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IL-15 in the Combination Immunotherapy of Cancer.

ABSTRACT: We completed clinical trials of rhIL-15 by bolus, subcutaneous, and continuous intravenous infusions (CIV). IL-15 administered by CIV at 2 mcg/kg/day yielded a 38-fold increase in 10- day number of circulating NK cells, a 358-fold increase in CD56bright NK cells and a 5.8-fold increase in CD8 T cells. However, IL-15 preparations administered as monotherapy were ineffective, due to actions of immunological checkpoints and due to the lack of tumor specific targeting by NK cells. To circumvent checkpoints, trials of IL-15 in combination with other anticancer agents were initiated. Tumor-bearing mice receiving IL-15 with antibodies to CTLA-4 and PD-L1 manifested marked prolongation of survival compared to mice receiving IL-15 with either agent alone. In translation, a phase I trial was initiated involving IL-15 (rhIL-15), nivolumab and ipilimumab in patients with malignancy (NCT03388632). In rhesus macaques CIV IL-15 at 20 ?g/kg/day for 10 days led to an 80-fold increase in number of circulating effector memory CD8 T cells. However, administration of ?c cytokines such as IL-15 led to paralysis/depression of CD4 T-cells that was mediated through transient expression of SOCS3 that inhibited the STAT5 signaling pathway. This lost CD4 helper role could be restored alternatively by CD40 agonists. In the TRAMP-C2 prostate tumor model the combination of IL-15 with agonistic anti-CD40 produced additive effects in terms of numbers of TRAMP-C2 tumor specific Spas/SCNC/9H tetramer positive CD8 T cells expressed and tumor responses. A clinical trial is being initiated for patients with cancer using an intralesional anti-CD40 in combination with CIV rhIL-15. To translate IL-15-mediated increases in NK cells, we investigated combination therapy of IL-15 with anticancer monoclonal antibodies including rituximab in mouse models of EL-4 lymphoma transfected with human CD20 and with alemtuzumab (CAMPATH-1H) in a xenograft model of adult T cell leukemia (ATL). IL-15 enhanced the ADCC and therapeutic efficacy of both antibodies. These results provided the scientific basis for trials of IL-15 combined with alemtuzumab (anti-CD52) for patients with ATL (NCT02689453), with obinutuzumab (anti-CD20) for patients with CLL (NCT03759184), and with avelumab (anti-PD-L1) in patients with T-cell lymphoma (NCT03905135) and renal cancer (NCT04150562). In the first trial, there was elimination of circulating ATL and CLL leukemic cells in select patients.

SUBMITTER: Waldmann TA

PROVIDER: S-EPMC7248178 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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IL-15 in the Combination Immunotherapy of Cancer.

Waldmann Thomas A TA Dubois Sigrid S Miljkovic Milos D MD Conlon Kevin C KC

Frontiers in immunology 20200519

We completed clinical trials of rhIL-15 by bolus, subcutaneous, and continuous intravenous infusions (CIV). IL-15 administered by CIV at 2 mcg/kg/day yielded a 38-fold increase in 10- day number of circulating NK cells, a 358-fold increase in CD56<sup>bright</sup> NK cells and a 5.8-fold increase in CD8 T cells. However, IL-15 preparations administered as monotherapy were ineffective, due to actions of immunological checkpoints and due to the lack of tumor specific targeting by NK cells. To circ ...[more]

PMID: 32508818

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Project description:Prostate cancer is the second most commonly diagnosed cancer in men with mortality rates, overtaking those for breast cancer in the last 2 years in the UK. Despite advances in prostate cancer treatments, over 25% of men do not survive over 5 years with advanced disease. Due to the success of immunotherapies in treating other cancers, this treatment modality has been investigated for Prostate cancer, however, the sole FDA approved immunotherapy so far (Provenge™) only extends life by a few months. Therefore, finding immunotherapeutic agents to treat prostate cancer is of major interest. Our group has previously shown that Interleukin-15 (IL-15), unlike other therapeutic cytokines such as IL-2 and IL-12, can stimulate expansion and activity of CD8 T cells and NK cells in vitro when they are exposed to prostate cancer cells, while studies in mice have shown a 50% reduction in tumor size with no apparent toxicity. In this study, we aim to examine potencies of IL-15 in combination with a cyclic dinucleotide (CDN) that activates the Stimulator of Interferon-Gene (STING) receptor. Selected CDNs (also known as STING agonists) have previously been shown to activate both T cells and dendritic cells through STING. We hypothesize that the combination of STING agonists and IL-15 can additively increase NK and T cell activity as they act to increase type I interferons (IFNs) through STING activation and IFN-γ through IL-15. In prostate cancer-lymphocyte co-cultures we now show that combination of IL-15 and the STING agonist ADU-S100 analog induces a marked killing of cancer cells above that seen with IL-15 or ADU-S100 alone. We show that this is related to a potent activation of NK cells resulting in increased perforin and CD69 expression, and up to a 13-fold increase in IFNγ secretion in the co-cultures. NK cells are responsible for killing of the cancer cells, as shown by a lack of cytotoxicity in NK depleted lymphocyte-tumor cell co-cultures, or in co-cultures of B and T cells with tumor cells. In summary, we propose that the combination of IL-15 and the sting agonist ADU-S100 analog may be potently effective in treatment of prostate cancer.

Project description:Interleukin-15 (IL-15) is a cytokine previously suggested as a potential immunotherapy for cancer treatment. IL-15 can effectively reduce tumor growth in many preclinical tumor models including prostate cancer. This is due to its ability to expand and activate immune cells, such as CD8+ T cells and natural killer cells. To increase the potency of IL-15, we have engineered a protein variant that can be modified to localize and be retained in tissues where it is administered. However, the production of recombinant IL-15, the purity, and correct refolding of the final protein is not always ideal. In the current study, we aimed to optimize the methodology for production and purification of a modified recombinant human IL-15 and investigate the efficacy of the produced protein in the treatment of prostate tumors. Human IL-15 with its polypeptide sequence modified at the C-terminus to enable thiol conjugation with membrane localizing peptides, was produced in E. coli and purified using mild denaturing conditions (2M urea) from a washing step or from solubilization of inclusion bodies. The purified protein from the wash fraction was conjugated to a myristoylated peptide to form a membrane-localizing IL-15 (cyto-IL-15). The efficacy of cyto-IL-15 was investigated in subcutaneous TRAMP-C2 prostate tumors in mice and compared with cyto-IL-15 derived from protein purified from inclusion bodies (cyto-IL-15 Gen). When mild denaturing conditions were used for purification, the largest amount of IL-15 was collected from the wash fraction and a smaller amount from inclusion bodies. The protein from the wash fraction was mainly present as a monomer, whereas the one from inclusion bodies formed homodimers and higher complexes. After cytotopic modification, the purified IL-showed great efficacy in delaying prostate tumor growth (∼50%) and increased mice survival by ∼1.8-fold compared with vehicle. This study demonstrates an alternative, inexpensive and efficient method to produce and purify a modified version of IL-15 using mild denaturing conditions. This IL-15, when cytotopically modified, showed great efficacy as a monotherapy in prostate tumors in mice further highlighting the potential of IL-15 as a cancer immunotherapy.

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IL-15 in the Combination Immunotherapy of Cancer.

Publications

IL-15 in the Combination Immunotherapy of Cancer.

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