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Immune checkpoint modulation enhances HIV-1 antibody induction.

ABSTRACT: Eliciting protective titers of HIV-1 broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development, but current vaccine strategies have yet to induce bnAbs in humans. Many bnAbs isolated from HIV-1-infected individuals are encoded by immunoglobulin gene rearrangments with infrequent naive B cell precursors and with unusual genetic features that may be subject to host regulatory control. Here, we administer antibodies targeting immune cell regulatory receptors CTLA-4, PD-1 or OX40 along with HIV envelope (Env) vaccines to rhesus macaques and bnAb immunoglobulin knock-in (KI) mice expressing diverse precursors of CD4 binding site HIV-1 bnAbs. CTLA-4 blockade augments HIV-1 Env antibody responses in macaques, and in a bnAb-precursor mouse model, CTLA-4 blocking or OX40 agonist antibodies increase germinal center B and T follicular helper cells and plasma neutralizing antibodies. Thus, modulation of CTLA-4 or OX40 immune checkpoints during vaccination can promote germinal center activity and enhance HIV-1 Env antibody responses.

SUBMITTER: Bradley T

PROVIDER: S-EPMC7031230 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Immune checkpoint modulation enhances HIV-1 antibody induction.

Bradley Todd T Kuraoka Masayuki M Yeh Chen-Hao CH Tian Ming M Chen Huan H Cain Derek W DW Chen Xuejun X Cheng Cheng C Ellebedy Ali H AH Parks Robert R Barr Maggie M Sutherland Laura L LL Scearce Richard M RM Bowman Cindy M CM Bouton-Verville Hilary H Santra Sampa S Wiehe Kevin K Lewis Mark G MG Ogbe Ane A Borrow Persephone P Montefiori David D Bonsignori Mattia M Anthony Moody M M Verkoczy Laurent L Saunders Kevin O KO Ahmed Rafi R Mascola John R JR Kelsoe Garnett G Alt Frederick W FW Haynes Barton F BF

Nature communications 20200219 1

Eliciting protective titers of HIV-1 broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development, but current vaccine strategies have yet to induce bnAbs in humans. Many bnAbs isolated from HIV-1-infected individuals are encoded by immunoglobulin gene rearrangments with infrequent naive B cell precursors and with unusual genetic features that may be subject to host regulatory control. Here, we administer antibodies targeting immune cell regulatory receptors CTLA-4, PD-1 or OX4 ...[more]

PMID: 32075963

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Project description:Immunomodulatory therapies targeting inhibitory checkpoint molecules have revolutionized the treatment of solid tumor malignancies. Concerns about whether systemic administration of an immune checkpoint inhibitor could impact primary brain tumors were answered with the observation of definitive responses in pediatric patients harboring hypermutated gliomas. Although initial clinical results in patients with glioblastoma (GBM) were disappointing, recently published results have demonstrated a potential survival benefit in patients with recurrent GBM treated with neoadjuvant programmed cell death protein 1 blockade. While these findings necessitate verification in subsequent studies, they support the possibility of achieving clinical meaningful immune responses in malignant primary brain tumors including GBM, a disease in dire need of additional therapeutic options. There are several challenges involved in treating glioma with immune checkpoint modulators including the immunosuppressive nature of GBM itself with high inhibitory checkpoint expression, the immunoselective blood brain barrier impairing the ability for peripheral lymphocytes to traffic to the tumor microenvironment and the high prevalence of corticosteroid use which suppress lymphocyte activation. However, by simultaneously targeting multiple costimulatory and inhibitory pathways, it may be possible to achieve an effective antitumoral immune response. To this end, there are now several novel agents targeting more recently uncovered "second generation" checkpoint molecules. Given the multiplicity of drugs being considered for combination regimens, an increased understanding of the mechanisms of action and resistance combined with more robust preclinical and early clinical testing will be needed to be able to adequately test these agents. This review summarizes our current understanding of T lymphocyte-modulating checkpoint molecules as it pertains to glioma with the hope for a renewed focus on the most promising therapeutic strategies.

Dataset Information

Immune checkpoint modulation enhances HIV-1 antibody induction.

Publications

Immune checkpoint modulation enhances HIV-1 antibody induction.

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