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Cyto-IL-15 synergizes with the STING agonist ADU-S100 to eliminate prostate tumors and confer durable immunity in
Efthymia Papaevangelou1,2, Ana M Esteves1, Prokar Dasgupta1,3
1Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom.
Introduction:
Prostate cancer is one of the most commonly diagnosed malignancies in men with high mortality rates. Despite the recent therapeutic advances, such as immunotherapies, survival of patients with advance disease remains significantly low. Blockade of immune checkpoints has led to low response rates in these patients probably due to the immunosuppressive microenvironment and low mutation burden of prostate tumors. Combination of multiple immunotherapeutic regimes has also been unsatisfactory due to augmented adverse effects. To activate multiple immune-stimulatory pathways in the hostile prostate cancer microenvironment, we used a combination of cytotopically modified interleukin-15 (cyto-IL-15) with the stimulator of interferon genes (STING) agonist, ADU-S100.
Methods:
To determine whether this combination regime could lead to both local and systemic anti-tumor effects, intratumoral administration of these agents was used in murine models of prostate cancer. Tumor growth and mouse survival were monitored, and ex vivo analyses, and RNA sequencing were performed on the tumors.
Results:
Intratumorally injected ADU-S100 and cyto-IL-15 synergized to eliminate tumors in 58-67% of mice with unilateral tumors and promoted abscopal immunity in 50% of mice with bilateral tumors treated only at one side. Moreover, this combination regime offered immunoprotection against tumor rechallenge in 83% of cured mice. The efficacy of the combination treatment was associated with a strong innate and adaptive immune activation and induction of apoptotic and necrotic cell death. Cytokines, including type I and II interferons, and cytokine signalling pathways were activated, NK and T cell mediated cytotoxicity was increased, and B cells were activated both locally and systemically. While ADU-S100 led to an ulcerative pathology at the injection site, no other adverse effects were observed.
Discussion:
Localised administration of a STING agonist together with cyto-IL-15 can confer significant systemic benefits and long-lasting immunity against prostate tumors while reducing immune related toxicities.
Insights
Combining a STING agonist (ADU-S100) with interleukin-15 (cyto-IL-15) effectively eliminated prostate tumors in mice, inducing systemic immunity and long-lasting protection against cancer recurrence.
Area of Science:
- Oncology
- Immunology
- Cancer Therapy
Background:
- Prostate cancer has high mortality rates, with limited survival for advanced disease.
- Current immunotherapies show low response rates due to immunosuppressive tumor microenvironments and low mutation burden.
- Combination immunotherapies often cause increased adverse effects.
Purpose of the Study:
- To investigate the efficacy of combining a STING agonist (ADU-S100) with cytotopically modified interleukin-15 (cyto-IL-15) in activating immune-stimulatory pathways.
- To determine if this combination therapy induces local and systemic anti-tumor effects in prostate cancer models.
Main Methods:
- Intratumoral administration of ADU-S100 and cyto-IL-15 in murine prostate cancer models.
- Monitoring tumor growth and mouse survival.
- Ex vivo analyses and RNA sequencing of tumors.
Main Results:
- The combination therapy synergistically eliminated tumors in 58-67% of mice with unilateral tumors.
- Abscopal immunity was promoted in 50% of mice with bilateral tumors.
- 83% of cured mice showed immunoprotection against tumor rechallenge, with activated innate and adaptive immunity.
Conclusions:
- Localized STING agonist and cyto-IL-15 combination therapy offers significant systemic benefits and long-lasting immunity against prostate tumors.
- This approach activates multiple immune pathways and induces tumor cell death.
- The combination therapy reduces immune-related toxicities compared to other approaches.
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