NIZ985 / Novartis - LARVOL DELTA

hetIL-15 and Fenofibrate combination alters the metabolic fitness of tumor-infiltrating CD8+T cells leading to TNBC tumor eradication in mice (AACR 2024) - "hetIL-15 monotherapy resulted in tumor eradication in 40% of treated mice and increased survival. Seahorse analysis of tumor-infiltrating CD8+T cells confirmed a rise in oxygen consumption rate (OCR) with substantial increase of spare respiratory capacity. Upon hetIL-15 treatment, tumor-infiltrating CD8+T cells showed elevated extracellular acidification rate (ECAR), resulting in a pronounced shift in the OCR/ECAR ratio in comparison to control, confirming their increased proliferating status."

IO biomarker • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • IFNG • IL15

Treatment With AZD5582 + hetIL-15 Disrupts the Reservoir Establishment in SIV-Infected Macaques (CROI 2024) - "Altogether, these findings suggest that treatment with AZD5582, alone or in combination with hetIL-15, may reduce the size of virus reservoir when administered at the time of ART initiation during acute SIV infection, thus suggesting a disruptive effect on the reservoir establishment. These data are consistent with previous work on the latency reversing activity of AZD5582 and provides rationale for further exploring this compound as a curative agent for HIV infection."

Human Immunodeficiency Virus • Infectious Disease • CD4 • CD8 • GZMB • IL15

A Phase I/Ib Study of NIZ985 Alone and in Combination With Spartalizumab (clinicaltrials.gov) - P1 | N=60 | Terminated | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Terminated; Business decision and not due to any safety concerns

Combination therapy • Metastases • Trial termination • Cutaneous Melanoma • Hematological Malignancies • Lung Cancer • Lymphoma • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

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) - P1 | "NIZ985 was well tolerated in the single-agent and NIZ985/spartalizumab regimens. The RDE was established at at 1 µg/kg TIW. Antitumor activity of the combination was observed against tumor types known to have a poor response to ICIs."

Combination therapy • Journal • Metastases • P1 data • Gastric Cancer • Gastrointestinal Cancer • Hepatology • Melanoma • Oncology • Pancreatic Cancer • Solid Tumor • CD8 • IL15

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 (J Immunother Cancer) - P1/2 | N=63 | NCT02452268 | Sponsor: Novartis Pharmaceuticals | "No dose-limiting toxicities occurred nor was the MTD identified. The most common treatment-related adverse event (TRAE) was injection site reaction (primarily grades 1–2; single-agent NIZ985: 85% (23/27)); NIZ985/spartalizumab: 89% [50/56]). The most common grade 3–4 TRAE was decreased lymphocyte count (single-agent NIZ985: 7% [2/27]; NIZ985/spartalizumab: 5% [3/56]). The best overall response was stable disease in the single-agent arm (30% (8/27)) and partial response in the NIZ985/spartalizumab arm (5% [3/56]; melanoma, pancreatic cancer, gastric cancer)."

P1 data • Gastric Cancer • Gastrointestinal Cancer • Melanoma • Oncology • Pancreatic Cancer • Solid Tumor

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) - P1 | "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 • Combination therapy • IO biomarker • P1 data • Hematological Malignancies • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD8 • IL15 • IL2

A Phase I/Ib Study of NIZ985 Alone and in Combination With Spartalizumab (clinicaltrials.gov) - P1 | N=60 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Jul 2024 ➔ Nov 2023 | Trial primary completion date: Jul 2024 ➔ Nov 2023

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Cutaneous Melanoma • Hematological Malignancies • Lung Cancer • Lymphoma • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

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 • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • IL15

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."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ITGAE • ITGAM

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 • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • IL15

A Phase I/Ib Study of NIZ985 Alone and in Combination With Spartalizumab (clinicaltrials.gov) - P1 | N=60 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=110 ➔ 60

Combination therapy • Enrollment change • Enrollment closed • Metastases • Cutaneous Melanoma • Hematological Malignancies • Lung Cancer • Lymphoma • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A Phase I/Ib Study of NIZ985 in Combination With PDR001 in Adults With Metastatic Cancers (clinicaltrials.gov) - P1 | N=83 | Terminated | Sponsor: Novartis Pharmaceuticals | Completed ➔ Terminated; business decision

Combination therapy • Metastases • Trial termination • Oncology • Prostate Cancer • Solid Tumor

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."

Circulating tumor cells • Journal • Preclinical • Surgery • Tumor cell • Breast Cancer • Colon Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CTCs • IL15

A Phase I/Ib Study of NIZ985 Alone and in Combination With Spartalizumab (clinicaltrials.gov) - P1 | N=110 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Mar 2024 ➔ Jul 2024 | Trial primary completion date: Mar 2024 ➔ Jul 2024

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Cutaneous Melanoma • Hematological Malignancies • Lung Cancer • Lymphoma • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A Phase I/Ib Study of NIZ985 Alone and in Combination With Spartalizumab (clinicaltrials.gov) - P1 | N=110 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Sep 2023 ➔ Mar 2024 | Trial primary completion date: Sep 2023 ➔ Mar 2024

Combination therapy • Trial completion date • Trial primary completion date • Cutaneous Melanoma • Hematological Malignancies • Lung Cancer • Lymphoma • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

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 • Gastrointestinal Cancer • Hepatology • Immunology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD8 • IL15

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 • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • IL15

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 • Breast Cancer • Colon Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • CTCs • IL15

A Phase I/Ib Study of NIZ985 in Combination With PDR001 in Adults With Metastatic Cancers (clinicaltrials.gov) - P1 | N=74 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed

Combination therapy • Trial completion • Oncology • Solid Tumor

A Phase I/Ib Study of NIZ985 Alone and in Combination With Spartalizumab (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: Novartis Pharmaceuticals | N=68 ➔ 90

Combination therapy • Enrollment change • Cutaneous Melanoma • Hematological Malignancies • Lymphoma • Melanoma • Oncology • Solid Tumor

A Phase I/Ib Study of NIZ985 Alone and in Combination With Spartalizumab (clinicaltrials.gov) - P1 | N=68 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Oct 2022 ➔ Jul 2023 | Trial primary completion date: Oct 2022 ➔ Jul 2023

Combination therapy • Trial completion date • Trial primary completion date • Cutaneous Melanoma • Hematological Malignancies • Lymphoma • Melanoma • Oncology • Solid Tumor

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) - P1 | "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 • Journal • P1 data • Eye Cancer • Fatigue • Immune Modulation • Immunology • Inflammation • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • CD163 • CD8 • CXCL10 • IFNG • IL15 • IL18 • TNFA

A Phase I/Ib Study of NIZ985 Alone and in Combination With Spartalizumab (clinicaltrials.gov) - P1; N=68; Recruiting; Sponsor: Novartis Pharmaceuticals; Trial completion date: May 2022 ➔ Oct 2022; Trial primary completion date: May 2022 ➔ Oct 2022

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Cutaneous Melanoma • Hematological Malignancies • Lymphoma • Melanoma • Oncology • Solid Tumor

[VIRTUAL] Phase I/Ib first-in-human study of HEK-NIZ985, a recombinant IL-15/IL-15Rα heterodimer, alone and in combination with spartalizumab, in adults with advanced and metastatic solid tumors (SITC 2020) - "Limited antitumor activity was reported during dose escalation; however, preliminary responses in both IO-experienced and IO-naïve patients were seen in combination with spartalizumab that warrant further investigation. Ethics Approval The study was approved by an independent ethics committee and/or institutional review board at each participating site."

Clinical • Combination therapy • IO Biomarker • P1 data • Melanoma • Oncology • Solid Tumor • CD8 • IL15

[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 • Breast Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Triple Negative Breast Cancer • CD8 • IL15 • IRF8 • ITGAE