent IL-12 signaling promoted durable anti-tumor responses against both regional and systemic disease in mice and was associated with improved systemic T cell persistence. Our study features a clinically-applicable strategy to improve the overall efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting both regional and systemic disease.

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“…‘AND-NOT’ gates enable the inhibition of CAR activation upon TSA binding following binding to a normal antigen [ 116 , 117 ]. Safety can further be managed through designed ‘ON/OFF’ switches where CAR expression can be held in an ‘OFF’ state, and removal of inhibition regulated by small molecules or hypoxia/proteases within the TME is required for CAR activation [ 116 , 118 , 119 ]. Similarly, CD70 target expression on T cells itself can result in CAR-T fratricide where gene-editing mediated knockdown of CD70 [ 120 ] would be required but poses further safety considerations pertaining to gene-editing-related off-target genome toxicity.…”

Section: Future Perspective Of Cell Therapy Against Rccmentioning

confidence: 99%

Current Treatment Options for Renal Cell Carcinoma: Focus on Cell-Based Immunotherapy

Hwang,

Mehra,

Chhetri

et al. 2024

Cancers

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Renal cell carcinoma (RCC) affects over 400,000 patients globally each year, and 30% of patients present with metastatic disease. Current standard of care therapy for metastatic RCC involve TKIs and ICIs, including combinatorial strategies, but this offers only modest clinical benefit. Novel treatment approaches are warranted, and cell-based immunotherapies for RCC hold significant promise. These are currently being tested in the pre-clinical setting and in early phase clinical trials. Here, we review the landscape of cellular immunotherapy for RCC in the context of currently available therapies, with a particular focus on defining the current best antigenic targets, the range of cell therapy products being explored in RCC, and how advanced engineering solutions may further enhance these therapies in the RCC space.

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Hypoxia-inducible CAR expression: An answer to the on-target/off-tumor dilemma?

Abstract: On-target/off-tumor toxicity is one of the major concerns regarding CAR T-cell therapy. Kosti et al. 1 demonstrate that this form of toxicity can be prevented by designing a CAR whose expression is controlled by oxygen levels in the tumor environment.

Cited by 7 publications

References 11 publications

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting

Current Treatment Options for Renal Cell Carcinoma: Focus on Cell-Based Immunotherapy

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