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10ms
A Phase I/Ib Study of NIZ985 Alone and in Combination With Spartalizumab (clinicaltrials.gov)
P1, N=60, Terminated, Novartis Pharmaceuticals | Active, not recruiting --> Terminated; Business decision and not due to any safety concerns
Trial termination • Combination therapy • Metastases
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Tevimbra (tislelizumab-jsgr) • spartalizumab (PDR001) • NIZ985
1year
First-in-human phase I/Ib study of NIZ985, a recombinant heterodimer of IL-15 and IL-15Rα, as a single agent and in combination with spartalizumab in patients with advanced and metastatic solid tumors. (PubMed, J Immunother Cancer)
NIZ985 was well tolerated in the single-agent and NIZ985/spartalizumab regimens. The RDE was established at 1 µg/kg TIW. Antitumor activity of the combination was observed against tumor types known to have a poor response to ICIs.
P1 data • Journal • Combination therapy • Metastases
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CD8 (cluster of differentiation 8) • IL15 (Interleukin 15)
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spartalizumab (PDR001) • NIZ985
over1year
A phase I/Ib study evaluating the safety and tolerability of NIZ985 alone and in combination with spartalizumab (anti–PD-1) in patients (pts) with solid tumors or lymphoma (ESMO 2023)
Clinical trial identification EudraCT 2109-0040690-42. The RDE was declared as 12 μg/kg NIZ985 SA and in combination. Additional pts with NSCLC have enrolled in EXP with tislelizumab.
Clinical • P1 data • Combination therapy • PD(L)-1 Biomarker • IO biomarker
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CD8 (cluster of differentiation 8) • IL2 (Interleukin 2) • IL15 (Interleukin 15)
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CD8 expression
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Tevimbra (tislelizumab-jsgr) • spartalizumab (PDR001) • NIZ985
over1year
Tumor eradication by hetIL-15 locoregional therapy correlates with an induced intratumoral CD103CD11b dendritic cell population. (PubMed, Cell Rep)
Therefore, hetIL-15, a cytokine directly affecting lymphocytes and inducing cytotoxic cells, also has an indirect rapid and significant effect on the recruitment of myeloid cells, initiating a cascade for tumor elimination through innate and adoptive immune mechanisms. The intratumoral CD103CD11bDC population induced by hetIL-15 may be targeted for the development of additional cancer immunotherapy approaches.
Journal • IO biomarker
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ITGAM (Integrin, alpha M) • ITGAE (Integrin Subunit Alpha E)
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NIZ985
over1year
A Phase I/Ib Study of NIZ985 Alone and in Combination With Spartalizumab (clinicaltrials.gov)
P1, N=60, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jul 2024 --> Nov 2023 | Trial primary completion date: Jul 2024 --> Nov 2023
Trial completion date • Trial primary completion date • Combination therapy • Metastases
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Tevimbra (tislelizumab-jsgr) • spartalizumab (PDR001) • NIZ985
over1year
Synergy of heterodimeric IL-15 immunotherapy and a Fatty Acid Metabolism Modulator enhances intratumoral lymphocyte metabolism and eradicates EO771 murine breast tumors (P885) (IMMUNOLOGY 2023)
We study hetIL-15, a cytokine that stimulates the generation, proliferation and cytotoxic function of CD8+ T and NK cells...In addition, combination therapy resulted in statistically significant tumor growth delay and complete eradication of the tumors in 85% of mice. Our results indicate that metabolic reprogramming of tumor-specific CD8+T cells might represent a strategy to promote survival in the metabolically hostile Tumor Microenvironment (TME), enhancing the clinical efficacy of immunotherapy.
Preclinical
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CD8 (cluster of differentiation 8) • IL15 (Interleukin 15)
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NIZ985
over1year
Heterodimeric IL-15 (hetIL-15) immunotherapy synergizes with Fatty Acid Metabolism Modulator (FAMM) to eradicate TNBC EO771 murine tumors (AACR 2023)
Our results indicate that hetIL-15 synergizes with metabolic reprogramming of T cells to achieve superior antitumor efficacy and complete cures. We suggest that metabolic reprogramming of tumor-specific CD8+Tcells might represent a strategy to promote survival in the metabolically hostile TME as part of an approach to enhance the clinical efficacy of immunotherapy.
Preclinical
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CD8 (cluster of differentiation 8) • IL15 (Interleukin 15)
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NIZ985
almost2years
Heterodimeric IL-15 (hetIL-15) reduces circulating tumor cells and metastasis formation improving chemotherapy and surgery in 4T1 mouse model of TNBC. (PubMed, Front Immunol)
Tumor resection supported by neoadjuvant and adjuvant administration of hetIL-15, either alone or in combination with doxorubicin, resulted in the cure of approximately half of the treated animals and the development of anti-4T1 tumor immunity. Our findings demonstrate a significant anti-metastatic potential of hetIL-15 in combination with chemotherapy and surgery and suggest exploring the use of this regimen for the treatment of TNBC.
Preclinical • Journal • Circulating tumor cells • Surgery • Tumor cell
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IL15 (Interleukin 15)
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doxorubicin hydrochloride • NIZ985
over2years
Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer. (PubMed, Cancer Cell)
Finally, exercise or NIZ985 both sensitize pancreatic tumors to αPD-1, with improved anti-tumor and survival benefits. Collectively, our findings highlight the therapeutic potential of an exercise-oncology axis and identify IL-15 activation as a promising treatment strategy for this deadly disease.
Journal
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CD8 (cluster of differentiation 8) • IL15 (Interleukin 15)
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NIZ985
over2years
Heterodimeric IL-15 (hetIL-15) immunotherapy reverses CD8+T cell metabolic dysfunction in murine breast tumors (AACR 2022)
Our results indicate that hetIL-15 not only increases the infiltration and the cytotoxic properties of the CD8+T cells inside the tumors, but also enhances the metabolic reprogramming of T cells to achieve superior antitumor efficacy. We suggest that metabolic reprogramming of tumor-specific CD8+T cells might represent a strategy to promote survival in the metabolically hostile TME as part of an approach to enhance the clinical efficacy of immunotherapy.
Preclinical
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CD8 (cluster of differentiation 8) • IL15 (Interleukin 15)
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NIZ985
over2years
hetIL-15 decreases tumor cell dissemination and colonization and synergizes with chemotherapy and surgery to cure murine 4T1 breast tumors (AACR 2022)
Our results demonstrate that hetIL-15 reduces metastatic disease and synergizes with doxorubicin and surgery to maximize the effectiveness of the treatment against breast cancer in mice. We suggest that the effect of hetIL-15 on metastatic disease is both at the level of dissemination and also colonization in the metastatic sites. This should be further explored in the clinical setting as a neoadjuvant and adjuvant therapy in combination with chemotherapy and surgery for the treatment of TNBC.
Preclinical
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CD8 (cluster of differentiation 8) • IL15 (Interleukin 15)
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doxorubicin hydrochloride • NIZ985
almost3years
Phase I study of single agent NIZ985, a recombinant heterodimeric IL-15 agonist, in adult patients with metastatic or unresectable solid tumors. (PubMed, J Immunother Cancer)
Subcutaneous NIZ985 TIW was generally well tolerated in patients with advanced cancer and produced immune activation paralleling preclinical observations, with induction of IFN-γ and proliferation of cytotoxic lymphocytes. Due to delayed SAEs at the two highest dose levels, administration is being changed to once-weekly in a revised protocol, as monotherapy and combined with checkpoint inhibitor spartalizumab. These alterations are expected to maximize the potential of NIZ985 as a novel immunotherapy.
Clinical • P1 data • Clinical Trial,Phase I • Journal
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CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • TNFA (Tumor Necrosis Factor-Alpha) • CXCL10 (Chemokine (C-X-C motif) ligand 10) • CD163 (CD163 Molecule) • IL18 (Interleukin 18)
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spartalizumab (PDR001) • NIZ985
over3years
[VIRTUAL] Heterodimeric IL-15 (hetIL-15) affects conventional dendritic cells and a distinct novel dendritic cell population in different mouse cancer models of breast and pancreatic cancer (AACR 2021)
hetIL-15 affects both T cells and conventional dendritic cells in syngeneic murine cancer models of breast and pancreatic cancer. We report that the treatment with hetIL-15 increases a novel distinct dendritic cell population (CD103intCD11b+) in all three models. Since we have previously reported that hetIL-15 induces long term immunological protection from tumor rechallenge, these findings suggest hetIL-15 as a promising therapeutic agent in treatment of triple negative breast and pancreatic cancer.
Preclinical
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CD8 (cluster of differentiation 8) • IRF8 (Interferon Regulatory Factor 8) • ITGAE (Integrin Subunit Alpha E)
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NIZ985
over4years
Heterodimeric IL-15 delays tumor growth and promotes intratumoral CTL and dendritic cell accumulation by a cytokine network involving XCL1, IFN-γ, CXCL9 and CXCL10. (PubMed, J Immunother Cancer)
Our results show that hetIL-15 administration enhances T cell entry into tumors, increasing the success rate of immunotherapy interventions. Our study further supports the incorporation of hetIL-15 in tumor immunotherapy approaches to promote the development of antitumor responses by favoring effector over regulatory cells and by promoting lymphocyte and DC localization into tumors through the modification of the tumor chemokine and cytokine milieu.
Journal
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BCL2 (B-cell CLL/lymphoma 2) • CD8 (cluster of differentiation 8) • CXCL10 (Chemokine (C-X-C motif) ligand 10) • CXCL9 (Chemokine (C-X-C motif) ligand 9) • GZMB (Granzyme B)
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NIZ985
over4years
[VIRTUAL] Complete regression of murine breast tumors by hetIL-15FC monotherapy correlates with infiltration by T, NK, cDC1 cells and a novel population of dendritic cells (AACR-II 2020)
Our results show complete eradication of EO771 tumors by hetIL-15FC treatment, correlating with different tumor infiltrating immune cell types. We propose that the anti-cancer activity of hetIL-15 in primary tumors is orchestrated by the interplay of CD8+T cells, cDC1s and a novel subset of antigen presenting cells with a distinct phenotypic profile. hetIL-15 supported a favorable metabolic profile of intra-tumoral effector lymphocytes, important for their function.
IO biomarker
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CD8 (cluster of differentiation 8) • IRF8 (Interferon Regulatory Factor 8) • CD24 (CD24 Molecule)
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NIZ985
over4years
[VIRTUAL] Combination of hetIL-15 with chemotherapy in triple negative breast and pancreatic cancer mouse models increases tumor necrosis and alleviates metastatic disease (AACR-II 2020)
We have produced the native heterodimeric form of IL-15 (hetIL-15), which has advanced in clinical trials due to its anticancer activities.Study design and We assessed the efficacy of hetIL-15 immunotherapy in combination with the chemotherapeutic agents gemcitabine or doxorubicin on the growth of primary pancreatic and breast tumors, and on the metastatic disease. Chemotherapy can be combined with hetIL-15 treatment in both breast and pancreatic mouse models. Despite small beneficial results in the size of primary tumor, histological evaluation revealed increased tumor necrosis and potential synergy of chemotherapy and immunotherapy. The observed decreased metastatic burden in the lungs in both cancer models indicates that hetIL-15 strongly reduces metastases in several cancer types and suggests that hetIL-15 is a promising therapeutic agent against metastatic disease.
Preclinical
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CD8 (cluster of differentiation 8)
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KRAS G12D • KRAS G12
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gemcitabine • doxorubicin hydrochloride • NIZ985
over4years
Regression of murine breast tumors after hetIL-15 monotherapy correlates with a novel population of intratumoral dendritic cells, in addition to increased infiltration of T, NK and cDC1 cells (IMMUNOLOGY 2020)
Complete eradication of EO771 tumors by hetIL-15 treatment correlates with different tumor infiltrating immune cell types. We propose that the anti-cancer activity of hetIL-15 in primary tumors is orchestrated by the interplay of CD8+T cells, cDC1 and a novel subset of antigen presenting cells with a distinct phenotypic profile. Effective hetIL-15 treatment leads to development of long term anti-tumor memory.
CD8 (cluster of differentiation 8) • IRF8 (Interferon Regulatory Factor 8)
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NIZ985