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The human IL-15 superagonist ALT-803 directs SIV-specific CD8⁺ T cells into B-cell follicles.

ABSTRACT: Sequestering of latent HIV in follicular helper T cells within B-cell follicles that largely exclude cytotoxic T cells is a major barrier to cellular immune-based approaches to eradicate HIV. Here, we show that the clinical-grade human interleukin-15 (IL-15) superagonist ALT-803 activates and redirects simian immunodeficiency virus (SIV)-specific CD8⁺ T cells from the peripheral blood into B-cell follicles. In agreement with the increased trafficking of SIV-specific cytotoxic T cells to sites of cryptic viral replication, lymph nodes of elite controlling macaques contained fewer cells expressing SIV RNA or harboring SIV DNA post-ALT-803 treatment. These data establish ALT-803 as an immunotherapeutic for HIV and other chronic viral pathogens that evade host immunity by persisting in B-cell follicles.

SUBMITTER: Webb GM

PROVIDER: S-EPMC5787870 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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The human IL-15 superagonist ALT-803 directs SIV-specific CD8<sup>+</sup> T cells into B-cell follicles.

Webb Gabriela M GM Li Shengbin S Mwakalundwa Gwantwa G Folkvord Joy M JM Greene Justin M JM Reed Jason S JS Stanton Jeffery J JJ Legasse Alfred W AW Hobbs Theodore T Martin Lauren D LD Park Byung S BS Whitney James B JB Jeng Emily K EK Wong Hing C HC Nixon Douglas F DF Jones R Brad RB Connick Elizabeth E Skinner Pamela J PJ Sacha Jonah B JB

Blood advances 20180101 2

Sequestering of latent HIV in follicular helper T cells within B-cell follicles that largely exclude cytotoxic T cells is a major barrier to cellular immune-based approaches to eradicate HIV. Here, we show that the clinical-grade human interleukin-15 (IL-15) superagonist ALT-803 activates and redirects simian immunodeficiency virus (SIV)-specific CD8<sup>+</sup> T cells from the peripheral blood into B-cell follicles. In agreement with the increased trafficking of SIV-specific cytotoxic T cells ...[more]

PMID: 29365313

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Project description:BackgroundWe set out to determine if the administration of subcutaneous (SQ) ALT-803 was non-inferior to standard intravesical BCG treatment in a carcinogen induced mouse (C57BL/6J) bladder cancer model.MethodsUsing this well-established carcinogen induced mouse model, we studied the effects of various dosing schemas of ALT-803 (SQ alone, SQ with intravesical BCG, intravesical alone, intravesical with intravesical BCG) compared to intravesical BCG alone (positive control) and PBS (negative control). The non-inferiority margin for the difference in bladder weight, as a surrogate for tumor mass, was defined as 7%.ResultsAll treatment groups (i.e., ALT-803 SQ alone, ALT-803 SQ with intravesical BCG, ALT-803 intravesical alone, ALT-803 intravesical with intravesical BCG and intravesical BCG alone) demonstrated a significant reduction in tumor burden as evident by bladder weights and H&E stain (p < 0.005). Non-inferiority tests between the intravesical BCG alone group and the additional treatment groups showed that SQ ALT-803 alone (p = 0.04) and BCG plus SQ ALT-803 (p = 0.009) were non-inferior to intravesical BCG alone. In this model, we did not see an appreciable infiltration of CD4+ T, CD8+ T or CD161/KLRB1+ natural killer (NK) cells in the bladder/tumor. When assessing peripheral blood mononuclear cells, SQ ALT-803 alone resulted in a robust induction of CD8+ T cells (p < 0.01), NKG2D+ NK cells (p < 0.005) and CD3+/NKG2D+ NKT cells (p < 0.005) compared to other groups, while in splenic tissue, SQ ALT-803 alone resulted in a robust induction of CD3+/NKG2D+ NKT cells (p < 0.005) compared to other groups.ConclusionSubcutaneous ALT-803 treatment alone or in combination with intravesical BCG was well tolerated and was not inferior to intravesical BCG alone. CD8+ T, NKG2D+ NK and CD3+/NKG2D+ NKT cell induction along with induction of key cytokines remain steadfast mechanisms behind ALT-803. The enhanced therapeutic index seen with BCG and ALT-803, administered SQ or intravesically, provides a powerful justification for the further development of these regimens.

Dataset Information

The human IL-15 superagonist ALT-803 directs SIV-specific CD8⁺ T cells into B-cell follicles.

Publications

The human IL-15 superagonist ALT-803 directs SIV-specific CD8<sup>+</sup> T cells into B-cell follicles.

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Dataset Information

The human IL-15 superagonist ALT-803 directs SIV-specific CD8+ T cells into B-cell follicles.

Publications

The human IL-15 superagonist ALT-803 directs SIV-specific CD8<sup>+</sup> T cells into B-cell follicles.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

The human IL-15 superagonist ALT-803 directs SIV-specific CD8⁺ T cells into B-cell follicles.