Inducible IL-12 or IL-18 secreting CAR T cells targeting the glyco-antigen CD176 exhibit potent activity against non-small cell lung cancer in preclinical models
(1) Malinconico C (2) Weber J (3) Polzien AJ (4) Bonifacius A (5) Umland M (6) Deveuve Q (7) Bargmann T (8) Zimmermann K (9) Gellert J (10) Neubert L (11) Dbel S (12) Schambach A (13) Braun A (14) Blasczyk R (15) Abken H (16) Hudecek M (17) Dragon AC (18) Eiz-Vesper B
Malinconico et al. engineered T cells with both a CAR targeting CD176 (expressed in NSCLC and other tumors), and an inducible cassette encoding either IL-18 or IL-12 that would be expressed following CAR activation of NF-κB. The resulting CD176-iIL18 or CD176-iIL12 TRUCKs showed antigen-dependent secretion of IL-18/IL-12, increased effector molecules, and heightened THP-1 monocyte chemoattraction. They also showed increased cytotoxicity and antitumor activity in vitro, against patient explants, and in vivo, and performed best when both CD4+ and CD8+ T cells were included. TRUCKs producing IL-12 outperformed those producing IL-18, but with more toxicity.
Contributed by Lauren Hitchings
(1) Malinconico C (2) Weber J (3) Polzien AJ (4) Bonifacius A (5) Umland M (6) Deveuve Q (7) Bargmann T (8) Zimmermann K (9) Gellert J (10) Neubert L (11) Dbel S (12) Schambach A (13) Braun A (14) Blasczyk R (15) Abken H (16) Hudecek M (17) Dragon AC (18) Eiz-Vesper B
Malinconico et al. engineered T cells with both a CAR targeting CD176 (expressed in NSCLC and other tumors), and an inducible cassette encoding either IL-18 or IL-12 that would be expressed following CAR activation of NF-κB. The resulting CD176-iIL18 or CD176-iIL12 TRUCKs showed antigen-dependent secretion of IL-18/IL-12, increased effector molecules, and heightened THP-1 monocyte chemoattraction. They also showed increased cytotoxicity and antitumor activity in vitro, against patient explants, and in vivo, and performed best when both CD4+ and CD8+ T cells were included. TRUCKs producing IL-12 outperformed those producing IL-18, but with more toxicity.
Contributed by Lauren Hitchings
ABSTRACT: To date, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide, underscoring the urgent need for new treatment options. The oncofetal carbohydrate CD176 is masked on healthy tissues but is present on a variety of cancer entities and is associated with cancer invasiveness and metastasis. In this study, we employed chimeric antigen receptor T cells (CAR-Ts) directed against CD176 for treatment of NSCLC. CD176-CAR-Ts were optimized with an additional inducible cassette encoding IL-18 (CD176-iIL18-TRUCKs) or IL-12 (CD176-iIL12-TRUCKs) to augment antitumor reactivity through autocrine and paracrine signaling. CD176-iIL18- and CD176-iIL12-TRUCKs eradicate NSCLC cells in a 3D tumor spheroid model and tissue slices derived from lung adenocarcinoma patients more potently than CD176-CAR-Ts. Administration of TRUCKs in a lung carcinoma xenograft mouse model results in partial or complete tumor eradication in all mice treated with CD176-iIL12-TRUCKs and in 50% of mice treated with CD176-iIL18-TRUCKs. This study highlights the potential of CD176 as a CAR-T-cell target and suggest CD176-CAR-Ts armored with IL-18 or IL-12 as promising new therapeutic approach for the treatment of NSCLC and several other CD176-positive cancer entities.
Author Info:
(1) Italian Institute of Technology Napoli Italy. ROR: https://ror.org/042t93s57 (2) University Hospital Wrzburg Wrzburg Germany. (3) Hannover Medical School Hannover Germany. (4
) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (5) Hannover Medical School Hannover Germany. (6) Universittsklinikum Wrzburg Wrzburg Germany. (7) Fraunhofer Institute for Toxicology and Experimental Medicine Hannover, Lower Saxony Germany. ROR: https://ror.org/02byjcr11 (8) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (9) Glycotope GmbH Berlin Germany. (10) Medizinische Hochschule Hannover Hannover, Low Saxony Germany. ROR: https://ror.org/00f2yqf98 (11) Technische Universitt Braunschweig Braunschweig Germany. ROR: https://ror.org/010nsgg66 (12) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (13) Fraunhofer Institute for Toxicology and Experimental Medicine Hannover, Lower Saxony Germany. ROR: https://ror.org/02byjcr11 (14) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (15) Leibniz Institute for Immunotherapy and Univ Regensberg Regensburg Germany. (16) Universittsklinikum Wrzburg Wrzburg Germany. ROR: https://ror.org/03pvr2g57 (17) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (18) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98
Citation: Cancer Immunol Res 2026 Sep 22 Epub09/22/2026
