Blockade or Deletion of IFNγ Reduces Macrophage Activation without Compromising CAR T-cell Function in Hematologic Malignancies

Bailey, Stefanie R.; Vatsa, Sonika; Larson, Rebecca C.; Bouffard, Amanda A.; Scarfò, Irene; Kann, Michael C.; Berger, Trisha R.; Leick, Mark B.; Wehrli, Marc; Schmidts, Andrea; Silva, Harrison; Lindell, Kevin A; Demato, Ashley; Gallagher, Kathleen M.E.; Frigault, Matthew J.; Maus, Marcela V.

doi:10.1158/2643-3230.bcd-21-0181

Cited by 69 publications

(55 citation statements)

References 44 publications

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“…The blockade of IFN-γ with emapalumab or the IFN-γ knock-out in CAR-T cells prevented the activation of pro-inflammatory macrophages together with the associated cytokine release. 51 , 56 , 57 While these studies did not show a negative impact on the efficacy of IFN-γ KO CAR-T cells, other studies showed that IFN-γ blockade decreased the accumulation of CD8 + T cells within tumors after treatment with an anti-HER2xCD3 TDB. In particular, the blockade of IFN-γ prevented the release of essential chemokines involved in T cell recruitment.…”

Section: Cytokine Targeted Approachesmentioning

confidence: 88%

Novel strategies for the mitigation of cytokine release syndrome induced by T cell engaging therapies with a focus on the use of kinase inhibitors

et al. 2022

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T cell engaging therapies, like CAR-T cells and T cell engagers, redirect T cells toward tumor cells, facilitating the formation of a cytotoxic synapse and resulting in subsequent tumor cell killing. T cell receptor or CAR-T downstream signaling triggers a release of pro-inflammatory cytokines, which can induce a Cytokine Release Syndrome (CRS). The incidence of CRS is still hardly predictable among individuals and remains one of the major dose-limiting safety liabilities associated with on-target activity of T cell engaging therapies. This emphasizes the need to elaborate mitigation strategies, which reduce cytokine release while retaining efficacy. Here, we review pre-clinical and clinical approaches applied for the management of CRS symptoms in the context of T cell engaging therapies, highlighting the use of tyrosine kinase inhibitors as an emerging mitigation strategy. In particular, we focus on the effects of Bruton’s tyrosine kinase (BTK), Src family including Lck, mammalian target of rapamycin (mTOR) and Janus tyrosine kinase (JAK) inhibitors on T cell functionality and cytokine release, to provide a rationale for their use as mitigation strategies against CRS in the context of T cell engaging therapies.

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Section: Cytokine Targeted Approachesmentioning

confidence: 88%

Novel strategies for the mitigation of cytokine release syndrome induced by T cell engaging therapies with a focus on the use of kinase inhibitors

et al. 2022

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“…The IL-6, IL-10, and IFN-γcytokines are the strongest contributors to CRS development, and IL-6 is a core cytokine in CRS pathophysiology ( 106 , 108-110 ). Cytokine responses generated by CAR-T and bystander macrophage activation can lead to Macrophage Activation Syndrome that contributes to therapy-derived immunotoxicity ( 111 ). A murine xenogeneic model of ALL with human 1928z CAR-T cell infusion was used to interrogate the role of different cell types in the production of inflammatory cytokines such as IL6 and IL1β that drive acute CRS identified macrophages as the main contributors to the pathogenesis of CRS ( 112 ).…”

Section: Biomarkers In Actmentioning

confidence: 99%

“…A murine xenogeneic model of ALL with human 1928z CAR-T cell infusion was used to interrogate the role of different cell types in the production of inflammatory cytokines such as IL6 and IL1β that drive acute CRS identified macrophages as the main contributors to the pathogenesis of CRS ( 112 ). In this line, INF-γ produced on CAR-T cell activation has been shown to activate macrophages triggering a CRS-like cytokine release, and IFN blockade abolished macrophage-mediated cytokine production, diminishing cytokine-derived toxicities, increasing CAR-T persistence, and improving overall antitumor response ( 111 ). Fever and high monocyte chemoattractant protein 1 (MCP-1) levels within 36 hours after the infusion of CAR-T cells are considered to be predictors of severe CRS and ICANS with the best sensitivity and specificity ( 113 ).…”

Section: Biomarkers In Actmentioning

confidence: 99%

Biological and Molecular Factors Predicting Response to Adoptive Cell Therapies in Cancer

Ferrer

Álvarez-Errico

Esteller

2022

JNCI: Journal of the National Cancer Institute

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Adoptive cell therapy (ACT) constitutes a major breakthrough in cancer management that has expanded in the past years due to impressive results showing durable and even curative responses for some patients with hematological malignancies. ACT leverages antigen specificity and cytotoxic mechanisms of the immune system, particularly relying on the patient´s T lymphocytes to target and eliminate malignant cells. This personalized therapeutic approach exemplifies the success of the joint effort of basic, translational and clinical researchers that has turned the patient´s immune system into a great ally in the search for a cancer cure. Adoptive cell therapies are constantly improving to reach a maximum beneficial clinical response. Despite being very promising therapeutic options for certain types of cancers, mainly melanoma and hematological malignancies, these individualized treatments still present several shortcomings including elevated costs, technical challenges, management of adverse side effects and a limited population of responder patients. Thus, it is crucial to discover and develop reliable and robust biomarkers to specifically and sensitively pinpoint the patients that will benefit the most from ACT, as well as those that are at higher risk of developing potentially serious toxicities. Although unique readouts of infused cell therapy success have not yet been identified, certain characteristics from the adoptive cells, the tumor and/or the tumor microenvironment have been recognized to predict patients' outcome upon ACT. Here, we comment on the importance of biomarkers to predict ACT chances of success to maximize efficacy of treatments and increase patients' survival.

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“…CAR T cells as effectors, NALM-6 tumor cells as targets, and pre-functionalized beads coated with IFN-γ capture antibody as cytokine sensors, were loaded sequentially onto a nanowell grid array, and the kinetics of killing and end-point cytokine secretion from the same cells was monitored using TIMING (Figure 1A-B, Supplementary Video 1). We chose to track IFN-γ because of the known impact of CAR T cell derived IFN-γ in shaping the susceptibility of tumors, enabling endogenous host immunity, and the potential for toxicity (17)(18)(19).…”

Section: Resultsmentioning

confidence: 99%

Multidimensional single-cell analysis identifies a role for CD2-CD58 interactions in clinical antitumor T cell responses

Romain¹,

Rezvan²,

Fathi³

et al. 2022

Journal of Clinical Investigation

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The in vivo persistence of adoptively transferred T cells is predictive of anti-tumor response.Identifying functional properties of infused T cells that lead to in vivo persistence and tumor eradication has remained elusive. We profiled CD19-specific CAR T cells that comprise the infusion products used to treat large B cell lymphomas using high-throughput single-cell technologies based on Timelapse Imaging Microscopy In Nanowell Grids (TIMING) that integrates killing, cytokine secretion, and transcriptional profiling. Our results show that the directional migration of CD19-specific CAR T cells is correlated with multifunctionality. We identified that CD2 on T cells is associated with directional migration and that the interaction between CD2 on T cells and CD58 on lymphoma cells accelerates killing and serial killing. Consistent with this, we observed elevated CD58 expression on pre-treatment tumor samples in patients with relapsed or refractory large B cell lymphomas treated with CD19-specific CAR T cell therapy was associated with complete clinical response and survival. These results highlight the importance of studying dynamic T-cell tumor cell interactions in identifying optimal antitumor responses.

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Blockade or Deletion of IFNγ Reduces Macrophage Activation without Compromising CAR T-cell Function in Hematologic Malignancies

Cited by 69 publications

References 44 publications

Novel strategies for the mitigation of cytokine release syndrome induced by T cell engaging therapies with a focus on the use of kinase inhibitors

Novel strategies for the mitigation of cytokine release syndrome induced by T cell engaging therapies with a focus on the use of kinase inhibitors

Biological and Molecular Factors Predicting Response to Adoptive Cell Therapies in Cancer

Multidimensional single-cell analysis identifies a role for CD2-CD58 interactions in clinical antitumor T cell responses

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