NIZ985

P1, N=60, Terminated, Novartis Pharmaceuticals | Active, not recruiting --> Terminated; Business decision and not due to any safety concerns

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.

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.

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.

P1, N=60, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jul 2024 --> Nov 2023 | Trial primary completion date: Jul 2024 --> Nov 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.

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.

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.

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.

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.

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.

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.