Dataset Information

Mechanisms involved in IL-15 superagonist enhancement of anti-PD-L1 therapy.

ABSTRACT:

Background

Immunotherapy targeting PD-1/PD-L1 fails to induce clinical responses in most patients with solid cancers. N-803, formerly ALT-803, is an IL-15 superagonist mutant and dimeric IL-15R?Sushi-Fc fusion protein complex that enhances CD8⁺ T and NK cell expansion and function and exhibits anti-tumor efficacy in preclinical models. Previous in vitro studies have shown that IL-15 increases PD-L1 expression, a negative regulator of CD8⁺ T and NK cell function. Most reported preclinical studies administered N-803 intraperitoneally not subcutaneously, the current clinical route of administration. N-803 is now being evaluated clinically in combination with PD-1/PD-L1 inhibitors. However, the mechanism of action has not been fully elucidated. Here, we examined the anti-tumor efficacy and immunomodulatory effects of combining N-803 with an anti-PD-L1 antibody in preclinical models of solid carcinomas refractory to anti-PD-L1 or N-803.

Methods

Subcutaneous N-803 and an anti-PD-L1 monoclonal antibody were administered as monotherapy or in combination to 4T1 triple negative breast and MC38-CEA colon tumor-bearing mice. Anti-tumor efficacy was evaluated, and a comprehensive analysis of the immune-mediated effects of each therapy was performed on the primary tumor, lung as a site of metastasis, and spleen.

Results

We demonstrate that N-803 treatment increased PD-L1 expression on immune cells in vivo, supporting the combination of N-803 and anti-PD-L1. N-803 plus anti-PD-L1 was well-tolerated, reduced 4T1 lung metastasis and MC38-CEA tumor burden, and increased survival as compared to N-803 and anti-PD-L1 monotherapies. Efficacy of the combination therapy was dependent on both CD8⁺ T and NK cells and was associated with increased numbers of these activated immune cells in the lung and spleen. Most alterations to NK and CD8⁺ T cell phenotype and number were driven by N-803. However, the addition of anti-PD-L1 to N-803?significantly enhanced CD8⁺ T cell effector function versus N-803 and anti-PD-L1 monotherapies, as indicated by increased Granzyme B and IFN? production, at the site of metastasis and in the periphery. Increased CD8⁺ T cell effector function correlated with higher serum IFN? levels, without related toxicities, and enhanced anti-tumor efficacy of the N-803 plus anti-PD-L1 combination versus either monotherapy.

Conclusions

We provide novel insight into the mechanism of action of N-803 plus anti-PD-L1 combination and offer preclinical proof of concept supporting clinical use of N-803 in combination with checkpoint inhibitors, including for patients non- and/or minimally responsive to either monotherapy.

SUBMITTER: Knudson KM

PROVIDER: S-EPMC6429734 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

Mechanisms involved in IL-15 superagonist enhancement of anti-PD-L1 therapy.

Knudson Karin M KM Hicks Kristin C KC Alter Sarah S Schlom Jeffrey J Gameiro Sofia R SR

Journal for immunotherapy of cancer 20190321 1

<h4>Background</h4>Immunotherapy targeting PD-1/PD-L1 fails to induce clinical responses in most patients with solid cancers. N-803, formerly ALT-803, is an IL-15 superagonist mutant and dimeric IL-15RαSushi-Fc fusion protein complex that enhances CD8<sup>+</sup> T and NK cell expansion and function and exhibits anti-tumor efficacy in preclinical models. Previous in vitro studies have shown that IL-15 increases PD-L1 expression, a negative regulator of CD8<sup>+</sup> T and NK cell function. Mos ...[more]

PMID: 30898149

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Project description:BACKGROUND:Anti(?)-programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) monotherapy fails to provide durable clinical benefit for most patients with carcinoma. Recent studies suggested that strategies to reduce immunosuppressive cells, promote systemic T-cell responses and lymphocyte trafficking to the tumor microenvironment (TME) may improve efficacy. N-809 is a first-in-class bifunctional agent comprising the interleukin (IL)-15 superagonist N-803 fused to two ?PD-L1 domains. Thus, N-809 can potentially stimulate effector immune cells through IL-15 and block immunosuppressive PD-L1. Here, we examined the antitumor efficacy and immunomodulatory effects of N-809 versus N-803+?PD-L1 combination. METHODS:The ability of N-809 to block PD-L1 and induce IL-15-dependent immune effects was examined in vitro and in vivo. Antitumor efficacy of N-809 or N-803+?PD-L1 was evaluated in two murine carcinoma models and an extensive analysis of immune correlates was performed in the tumor and tumor-draining lymph node (dLN). RESULTS:We demonstrate that N-809 blocks PD-L1 and induces IL-15-dependent immune effects. N-809 was well-tolerated and reduced 4T1 lung metastasis, decreased MC38 tumor burden and increased survival versus N-803+?PD-L1. Compared with N-803+?PD-L1, N-809 enhanced natural killer (NK) and CD8+ T-cell activation and function in the dLN and TME, relating to increased gene expression associated with interferon and cytokine signaling, lymphoid compartment, costimulation and cytotoxicity. The higher number of TME CD8+ T cells was attributed to enhanced infiltration, not in situ expansion. Increased TME NK and CD8+ T-cell numbers correlated with augmented chemokine ligands and receptors. Moreover, in contrast to N-803+?PD-L1, N-809 reduced immunosuppressive regulatory T cells (Treg), monocytic myeloid-derived suppressor cells (M-MDSC) and M2-like macrophages in the TME. CONCLUSIONS:Our results suggest that N-809 functions by a novel immune mechanism to promote antitumor efficacy. Foremost, N-809 enhances intratumoral lymphocyte numbers by increasing trafficking via altered chemokine levels in the TME and chemokine receptor expression on CD8+ T cells and NK cells. In addition, N-809 reduces immunosuppressive and pro-tumorigenic immune cells in the TME, including Treg, M2-like macrophages and M-MDSC. Overall, these novel effects of N-809 promote an inflamed TME, leading to lower tumor burden and increased survival. These results provide mechanistic insight and rationale supporting the potential clinical study of N-809 in patients with carcinoma.

Project description:Simple Summary Although immune checkpoint blockade has yielded unprecedented and durable responses in cancer patients, the efficacy of this treatment remains limited. Radiation therapy can induce immunogenic cell death that contributes to the local efficacy of irradiation. However, radiation-induced systemic responses are scarce. Studies combining radiation with checkpoint inhibitors suggest a synergistic potential of this strategy. In this review, we focused on parameters that can be optimized to enhance the anti-tumor immune response that results from this association, in order to achieve data on dose, fractionation, target volume, lymph nodes sparing, radiation particles, and other immunomodulatory agents. These factors should be considered in future trials for better clinical outcomes. To this end, we discussed the main preclinical and clinical data available to optimize the efficacy of the treatment combination. Abstract Immune checkpoint inhibitors have been associated with long-term complete responses leading to improved overall survival in several cancer types. However, these novel immunotherapies are only effective in a small proportion of patients, and therapeutic resistance represents a major limitation in clinical practice. As with chemotherapy, there is substantial evidence that radiation therapy promotes anti-tumor immune responses that can enhance systemic responses to immune checkpoint inhibitors. In this review, we discuss the main preclinical and clinical evidence on strategies that can lead to an enhanced response to PD-1/PD-L1 blockade in combination with radiation therapy. We focused on central issues in optimizing radiation therapy, such as the optimal dose and fractionation for improving the therapeutic ratio, as well as the impact on immune and clinical responses of dose rate, target volume, lymph nodes irradiation, and type of radiation particle. We explored the addition of a third immunomodulatory agent to the combination such as other checkpoint inhibitors, chemotherapy, and treatment targeting the tumor microenvironment components. The strategies described in this review provide a lead for future clinical trials.

Dataset Information

Mechanisms involved in IL-15 superagonist enhancement of anti-PD-L1 therapy.

Background

Methods

Results

Conclusions

Publications

Mechanisms involved in IL-15 superagonist enhancement of anti-PD-L1 therapy.

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