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IL-15-secreting CAR natural killer cells directed toward the pan-cancer target CD70 eliminate both cancer cells and cancer-associated fibroblasts.
Van den Eynde, Astrid; Gehrcken, Laura; Verhezen, Tias; Lau, Ho Wa; Hermans, Christophe; Lambrechts, Hilde; Flieswasser, Tal; Quatannens, Delphine; Roex, Gils; Zwaenepoel, Karen; Marcq, Elly; Joye, Philippe; Cardenas De La Hoz, Edgar; Deben, Christophe; Gasparini, Alessia; Montay-Gruel, Pierre; Le Compte, Maxim; Lion, Eva; Lardon, Filip; Van Laere, Steven; Siozopoulou, Vasiliki; Campillo-Davo, Diana; De Waele, Jorrit; Pauwels, Patrick; Jacobs, Julie; Smits, Evelien; Van Audenaerde, Jonas R M.
Afiliação
  • Van den Eynde A; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium. astrid.vandeneynde@uantwerpen.be.
  • Gehrcken L; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
  • Verhezen T; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
  • Lau HW; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
  • Hermans C; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
  • Lambrechts H; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
  • Flieswasser T; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
  • Quatannens D; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
  • Roex G; Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Edegem, Belgium.
  • Zwaenepoel K; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
  • Marcq E; Department of Pathology, Antwerp University Hospital, Edegem, Belgium.
  • Joye P; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
  • Cardenas De La Hoz E; Lab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium.
  • Deben C; Brussels Center for Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
  • Gasparini A; Molecular Imaging Center Antwerp (MICA), University of Antwerp, Wilrijk, Belgium.
  • Montay-Gruel P; Industrial Vision Lab (InViLab), University of Antwerp, Antwerp, Belgium.
  • Le Compte M; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
  • Lion E; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
  • Lardon F; Iridium Netwerk, Radiation Oncology, Antwerp, Belgium.
  • Van Laere S; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
  • Siozopoulou V; Iridium Netwerk, Radiation Oncology, Antwerp, Belgium.
  • Campillo-Davo D; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
  • De Waele J; Laboratory of Experimental Hematology (LEH), Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Edegem, Belgium.
  • Pauwels P; Center for Cell Therapy and Regenerative Medicine (CCRG), Antwerp University Hospital, Edegem, Belgium.
  • Jacobs J; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
  • Smits E; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
  • Van Audenaerde JRM; Department of Pathology, Antwerp University Hospital, Edegem, Belgium.
J Hematol Oncol ; 17(1): 8, 2024 02 09.
Article em En | MEDLINE | ID: mdl-38331849
ABSTRACT

BACKGROUND:

It remains challenging to obtain positive outcomes with chimeric antigen receptor (CAR)-engineered cell therapies in solid malignancies, like colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). A major obstacle is the lack of targetable surface antigens that are not shared by healthy tissues. CD70 emerges as interesting target, due to its stringent expression pattern in healthy tissue and its apparent role in tumor progression in a considerable amount of malignancies. Moreover, CD70 is also expressed on cancer-associated fibroblasts (CAFs), another roadblock for treatment efficacy in CRC and PDAC. We explored the therapeutic potential of CD70 as target for CAR natural killer (NK) cell therapy in CRC, PDAC, focusing on tumor cells and CAFs, and lymphoma.

METHODS:

RNA-seq data and immunohistochemical analysis of patient samples were used to explore CD70 expression in CRC and PDAC patients. In addition, CD70-targeting CAR NK cells were developed to assess cytotoxic activity against CD70+ tumor cells and CAFs, and the effect of cytokine stimulation on their efficacy was evaluated. The in vitro functionality of CD70-CAR NK cells was investigated against a panel of tumor and CAF cell lines with varying CD70 expression. Lymphoma-bearing mice were used to validate in vivo potency of CD70-CAR NK cells. Lastly, to consider patient variability, CD70-CAR NK cells were tested on patient-derived organoids containing CAFs.

RESULTS:

In this study, we identified CD70 as a target for tumor cells and CAFs in CRC and PDAC patients. Functional evaluation of CD70-directed CAR NK cells indicated that IL-15 stimulation is essential to obtain effective elimination of CD70+ tumor cells and CAFs, and to improve tumor burden and survival of mice bearing CD70+ tumors. Mechanistically, IL-15 stimulation resulted in improved potency of CD70-CAR NK cells by upregulating CAR expression and increasing secretion of pro-inflammatory cytokines, in a mainly autocrine or intracellular manner.

CONCLUSIONS:

We disclose CD70 as an attractive target both in hematological and solid tumors. IL-15 armored CAR NK cells act as potent effectors to eliminate these CD70+ cells. They can target both tumor cells and CAFs in patients with CRC and PDAC, and potentially other desmoplastic solid tumors.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fibroblastos Associados a Câncer / Linfoma Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fibroblastos Associados a Câncer / Linfoma Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article