Abstract
Background: Small cell lung cancer (SCLC) is a deadly disease with a 5-year survival of less than 7%. The addition of immunotherapy to chemotherapy was recently approved as first-line treatment; however, the improved clinical benefit is modest, highlighting an urgent need for new treatment strategies. Nemvaleukin alfa, a novel engineered interleukin-2 fusion protein currently in phase I-III studies, is designed to selectively expand cytotoxic natural killer (NK) cells and CD8 + T cells. Here, using a novel SCLC murine model, we investigated the effects of a mouse version of nemvaleukin (mNemvaleukin) on tumor growth and antitumor immunity. Methods: A novel Rb1 -/- p53 -/- p130 -/- SCLC model that mimics human disease was generated. After confirming tumor burden by MRI, mice were randomized into four treatment groups: vehicle, mNemvaleukin alone, chemotherapy (cisplatin+etoposide) alone, or the combination of mNemvaleukin and chemotherapy. Tumor growth was measured by MRI and survival was recorded. Tumor-infiltrating lymphocytes and peripheral blood immune cells were analyzed by flow cytometry. Cytokine and chemokine secretion were quantified and transcriptomic analysis was performed to characterize the immune gene signatures. Results: mNemvaleukin significantly inhibited SCLC tumor growth, which was further enhanced by the addition of chemotherapy. Combining mNemvaleukin with chemotherapy provided the most significant survival benefit. Profiling of tumor-infiltrating lymphocytes revealed mNemvaleukin expanded the total number of tumor-infiltrating NK and CD8 + T cells. Furthermore, mNemvaleukin increased the frequencies of activated and proliferating NK and CD8 + T cells in tumors. Similar immune alterations were observed in the peripheral blood of mNemvaleukin-treated mice. Of note, combining mNemvaleukin with chemotherapy had the strongest effects in activating effector and cytotoxic CD8 + T cells. mNemvaleukin alone, and in combination with chemotherapy, promoted proinflammatory cytokine and chemokine production, which was further confirmed by transcriptomic analysis. Conclusions: mNemvaleukin, a novel cytokine-based immunotherapy, significantly inhibited murine SCLC tumor growth and prolonged survival, which was further enhanced by the addition of chemotherapy. mNemvaleukin alone, and in combination with chemotherapy, drove a strong antitumor immune program elicited by cytotoxic immune cells. Our findings support the evaluation of nemvaleukin alone or in combination with chemotherapy in clinical trials for the treatment of SCLC.
Original language | English (US) |
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Article number | e004913 |
Journal | Journal for immunotherapy of cancer |
Volume | 10 |
Issue number | 9 |
DOIs | |
State | Published - Sep 8 2022 |
Funding
The authors thank Alkermes for funding support and also the members of the Wong laborartory for their experimental support and insightful discussion. HCL, JEL, and RJW are current employees of and hold stock in Alkermes. Research performed at New York University Grossman School of Medicine in the laboratory of KKW was funded by Alkermes. KKW is a founder and equity holder of G1 Therapeutics and has sponsored research agreements with MedImmune, Takeda, TargImmune, Bristol-Myers Squibb (BMS), Mirati, Merus, and Alkermes, and consulting and sponsored research agreements with AstraZeneca, Janssen, Pfizer, Novartis, Merck, Ono, and Array. VV has advisory/consult role at Genentech, Merck, BMS, AstraZeneca, Foundation Medicine, Nektar Therapeutics, Alkermes, Reddy labs, and Millennium Pharma.
Keywords
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cytokines
- Lung Neoplasms
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Molecular Medicine
- Oncology
- Pharmacology
- Cancer Research