Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity.

Humans Receptors, Chimeric Antigen Neoplasms / therapy T-Lymphocytes Immunotherapy, Adoptive Cancer Vaccines Receptors, Antigen, T-Cell / metabolism
CAR T IFN-γ antigen loss antigen spreading antigenic heterogeneity cancer chimeric antigen receptor T cell immunotherapy solid tumor tumor heterogeneity vaccine

Journal

Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066

Informations de publication

Date de publication:
20 07 2023
Historique:
received: 09 10 2022
revised: 30 03 2023
accepted: 02 06 2023
medline: 31 7 2023
pubmed: 7 7 2023
entrez: 6 7 2023
Statut: ppublish

Résumé

Chimeric antigen receptor (CAR) T cell therapy effectively treats human cancer, but the loss of the antigen recognized by the CAR poses a major obstacle. We found that in vivo vaccine boosting of CAR T cells triggers the engagement of the endogenous immune system to circumvent antigen-negative tumor escape. Vaccine-boosted CAR T promoted dendritic cell (DC) recruitment to tumors, increased tumor antigen uptake by DCs, and elicited the priming of endogenous anti-tumor T cells. This process was accompanied by shifts in CAR T metabolism toward oxidative phosphorylation (OXPHOS) and was critically dependent on CAR-T-derived IFN-γ. Antigen spreading (AS) induced by vaccine-boosted CAR T enabled a proportion of complete responses even when the initial tumor was 50% CAR antigen negative, and heterogeneous tumor control was further enhanced by the genetic amplification of CAR T IFN-γ expression. Thus, CAR-T-cell-derived IFN-γ plays a critical role in promoting AS, and vaccine boosting provides a clinically translatable strategy to drive such responses against solid tumors.

Identifiants

DOI: 10.1016/j.cell.2023.06.002 PMID: 37413990 PMC: PMC10372881
pubmed: 37413990
pii: S0092-8674(23)00642-6
doi: 10.1016/j.cell.2023.06.002
pmc: PMC10372881
mid: NIHMS1908849
pii:
doi:

Substances chimiques

Receptors, Chimeric Antigen 0
Cancer Vaccines 0
Receptors, Antigen, T-Cell 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

3148-3165.e20

Subventions

Organisme : NCI NIH HHS
ID : P30 CA014051
Pays : United States
Organisme : NIAID NIH HHS
ID : DP2 AI164319
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA247632
Pays : United States
Organisme : NIBIB NIH HHS
ID : R01 EB022433
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests L.M. and D.J.I. are inventors on patents filed in relation to the amphiphile-vaccine technology. D.J.I. is a co-founder, shareholder, and consultant for Elicio Therapeutics, which has licensed patents related to the amphiphile-vaccine technology.

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Auteurs

Leyuan Ma (L)

David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: leyuan.ma@pennmedicine.upenn.edu.

Alexander Hostetler (A)

David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.

Duncan M Morgan (DM)

David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Chemical Engineering, MIT, Cambridge, MA, USA.

Laura Maiorino (L)

David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.

Ina Sulkaj (I)

David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.

Charles A Whittaker (CA)

David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.

Alexandra Neeser (A)

Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA.

Ivan Susin Pires (IS)

David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.

Parisa Yousefpour (P)

David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.

Justin Gregory (J)

David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.

Kashif Qureshi (K)

David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.

Jonathan Dye (J)

David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.

Wuhbet Abraham (W)

David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.

Heikyung Suh (H)

David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.

Na Li (N)

David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.

J Christopher Love (JC)

David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Chemical Engineering, MIT, Cambridge, MA, USA; Ragon Institute of Massachusetts General Hospital, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Darrell J Irvine (DJ)

David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Materials Science and Engineering, MIT, Cambridge, MA 02139, USA; Department of Biological Engineering, MIT, Cambridge, MA 02139, USA; Ragon Institute of Massachusetts General Hospital, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: djirvine@mit.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Vaccine-boosted CAR T crosstalk with host...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Récepteurs cytoplasmiques et nucléaires › Récepteurs chimériques pour l'antigène › Vaccine-boosted CAR T crosstalk with host...
questionsmedicales.fr › Tumeurs › Vaccine-boosted CAR T crosstalk with host...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes T › Vaccine-boosted CAR T crosstalk with host...
questionsmedicales.fr › Techniques d'investigation › Techniques immunologiques › Immunisation passive › Transfert adoptif › Immunothérapie adoptive › Vaccine-boosted CAR T crosstalk with host...
questionsmedicales.fr › Mélanges complexes › Produits biologiques › Vaccins › Vaccins anticancéreux › Vaccine-boosted CAR T crosstalk with host...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs immunologiques › Récepteurs aux antigènes › Récepteurs aux antigènes des cellules T › Vaccine-boosted CAR T crosstalk with host...