Journal Article
. 2015 Jan; 3(8):e954869.
doi: 10.4161/21624011.2014.954869.

New insights into the mechanism of action of immune checkpoint antibodies

Aurélien Marabelle 1 Holbrook Kohrt 2 Ronald Levy 2 
  • PMID: 25610751
  •     10 References
  •     6 citations


Preclinical models have been developed and applied to predict the clinical efficacy of immune checkpoint antibodies. Now these models can be used to dissect the mechanisms by which such immunotherapeutic antibodies work and to build the rationale for combining immune checkpoint-targeting antibodies with potential synergistic activity in cancer patients.

Keywords: CTLA-4; GITR; OX40; cancer; immune checkpoint antibodies; immunotherapy.

Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells.
Mark J Selby, John J Engelhardt, +4 authors, Alan J Korman.
Cancer Immunol Res, 2014 Apr 30; 1(1). PMID: 24777248
Highly Cited.
Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy.
Dmitriy Zamarin, Rikke B Holmgaard, +6 authors, James P Allison.
Sci Transl Med, 2014 Mar 07; 6(226). PMID: 24598590    Free PMC article.
Highly Cited.
Antitumor activities of agonistic anti-TNFR antibodies require differential FcγRIIB coengagement in vivo.
Fubin Li, Jeffrey V Ravetch.
Proc Natl Acad Sci U S A, 2013 Nov 13; 110(48). PMID: 24218606    Free PMC article.
Local secretion of anti-CTLA-4 enhances the therapeutic efficacy of a cancer immunotherapy with reduced evidence of systemic autoimmunity.
Andrew D Simmons, Marina Moskalenko, +5 authors, Karin Jooss.
Cancer Immunol Immunother, 2008 Feb 01; 57(8). PMID: 18236040
Controlled local delivery of CTLA-4 blocking antibody induces CD8+ T-cell-dependent tumor eradication and decreases risk of toxic side effects.
Marieke F Fransen, Tetje C van der Sluis, +2 authors, Cornelis J M Melief.
Clin Cancer Res, 2013 Jun 22; 19(19). PMID: 23788581
T-cell modulation combined with intratumoral CpG cures lymphoma in a mouse model without the need for chemotherapy.
Roch Houot, Ronald Levy.
Blood, 2008 Oct 23; 113(15). PMID: 18941113    Free PMC article.
Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies.
Yannick Bulliard, Rose Jolicoeur, +6 authors, Jennifer L Brogdon.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897982    Free PMC article.
Highly Cited.
OX40 engagement depletes intratumoral Tregs via activating FcγRs, leading to antitumor efficacy.
Yannick Bulliard, Rose Jolicoeur, +3 authors, Jennifer L Brogdon.
Immunol Cell Biol, 2014 Apr 16; 92(6). PMID: 24732076
Highly Cited.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
Highly Cited.
Depleting tumor-specific Tregs at a single site eradicates disseminated tumors.
Aurélien Marabelle, Holbrook Kohrt, +13 authors, Ronald Levy.
J Clin Invest, 2013 Jun 04; 123(6). PMID: 23728179    Free PMC article.
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Felipe Vences-Catalán, Ranjani Rajapaksa, +4 authors, Shoshana Levy.
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Claire Deligne, Benoît Milcent, +2 authors, Sophie Sibéril.
Front Immunol, 2017 Sep 01; 8. PMID: 28855903    Free PMC article.
Resistance to CTLA-4 checkpoint inhibition reversed through selective elimination of granulocytic myeloid cells.
Paul E Clavijo, Ellen C Moore, +6 authors, Clint T Allen.
Oncotarget, 2017 Sep 17; 8(34). PMID: 28915554    Free PMC article.
A safe and highly efficient tumor-targeted type I interferon immunotherapy depends on the tumor microenvironment.
Anje Cauwels, Sandra Van Lint, +11 authors, Jan Tavernier.
Oncoimmunology, 2018 Feb 06; 7(3). PMID: 29399401    Free PMC article.
Liposomal TLR9 Agonist Combined with TLR2 Agonist-Fused Antigen Can Modulate Tumor Microenvironment through Dendritic Cells.
Kuan-Yin Shen, Hsin-Yu Liu, +4 authors, Shih-Jen Liu.
Cancers (Basel), 2020 Apr 02; 12(4). PMID: 32231003    Free PMC article.