09.01 Armoring anti-HER2 CAR-T cells with C-C-motive receptor 8 (CCR8) and a dominant negative TGF-b receptor (DNR) to enable efficacy in solid tumor models

BackgroundChimeric antigen receptor (CAR) T cells have shown great efficacy in treating hematological malignancies. Nonetheless, in solid tumors CAR T cells have yet to demonstrate significant clinical efficacy. In solid tumors, CAR T cells are frequently prevented access to tumor tissue and face pr...

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Published in:Journal for immunotherapy of cancer 2022-09, Vol.10 (Suppl 1), p.A3-A4
Main Authors: Strzalkowski, TJ, Cadilha, BL, Dalloul, I, Manske, K, Endres, S, Kobold, S
Format: Article
Language:English
Subjects:
Antigens
Chemokines
Employment
Immunotherapy
Intellectual property
Lymphocytes
Oral Presentations
Stock options
Tumors
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Summary:BackgroundChimeric antigen receptor (CAR) T cells have shown great efficacy in treating hematological malignancies. Nonetheless, in solid tumors CAR T cells have yet to demonstrate significant clinical efficacy. In solid tumors, CAR T cells are frequently prevented access to tumor tissue and face profound suppression at the tumor site. To overcome this issue, our group could previously demonstrate that arming CAR T cells with C-C-motive-receptor 8 for improved tumor-directed migration along the C-C-chemokine ligand 1 - CCR8 axis and a dominant-negative receptor against TGF-β for resistance to suppression enable activity in pancreatic cancer models. The value of this approach for other entities was however unclear. We now investigated the potential of this combination for treatment of HER2-positive cancer models in conjunction with a HER2-targeted CAR.Materials and MethodsPrimary murine and human T cells were isolated and activated. T cells were retrovirally transduced. Phenotype, activation, exhaustion and proliferation were monitored in vitro. Cytokine production was assessed with ELISA. In vivo, survival and tumor growth of mice that were subcutaneously injected with tumor cells and treated with CAR T cells carrying either CCR8, DNR or both receptors were measured. To look at chemokine expression in tumor material, mRNA was isolated from tumor material and RT-qPCR was performed.ResultsWe found that expression of CCR8 can redirect CAR T cells to the tumor and a DNR can prevent immunosuppression of CAR T cells in the tumor microenvironment. The improved functionality of CAR-CCR8-DNR T cells compared to CAR T cells against the HER2 antigen could be demonstrated in vitro and in vivo in human HER2+ tumor models.ConclusionsEquipping CAR T cells with CCR8 and DNR emerges as a strategy not only limited to certain antigens, but as a potential universal approach to render cellular therapies more effective. The modularity of this concept promises further preclinical and perhaps clinical development to improve personalized immunotherapy.Disclosure Information T.J. Strzalkowski: None. B.L. Cadilha: A. Employment (full or part-time); Significant; University Hospital, LMU Munich. I. Dalloul: A. Employment (full or part-time); Significant; University Hospital, LMU Munich. K. Manske: A. Employment (full or part-time); Significant; University Hospital, LMU Munich. S. Endres: A. Employment (full or part-time); Significant; University Hospital, LMU Munich. B. Research Grant
ISSN:2051-1426
DOI:10.1136/jitc-2022-ITOC9.6