Analysis and Augmentation of the Immunologic Bystander Effects of CAR T Cell Therapy in a Syngeneic Mouse Cancer Model

Klampatsa, Astero; Leibowitz, Michael S.; Sun, Jing; Liousia, Maria; Arguiri, Evguenia; Albelda, Steven Μ.

doi:10.1016/j.omto.2020.07.005

Cited by 38 publications

(65 citation statements)

References 67 publications

(114 reference statements)

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“…These finding suggest that tumor-dependent characteristics (i.e., tumor mutational burden and IFNγ responsiveness) and features of the TME (i.e., CD3 infiltration) may impact CAR T cell responsiveness. Therefore, improving the effectiveness of CAR T cell therapy more broadly for solid tumors may require additional strategies to enhance the induction of host antitumor responses (8,13,40,41).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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Chimeric antigen receptor (CAR) T cells mediate potent antigen-specific antitumor activity, however, their indirect effects on the endogenous immune system is not well characterized. Remarkably, we demonstrate that CAR T cell treatment of mouse syngeneic glioblastoma activates intratumoral myeloid cells and induces endogenous T cell memory responses coupled with feed-forward propagation of CAR T responses. IFNγ production by CAR T cells and IFNγ-responsiveness of host immune cells is critical for tumor immune landscape remodeling to promote a more activated and less suppressive tumor microenvironment. The clinical relevance of these observations is supported by studies showing that human IL13Rα2-CAR T cells activate patient-derived endogenous T cells and monocyte/macrophages through IFN-signaling, as well as induce the generation of tumor-specific T cell responses in a responding patient with GBM. These studies establish that CAR T therapy has the potential to shape the tumor microenvironment, creating a context permissible for eliciting endogenous antitumor immunity. SIGNIFICANCE:Our findings highlight the critical role of IFNγ-signaling for a productive CAR T therapy in GBM. We establish that CAR T cells can activate resident myeloid populations and promote endogenous T cell immunity, emphasizing on the importance of host innate and adaptive immunity for CAR T therapy of solid tumors.Research.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…The loss of cell surface MSLN represents a limitation to MSLNtargeted therapy. In addition, due to the heterogeneity of MSLN expression (not all tumor cells express MSLN and within MSLN þ tumors the expression levels may vary), not all tumor cells will be targeted by MSLN CAR T cells, but activation of MSLN CAR T cells can in turn mediate killing of MSLN À tumor cells via by-stander killing and epitope spreading (30,31). Interestingly, absence of detection of MSLN cell surface expression by FACS analysis does not necessarily imply complete absence of cell surface expression (due to the limit of detection by FACS) nor precludes specific recognition of very low levels of target antigens by CAR T cells.…”

Section: Discussionmentioning

confidence: 99%

Mesothelin-Specific CAR T Cells Target Ovarian Cancer

et al. 2021

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New therapeutic options for patients with ovarian cancer are urgently needed. Therefore, we evaluated the efficacy of two second-generation mesothelin (MSLN)-directed CAR T cells in orthotopic mouse models of ovarian cancer. Treatment with CAR T cells expressing an MSLN CAR construct including the CD28 domain (M28z) significantly prolonged survival, but no persistent tumor control was observed. Despite lower response rates, MSLN-4-1BB (MBBz) CAR T cells induced long-term remission in some SKOV3-bearing mice. Tumor-infiltrating M28z and MBBz CAR T cells upregulated PD-1 and LAG3 in an antigendependent manner while MSLN þ tumor cells expressed the corresponding ligands (PD-L1 and HLA-DR), demonstrating that coin-hibitory pathways impede CAR T-cell persistence in the ovarian tumor microenvironment. Furthermore, profiling plasma soluble factors identified a cluster of M28z-and MBBz-treated mice characterized by elevated T-cell secreted factors that had increased survival, higher CD8 þ T-cell tumor infiltration, less exhausted CAR T-cell phenotypes, and increased HLA-DR expression by tumor cells. Altogether, our study demonstrates the therapeutic potential of MSLN-CAR T cells to treat ovarian cancer.Significance: These findings demonstrate that MSLN-directed CAR T cells can provide antitumor immunity against ovarian cancer.

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“…This includes regional CAR-T cell delivery, utilization of fully human anti-MSLN scFV, and combination with checkpoint inhibitors and chemotherapies. Other strategies, still in preclinical testing, such as augmentation of bystander effects [124], blockade of inhibitory factors (such as TGFβ, adenosine, or PGE2), CAR-T cells engineered to secrete inflammatory cytokines or tumor homing chemokine receptors, or CAR T cells with genetic manipulations that make them more resistant to chronic T cell activation and hypofunction may be needed to enhance their performance [74,83,112,115].…”

Section: Resultsmentioning

confidence: 99%