IFNγ Is Critical for CAR T Cell–Mediated Myeloid Activation and Induction of Endogenous Immunity

Alizadeh, Darya; Wong, Robyn A.; Gholamin, Sharareh; Maker, Madeleine; Aftabizadeh, Maryam; Yang, Xin; Pecoraro, Joseph R.; Jeppson, John D.; Wang, Dongrui; Aguilar, Brenda; Starr, Renate; Larmonier, Claire B.; Larmonier, Nicolas; Chen, Min-Hsuan; Wu, Xiwei; Ribas, Antoni; Badie, Behnam; Forman, Stephen J.; Brown, Christine E.

doi:10.1158/2159-8290.cd-20-1661

Cited by 102 publications

(115 citation statements)

References 52 publications

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“…However, the CAR-19 infusion induced a complete tumor eradication (i.e., both CD19 wt and CD19 L174V mutated clones) and an ongoing remission of more than 2 years post-CAR-19 infusion (Figure 5a, bottom). Taken together with 6/8 patients lacking CD19 who responded to axi-cel in the ZUMA-1 registration study 6 and with recent pre-clinical studies 52,53 , these findings indicate antigen-mediated tumor killing is not the only mechanism of tumor eradication, and alternate mechanisms may predominate. Fig.…”

Section: Target-independent Car-t Anti-tumor Activitysupporting

confidence: 57%

“…We provide cell-intrinsic alternatives to loss of the CD19 CAR target, a mechanism that, while logical, appears to be of unclear real-world importance 52,53 . In this cohort, genomic alterations of CD19 or reduced expression by flow cytometry did not significantly affect outcome, revealing for the first time that the CD19-independent genomic drivers of CAR-19 resistance appear by far the more clinically important and inter-connected with the TME.…”

Section: Discussionmentioning

confidence: 99%

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Genomic drivers of large B-cell lymphoma resistance to CD19 CAR-T therapy

Jain

Ziccheddu

Coughlin

et al. 2021

Preprint

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Chimeric antigen receptor-reprogrammed autologous T cells directed to CD19 are breakthrough immunotherapies for heavily pretreated patients with aggressive B-cell lymphomas but still fail to cure most patients. Host inflammatory and tumor microenvironmental factors associate with CAR-19 resistance, but the tumor-intrinsic factors underlying these phenomena remain undefined. To characterize genomic drivers of resistance, we interrogated whole genome sequencing of 30 tumor samples from 28 uniformly CAR-19-treated large-cell lymphoma patients. We reveal that patterns of genomic complexity (i.e., chromothripsis and APOBEC mutational activity), and distinct genomic alterations (deletions of RB1 or RHOA) associate with more exhausted immune microenvironments and poor outcome after CAR-19 therapy. Strikingly, pretreatment reduced expression or sub-clonal mutation of CD19 did not affect responses, suggesting CAR-19 therapy successes are due not only to direct antigen-dependent cytotoxicity but require surmounting immune exhaustion in tumor microenvironments to permit broader host responses that eliminate tumors

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Section: Target-independent Car-t Anti-tumor Activitysupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Genomic drivers of large B-cell lymphoma resistance to CD19 CAR-T therapy

Jain

Ziccheddu

Coughlin

et al. 2021

Preprint

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“…Their data also revealed that IL-36g armored CAR T cells activate endogenous antigenpresenting cells (APCs) and T cells through promotion of a secondary antitumor response and delayed the progression of antigen-negative tumor challenge in an experimental model of Bcell lymphoma (45). A separate study has also reported that effective CAR T cell antitumor activity of IL13Ra2-CAR T cells against mouse syngeneic glioblastoma (GBM) is significantly dependent on the activation of patient-derived endogenous T cells and monocyte/ macrophages at the tumor site in an IFNg-dependent manner (101). Currently, a phase 2 clinical trial for IL-7 and CCL-19 expressing CAR T cells against Refractory/Relapsed B Cell Lymphoma is in recruiting status (NCT03929107).…”

Section: Activation Of Endogenous Immune Systemmentioning

confidence: 99%

“…Various studies have shown that infiltration of endogenous immune cells (in particular T lymphocytes) into the tumor sites can expand the efficacy of CAR T cell therapy ( 87 , 101 ). In line with this notion, Adachi et al., reported that overexpression of IL-7 and CCL19, as two essential cytokines for generation of less-differentiated, long-lived non-exhausted (CAR) T cells and recruitment of endogenous DCs and T cells, in CAR T cells (termed 7x19 CAR T cells) increased infiltration of DCs and T cells into tumor sites following 7 × 19 CAR T cell therapy.…”

Section: Activation Of Endogenous Immune Systemmentioning

confidence: 99%

Genetic Modification of Cytokine Signaling to Enhance Efficacy of CAR T Cell Therapy in Solid Tumors

et al. 2021

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Chimeric antigen receptor (CAR) T cell therapy has shown unprecedented success in treating advanced hematological malignancies. Its effectiveness in solid tumors has been limited due to heterogeneous antigen expression, a suppressive tumor microenvironment, suboptimal trafficking to the tumor site and poor CAR T cell persistence. Several approaches have been developed to overcome these obstacles through various strategies including the genetic engineering of CAR T cells to blunt the signaling of immune inhibitory receptors as well as to modulate signaling of cytokine/chemokine molecules and their receptors. In this review we offer our perspective on how genetically modifying cytokine/chemokine molecules and their receptors can improve CAR T cell qualities such as functionality, persistence (e.g. resistance to pro-apoptotic signals) and infiltration into tumor sites. Understanding how such modifications can overcome barriers to CAR T cell effectiveness will undoubtedly enhance the potential of CAR T cells against solid tumors.

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“…9 Further studies are needed to determine how the type of cell therapy used may affect the extent of antigen spreading, and how treatment strategies can potentially be combined to optimize antitumor immunity. [10][11][12][13] Open access…”

Section: Barriers To Progress Scientific Challengesmentioning

confidence: 99%

Challenges and next steps in the advancement of immunotherapy: summary of the 2018 and 2020 National Cancer Institute workshops on cell-based immunotherapy for solid tumors

Fogli

Aurigemma

Sommers

et al. 2021

J Immunother Cancer

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Cell-based immunotherapies have had remarkable success in the clinic, specifically in the treatment of hematologic malignancies. However, these strategies have had limited efficacy in patients with solid tumors. To better understand the challenges involved, the National Cancer Institute (NCI) convened an initial workshop with immuno-oncology thought leaders in December 2018 and a follow-up workshop in December 2020. The goals of the NCI workshops on cell-based immunotherapy for solid tumors were to discuss the current state of the field of cell-based immunotherapy, obtain insights into critical knowledge gaps, and identify ways in which NCI could facilitate progress. At both meetings, subjects emphasized four main types of challenges in further developing cell-based immunotherapy for patients with solid tumors: scientific, technical, clinical, and regulatory. The scientific barriers include selecting appropriate targets, ensuring adequate trafficking of cell therapy products to tumor sites, overcoming the immunosuppressive tumor microenvironment, and identifying appropriate models for these investigations. While mouse models may provide some useful data, the majority of those that are commonly used are immunodeficient and unable to fully recapitulate the immune response in patients. There is therefore a need for enhanced support of small early-phase human clinical studies, preferably with adaptive trial designs, to provide proof of concept for novel cell therapy approaches. Furthermore, the requirements for manufacturing, shipping, and distributing cell-based therapies present technical challenges and regulatory questions, which many research institutions are not equipped to address. Overall, workshop subjects identified key areas where NCI support might help the research community in driving forward innovation and clinical utility: 1) provide focused research support on topics such as tumor target selection, immune cell fitness and persistence, cell trafficking, and the immunosuppressive tumor microenvironment; 2) support the rapid translation of preclinical findings into proof of concept clinical testing, harmonize clinical trial regimens, and facilitate early trial data sharing (including negative results); 3) expand manufacturing support for cell therapies, including vectors and reagents, and provide training programs for technical staff; and 4) develop and share standard operating procedures for cell handling and analytical assays, and work with the Food and Drug Administration to harmonize product characterization specifications.

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IFNγ Is Critical for CAR T Cell–Mediated Myeloid Activation and Induction of Endogenous Immunity

Cited by 102 publications

References 52 publications

Genomic drivers of large B-cell lymphoma resistance to CD19 CAR-T therapy

Genomic drivers of large B-cell lymphoma resistance to CD19 CAR-T therapy

Genetic Modification of Cytokine Signaling to Enhance Efficacy of CAR T Cell Therapy in Solid Tumors

Challenges and next steps in the advancement of immunotherapy: summary of the 2018 and 2020 National Cancer Institute workshops on cell-based immunotherapy for solid tumors

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