- Poster presentation
- Open Access
Combinatorial therapy with an IL-15 superagonist (ALT-803) and anti-PD-L1 mAb augment T cell mediated anti-tumor immunity in mice
© Johnson et al.; licensee BioMed Central Ltd. 2014
- Published: 6 November 2014
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- Inhibitory Pathway
- Checkpoint Inhibitor
- Hematologic Tumor
- Cytokine Therapy
- Exogenous Cytokine
The adoptive transfer of tumor-reactive T cells has shown great promise in treating patients with metastatic cancer. However, effective T cell responses are limited by the availability of T cell growth factors such as IL-2 and tumor-induced suppressive pathways. As tumor-induced suppression may hamper cytokine responsiveness, we hypothesized that combinatorial therapy providing exogenous cytokine with blockade of inhibitory pathways would lead to synergistic anti-tumor responses. We evaluated this hypothesis by treating mice with palpable B16 melanoma tumors with lymphodepletion and transfer of activated, tumor-reactive CD8+ T cells (pmel-1 TCR transgenic). The persistence of the adoptively transferred tumor-reactive CD8+ T cells was dramatically augmented in the recipient mice with injections of an IL-15 superagonist (ALT-803) which, compared with IL-2, has greater biological activity and does not expand T regulatory cells. The ALT-803-treated mice also survived significantly longer than the untreated mice. B16 melanoma tumor cells were found to express PD-L1 and activated CD8+ T cells have PD-1 on their surface. Thus, we also gave mice anti-PD-L1 mAb treatment to block this PD-1/PD-L-1 inhibitory pathway. Our preliminary data suggest that combinatorial therapy with anti-PD-L1 mAb led to synergistic improvement in anti-tumor efficacy. We are now determining the optimal timing and dosing of ALT-803 and anti-PD-L1 mAb therapy to confirm these results. Currently, ALT-803 is in clinical trials for treating patients with various solid and hematologic tumors. Our findings suggest combinatorial therapy relieving T cell dysfunction using checkpoint inhibitors and providing ALT-803 cytokine therapy may lead to substantially improved outcomes over currently available therapies for patients with metastatic cancer.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.