bims-adocet 2024-10-13 papers

Issue of 2024–10–13
six papers selected by
Shani Kassia Lyskov, Tel Aviv University

Cancer Immunol Immunother. 2024 Oct 05. 73(12): 256

Antitumor effects of intracranial injection of B7-H3-targeted Car-T and Car-Nk cells in a patient-derived glioblastoma xenograft model.

Tetsuro Tachi, Noriyuki Kijima, Hideki Kuroda, Syunya Ikeda, Koki Murakami, Tomoyoshi Nakagawa, Moto Yaga, Kanji Nakagawa, Reina Utsugi, Ryuichi Hirayama, Yoshiko Okita, Naoki Kagawa, Haruhiko Kishima, Chihaya Imai, Naoki Hosen.

BACKGROUND: Glioblastoma multiforme (GBM) is the most lethal primary brain tumor for which novel therapies are needed. Recently, chimeric antigen receptor (CAR) T cell therapy has been shown to be effective against GBM, but it is a personalized medicine and requires high cost and long time for the cell production. CAR-transduced natural killer (NK) cells can be used for "off-the-shelf" cellular immunotherapy because they do not induce graft-versus-host disease. Therefore, we aimed to analyze the anti-GBM effect of CAR-T or NK cells targeting B7-H3, which is known to be highly expressed in GBM.
METHODS: CAR-T cells targeting B7-H3 were generated using previously reported anti-B7-H3 scFv sequences. Cord blood (CB)-derived NK cells transduced with the B7-H3 CAR were also generated. Their anti-GBM effect was analyzed in vitro. The antitumor effect of intracranial injection of the B7-H3 CAR-T or NK cells was investigated in an in vivo xenograft model with patient-derived GBM cells.
RESULTS: Both B7-H3 CAR-T cells and CAR-NK cells exhibited marked cytotoxicity against patient-derived GBM cells in vitro. Furthermore, intracranial injection of CAR-T cells and CAR-NK cells targeting B7-H3 resulted in a significant antitumor effect against patient-derived GBM xenografts.
CONCLUSION: Not only CAR-T cells but also CB-derived CAR-NK cells targeting B7-H3 may have the potential to eliminate GBM cells.

Keywords: Antitumor effect; B7-H3; CAR-NK cell therapy; Glioblastoma (GBM)

DOI: https://doi.org/10.1007/s00262-024-03808-0

Oncoimmunology. 2024 ;13(1): 2412371

Peptide-guided adaptor-CAR T-Cell therapy for the treatment of SSTR2-expressing neuroendocrine tumors.

Christian Pellegrino, Nicholas Favalli, Laura Volta, Ramon Benz, Sara Puglioli, Gabriele Bassi, Kathrin Zitzmann, Christoph Josef Auernhammer, Svenja Nölting, Chiara F Magnani, Dario Neri, Felix Beuschlein, Markus G Manz.

Somatostatin receptor type 2 (SSTR2) is one of the five subtypes of somatostatin receptors and is overexpressed on the surface of most gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs), pituitary tumors, paraganglioma, and meningioma, as well as hepatocellular carcinoma and breast cancer. Chimeric antigen receptor (CAR) T-cells are genetically engineered to express an artificial, T-cell activating binder, leading upon ligation to biocidal activity against target-antigen expressing cells. Adaptor-CAR T-cells recognize, via the CAR, a tag on an antigen-binding molecule, building an activating bridge between the CAR and the target cell. We hypothesized that a novel fluorescent-peptide antagonist of SSTR2, called Octo-Fluo, in combination with anti-FITC adaptor CAR (AdFITC(E2)-CAR) T-cells, may function as an on-off tunable activating bridge between the CAR and SSTR2 expressing target cells. In vitro studies confirmed the binding of Octo-Fluo to Bon1-SSTR2 mCherry-Luc cells without evidence of internalization. AdFITC(E2)-CAR T-cells were activated and efficiently induced Bon1-SSTR2 cell death in vitro, in an Octo-Fluo concentration-dependent manner. Similarly, AdFITC(E2)-CAR T-cells in combination with Octo-Fluo efficiently infiltrated the tumor and eliminated Bon1-SSTR2 tumors in immunodeficient mice in therapeutic settings. Both, AdFITC(E2)-CAR T-cell tumor infiltration and biocidal activity were Octo-Fluo concentration-dependent, with high doses of Octo-Fluo, saturating both the CAR and the SSTR2 antigen independently, leading to the loss of tumor infiltration and biocidal activity due to the loss of bridge formation. Our findings demonstrate the potential of using AdFITC(E2)-CAR T-cells with Octo-Fluo as a versatile, on-off tunable bispecific adaptor for targeted CAR T-cell immunotherapy against SSTR2-positive NETs.

Keywords: Adaptor-CAR T-cell; Octo-fluo bispecific adaptor; SSTR2; neuroendocrine tumors

DOI: https://doi.org/10.1080/2162402X.2024.2412371

Immunity. 2024 Oct 08. pii: S1074-7613(24)00456-4. [Epub ahead of print]57(10): 2260-2262

TIL the end: Tracking T cell clonotype dynamics during adoptive cell therapy.

Anthony C Buzzai, Thomas Tüting.

Understanding the factors that lead to the therapeutic success of adoptive cell therapies using tumor-infiltrating lymphocytes (TIL-ACT) will improve current treatment protocols. In this issue of Immunity, Chiffelle et al. comprehensively compare the dynamics of CD8+ T cell clonotypes during the course of ACT between responding and non-responding patients.

DOI: https://doi.org/10.1016/j.immuni.2024.09.012

Immunother Adv. 2024 ;4(1): ltae007

A rapid method to assess the in vivo multi-functionality of adoptively transferred engineered TCR T cells.

Anthony T Tan, Shou Kit Hang, Nicole Tan, Thinesh L Krishnamoorthy, Wan Cheng Chow, Regina Wanju Wong, Lu-En Wai, Antonio Bertoletti.

Introduction: The clinical efficacy of chimeric antigen and T cell receptor (TCR) T cell immunotherapies is attributed to their ability to proliferate and persist in vivo. Since the interaction of the engineered T cells with the targeted tumour or its environment might suppress their function, their functionality should be characterized not only before but also after adoptive transfer.
Materials and methods: We sought to achieve this by adapting a recently developed Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapid whole blood T cell assay to stimulate engineered TCR T cells in small volumes of whole blood (<1 ml) without in vitro cellular purification. As a proof-of-concept, we used this method to longitudinally study two patients with primary Hepatitis B Virus (HBV)-related hepatocellular carcinoma who received multiple dose-escalating infusions of transiently functional mRNA-engineered HBV-TCR T cells.
Results: We demonstrated that a simple pulsing of whole blood with a peptide corresponding to the epitope recognized by the specific HBV-TCR elicited Th1 cytokine secretion in both patients only after HBV-TCR T cell treatment and not before. The amount of cytokines secreted also showed an infusion-dose-dependent association.
Discussions: These findings support the utility of the whole blood cytokine release assay in monitoring the in vivo function and quantity of engineered T cell products following adoptive transfer.

Keywords: T cell therapy; adoptive cell transfer; hepatitis B; hepatocellular carcinoma

DOI: https://doi.org/10.1093/immadv/ltae007

Cell Mol Immunol. 2024 Oct 08.

Silencing of SIRPα enhances the antitumor efficacy of CAR-M in solid tumors.

Han Zhang, Yi Huo, Wenjing Zheng, Peng Li, Hui Li, Lingling Zhang, Longqi Sa, Yang He, Zihao Zhao, Changhong Shi, Lequn Shan, Angang Yang, Tao Wang.

The potential of macrophage-mediated phagocytosis as a cancer treatment is promising. Blocking the CD47-SIRPα interaction with a CD47-specific antibody significantly enhances macrophage phagocytosis. However, concerns regarding their toxicity to nontumor cells remain substantial. Here, we engineered chimeric antigen receptor macrophages (CAR-Ms) by fusing a humanized single-chain variable fragment with FcγRIIa and integrating short hairpin RNA to silence SIRPα, thereby disrupting the CD47-SIRPα signaling pathway. These modified CAR-shSIRPα-M cells exhibited an M1-like phenotype, superior phagocytic function, substantial cytotoxic effects on HER2-positive tumor cells, and the ability to eliminate patient-derived organoids. In vivo, CAR-M cells significantly inhibited tumor growth and prolonged survival in tumor-bearing mice. Notably, CAR-shSIRPα-M cells enhanced cytotoxic T-cell infiltration into tumors, thereby enhancing the antitumor response in both the humanized immune system mouse model and immunocompetent mice. Mechanistically, SIRPα inhibition activated inflammatory pathways and the cGAS-STING signaling cascade in CAR-M cells, leading to increased production of proinflammatory cytokines, reactive oxygen species, and nitric oxide, thereby enhancing their antitumor effects. These findings underscore the potential of SIRPα inhibition as a novel strategy to increase the antitumor efficacy of CAR-M cells in cancer immunotherapy, particularly against solid tumors.

Keywords: CAR-M; Cancer immunotherapy; Phagocytosis; SIRPα; Solid tumor

DOI: https://doi.org/10.1038/s41423-024-01220-3

Nat Commun. 2024 Oct 06. 15(1): 8658

GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency.

The intensive nutrient requirements needed to sustain T cell activation and proliferation, combined with competition for nutrients within the tumor microenvironment, raise the prospect that glucose availability may limit CAR-T cell function. Here, we seek to test the hypothesis that stable overexpression (OE) of the glucose transporter GLUT1 in primary human CAR-T cells would improve their function and antitumor potency. We observe that GLUT1OE in CAR-T cells increases glucose consumption, glycolysis, glycolytic reserve, and oxidative phosphorylation, and these effects are associated with decreased T cell exhaustion and increased Th17 differentiation. GLUT1OE also induces broad metabolic reprogramming associated with increased glutathione-mediated resistance to reactive oxygen species, and increased inosine accumulation. When challenged with tumors, GLUT1OE CAR-T cells secrete more proinflammatory cytokines and show enhanced cytotoxicity in vitro, and demonstrate superior tumor control and persistence in mouse models. Our collective findings support a paradigm wherein glucose availability is rate limiting for effector CAR-T cell function and demonstrate that enhancing glucose availability via GLUT1OE could augment antitumor immune function.

DOI: https://doi.org/10.1038/s41467-024-52666-y