Functional Activity of Cytokine-Induced Killer Cells Enhanced by CAR-CD19 Modification or by Soluble Bispecific Antibody Blinatumomab

Author:

Zaninelli Silvia1,Panna Silvia1,Tettamanti Sarah2,Melita Giusi2ORCID,Doni Andrea3,D’Autilia Francesca3,Valgardsdottir Rut1,Gotti Elisa1,Rambaldi Alessandro45ORCID,Golay Josée1ORCID,Introna Martino1

Affiliation:

1. Center of Cellular Therapy “G. Lanzani”, Division of Hematology, ASST Papa Giovanni XXIII, 24122 Bergamo, Italy

2. M. Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy

3. Unit of Multiscale and Nanostructural Imaging, IRCCS Humanitas Research Hospital, 20089 Milano, Italy

4. Hematology and Bone Marrow Transplant Unit, ASST Papa Giovanni XXIII Hospital, 24127 Bergamo, Italy

5. Department of Oncology and Hematology, Università degli Studi di Milano, 20122 Milan, Italy

Abstract

Strategies to increase the anti-tumor efficacy of cytokine-induced killer cells (CIKs) include genetic modification with chimeric antigen receptors (CARs) or the addition of soluble T-cell engaging bispecific antibodies (BsAbs). Here, CIKs were modified using a transposon system integrating two distinct anti-CD19 CARs (CAR-MNZ and CAR-BG2) or combined with soluble CD3xCD19 BsAb blinatumomab (CIK + Blina). CAR-MNZ bearing the CD28-OX40-CD3ζ signaling modules, and CAR-BG2, designed on the Tisagenlecleucel CAR sequence (Kymriah®), carrying the 4-1BB and CD3ζ signaling elements, were employed. After transfection and CIK expansion, cells expressed CAR-CD19 to a similar extent (35.9% CAR-MNZ and 17.7% CAR-BG2). In vitro evaluations demonstrated robust proliferation and cytotoxicity (~50% cytotoxicity) of CARCIK-MNZ, CARCIK-BG2, and CIK + Blina against CD19+ target cells, suggesting similar efficacy. All effectors formed an increased number of synapses, activated NFAT and NFkB, and secreted IL-2 and IFN-ɣ upon encountering targets. CIK + Blina displayed strongest NFAT and IFN-ɣ induction, whereas CARCIK-BG2 demonstrated superior synapse formation. All the effectors have shown therapeutic activity in vivo against the CD19+ Daudi tumor model, with CARCIK cells showing a more durable response compared to CIK + Blina, likely due to the short half-life of Blina in this model.

Funder

Associazione Italiana Ricerca contro il Cancro

“Innovative CAR Therapy Platforms” (INCAR) and AIRC 5 × 1000 grant

Fondazione Regionale per la Ricerca Biomedica

Publisher

MDPI AG

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