Mechanisms of response and resistance to CAR T cell therapies

Berger, Trisha R.; Maus, Marcela V.

doi:10.1016/j.coi.2021.02.010

Cited by 24 publications

(26 citation statements)

References 55 publications

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“…The low arginine availability in the TME also impairs CAR-T-cell proliferation, undermining their efficacy against hematological and solid tumors [ 146 ]. The extracellular arginine dependency of T cells partially originates from the low expression of arginine synthesis enzymes in T cells, and exogenous expression of these enzymes might recover effector T-cell function in the TME.…”

Section: Amino Acid Metabolism In the Context Of The Anticancer Immune Responsementioning

confidence: 99%

Amino Acid Metabolism in Cancer Drug Resistance

Yoo

Han

2022

Cells

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Despite the numerous investigations on resistance mechanisms, drug resistance in cancer therapies still limits favorable outcomes in cancer patients. The complexities of the inherent characteristics of tumors, such as tumor heterogeneity and the complicated interaction within the tumor microenvironment, still hinder efforts to overcome drug resistance in cancer cells, requiring innovative approaches. In this review, we describe recent studies offering evidence for the essential roles of amino acid metabolism in driving drug resistance in cancer cells. Amino acids support cancer cells in counteracting therapies by maintaining redox homeostasis, sustaining biosynthetic processes, regulating epigenetic modification, and providing metabolic intermediates for energy generation. In addition, amino acid metabolism impacts anticancer immune responses, creating an immunosuppressive or immunoeffective microenvironment. A comprehensive understanding of amino acid metabolism as it relates to therapeutic resistance mechanisms will improve anticancer therapeutic strategies.

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Section: Amino Acid Metabolism In the Context Of The Anticancer Immune Responsementioning

confidence: 99%

Amino Acid Metabolism in Cancer Drug Resistance

Yoo

Han

2022

Cells

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“…Barriers to effective CART-cell therapy in solid tumors include limited trafficking to the tumors, low persistence, and impaired functions due to the immunosuppressive and hostile tumor microenvironment (TME). Tumor escape due to antigen (Ag) loss or low Ag expression has become an important resistance mechanism to CART-cell therapy in hematological malignancies [1][2][3] and is likely to also emerge as an important barrier to success in solid tumors, which manifest greater heterogeneity in target Ag expression. Indeed, Ag escape and induced adaptive resistance has also been reported in patients with recurrent glioblastoma who were treated with a single dose of CART cells redirected to the epidermal growth factor receptor variant III (EGFRvIII) mutation.…”

Section: Introductionmentioning

confidence: 99%

Epitope spreading driven by the joint action of CART cells and pharmacological STING stimulation counteracts tumor escape via antigen-loss variants

Conde

Vercher

Soria-Castellano

et al. 2021

J Immunother Cancer

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BackgroundTarget antigen (Ag) loss has emerged as a major cause of relapse after chimeric antigen receptor T (CART)-cell therapy. We reasoned that the combination of CART cells, with the consequent tumor debulking and release of Ags, together with an immunomodulatory agent, such as the stimulator of interferon gene ligand (STING-L) 2′3′-cyclic GMP-AMP (2′3′-cGAMP), may facilitate the activation of an endogenous response to secondary tumor Ags able to counteract this tumor escape mechanism.MethodsMice bearing B16-derived tumors expressing prostate-specific membrane Ag or gp75 were treated systemically with cognate CART cells followed by intratumoral injections of 2′3′-cGAMP. We studied the target Ag inmunoediting by CART cells and the effect of the CART/STING-L combination on the control of STING-L-treated and STING-L-non-treated tumors and on the endogenous antitumor T-cell response. The role of Batf3-dependent dendritic cells (DCs), stimulator of interferon gene (STING) signaling and perforin (Perf)-mediated killing in the efficacy of the combination were analyzed.ResultsUsing an immune-competent solid tumor model, we showed that CART cells led to the emergence of tumor cells that lose the target Ag, recreating the cancer immunoediting effect of CART-cell therapy. In this setting, the CART/STING-L combination, but not the monotherapy with CART cells or STING-L, restrained tumor progression and enhanced overall survival, showing abscopal effects on distal STING-L-non-treated tumors. Interestingly, a secondary immune response against non-chimeric antigen receptor-targeted Ags (epitope spreading), as determined by major histocompatibility complex-I-tetramer staining, was fostered and its intensity correlated with the efficacy of the combination. This was consistent with the oligoclonal expansion of host T cells, as revealed by in-depth T-cell receptor repertoire analysis. Moreover, only in the combination group did the activation of endogenous T cells translate into a systemic antitumor response. Importantly, the epitope spreading and the antitumor effects of the combination were fully dependent on host STING signaling and Batf3-dependent DCs, and were partially dependent on Perf release by CART cells. Interestingly, the efficacy of the CART/STING-L treatment also depended on STING signaling in CART cells.ConclusionsOur data show that 2′3′-cGAMP is a suitable adjuvant to combine with CART-cell therapy, allowing the induction of an endogenous T-cell response that prevents the outgrowth of Ag-loss tumor variants.

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“…This might also be useful in CAR T-cell adoptive therapy. 60 61 Indeed, we have observed the increased sCD137 phenomenon in six out of six patients intratumorally given low doses of Urelumab, and increased levels of circulating sCD137 have been reported in the plasma of patients with cancer receiving systemic treatment with the anti-CD137 mAb Utomilumab 27 or with the new CD137 agonists such as the bispecific construct FAP-4-1BBL 62 and the PDL1-CD137 bispecific antibody GEN1046. 63 In the case of CARs, sCD137 becomes a biomarker candidate to pharmacodynamically monitor both CD137 and CD28 encompassing CARs since both of them readily costimulated the expression of soluble and surface CD137.…”

Section: Openmentioning

confidence: 89%

Soluble CD137 as a dynamic biomarker to monitor agonist CD137 immunotherapies

Glez-Vaz

Olivera

Cirella

et al. 2022

J Immunother Cancer

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BackgroundOn the basis of efficacy in mouse tumor models, multiple CD137 (4-1BB) agonist agents are being preclinically and clinically developed. The costimulatory molecule CD137 is inducibly expressed as a transmembrane or as a soluble protein (sCD137). Moreover, the CD137 cytoplasmic signaling domain is a key part in approved chimeric antigen receptors (CARs). Reliable pharmacodynamic biomarkers for CD137 ligation and costimulation of T cells will facilitate clinical development of CD137 agonists in the clinic.MethodsWe used human and mouse CD8 T cells undergoing activation to measure CD137 transcription and protein expression levels determining both the membrane-bound and soluble forms. In tumor-bearing mice plasma sCD137 concentrations were monitored on treatment with agonist anti-CD137 monoclonal antibodies (mAbs). Human CD137 knock-in mice were treated with clinical-grade agonist anti-human CD137 mAb (Urelumab). Sequential plasma samples were collected from the first patients intratumorally treated with Urelumab in the INTRUST clinical trial. Anti-mesothelin CD137-encompassing CAR-transduced T cells were stimulated with mesothelin coated microbeads. sCD137 was measured by sandwich ELISA and Luminex. Flow cytometry was used to monitor CD137 surface expression.ResultsCD137 costimulation upregulates transcription and protein expression of CD137 itself including sCD137 in human and mouse CD8 T cells. Immunotherapy with anti-CD137 agonist mAb resulted in increased plasma sCD137 in mice bearing syngeneic tumors. sCD137 induction is also observed in human CD137 knock-in mice treated with Urelumab and in mice transiently humanized with T cells undergoing CD137 costimulation inside subcutaneously implanted Matrigel plugs. The CD137 signaling domain-containing CAR T cells readily released sCD137 and acquired CD137 surface expression on antigen recognition. Patients treated intratumorally with low dose Urelumab showed increased plasma concentrations of sCD137.ConclusionsCD137 in plasma and CD137 surface expression can be used as quantitative parameters dynamically reflecting therapeutic costimulatory activity elicited by agonist CD137-targeted agents.

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Mechanisms of response and resistance to CAR T cell therapies

Cited by 24 publications

References 55 publications

Amino Acid Metabolism in Cancer Drug Resistance

Amino Acid Metabolism in Cancer Drug Resistance

Epitope spreading driven by the joint action of CART cells and pharmacological STING stimulation counteracts tumor escape via antigen-loss variants

Soluble CD137 as a dynamic biomarker to monitor agonist CD137 immunotherapies

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