rhIL-7-hyFc, a long-acting interleukin-7, improves efficacy of CAR-T cell therapy in solid tumors.
Adoptive cell therapy - ACT
Chimeric antigen receptor - CAR
Hepatocellular Carcinoma
Monoclonal antibody
Solid tumor
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
23 Jul 2024
23 Jul 2024
Historique:
accepted:
10
07
2024
medline:
24
7
2024
pubmed:
24
7
2024
entrez:
23
7
2024
Statut:
epublish
Résumé
Chimeric antigen receptor T-cell (CAR-T) therapy has achieved remarkable remission in patients with B-cell malignancies. However, its efficacy in treating solid tumors remains limited. Here, we investigated a combination therapy approach using an engineered long-acting interleukin (IL)-7 (rhIL-7-hyFc or NT-I7) and CAR-T cells targeting three antigens, glypican-2 (GPC2), glypican-3 (GPC3), and mesothelin (MSLN), against multiple solid tumor types including liver cancer, neuroblastoma, ovarian cancer, and pancreatic cancer in mice. CAR-T cells targeting GPC2, GPC3, and MSLN were used in combination with NT-I7 to assess the anticancer activity. Xenograft tumor models, including the liver cancer orthotopic model, were established using NOD scid gamma mice engrafted with cell lines derived from hepatocellular carcinoma, neuroblastoma, ovarian cancer, and pancreatic cancer. The mice were monitored by bioluminescence in vivo tumor imaging and tumor volume measurement using a caliper. Immunophenotyping of CAR-T cells on NT-I7 stimulation was evaluated for memory markers, exhaust markers, and T-cell signaling molecules by flow cytometry and western blotting. Compared with the IL-2 combination, preclinical evaluation of NT-I7 exhibited regression of solid tumors via enhanced occupancy of CD4 This study provides a rationale for NT-I7 plus CAR-T cell combination therapy for solid tumors in humans.
Sections du résumé
BACKGROUND
BACKGROUND
Chimeric antigen receptor T-cell (CAR-T) therapy has achieved remarkable remission in patients with B-cell malignancies. However, its efficacy in treating solid tumors remains limited. Here, we investigated a combination therapy approach using an engineered long-acting interleukin (IL)-7 (rhIL-7-hyFc or NT-I7) and CAR-T cells targeting three antigens, glypican-2 (GPC2), glypican-3 (GPC3), and mesothelin (MSLN), against multiple solid tumor types including liver cancer, neuroblastoma, ovarian cancer, and pancreatic cancer in mice.
METHODS
METHODS
CAR-T cells targeting GPC2, GPC3, and MSLN were used in combination with NT-I7 to assess the anticancer activity. Xenograft tumor models, including the liver cancer orthotopic model, were established using NOD scid gamma mice engrafted with cell lines derived from hepatocellular carcinoma, neuroblastoma, ovarian cancer, and pancreatic cancer. The mice were monitored by bioluminescence in vivo tumor imaging and tumor volume measurement using a caliper. Immunophenotyping of CAR-T cells on NT-I7 stimulation was evaluated for memory markers, exhaust markers, and T-cell signaling molecules by flow cytometry and western blotting.
RESULTS
RESULTS
Compared with the IL-2 combination, preclinical evaluation of NT-I7 exhibited regression of solid tumors via enhanced occupancy of CD4
CONCLUSION
CONCLUSIONS
This study provides a rationale for NT-I7 plus CAR-T cell combination therapy for solid tumors in humans.
Identifiants
pubmed: 39043602
pii: jitc-2024-008989
doi: 10.1136/jitc-2024-008989
pii:
doi:
Substances chimiques
Interleukin-7
0
Receptors, Chimeric Antigen
0
IL7 protein, human
0
Mesothelin
J27WDC343N
Msln protein, mouse
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: MH and DL are inventors on the related patent application no. 63/196556 assigned to the NIH, “Combination immunotherapy for the treatment of glypican-3 (GPC3)-expressing tumors”. MH and DL have patents related to antibody and cell-based immunotherapies and may receive blind royalties from the NIH. MH received research funds from NeoImmuneTech via Cooperative Research and Development Agreement (CRADA) assigned to the NIH. AW, SF-M, and BHL are employees of NeoImmuneTech. The authors declare no other conflicts of interest.