ALT-803 is a fusion protein complex consisting of an interleukin (IL)-15 superagonist and a dimeric IL-15 receptor alpha sushi domain IgG1 Fc fusion protein. When administered to mice, ALT-803 is capable of inducing natural killer (NK) and CD8 T cell proliferation and activation, and effectively promoting potent anti-tumor responses. Currently, ALT-803 is in clinical trials for treatment of various solid tumors and hematological malignancies. In the initial phase of these clinical studies, intravenous (iv) injection was used according to the route used in pre-clinical efficacy studies. In order to evaluate the possible advantage of subcutaneous (sc) injection versus iv injection, this study compared the biological activity of the two treatment regimens of ALT-803 in pre-clinical in vivo models. The pharmacokinetics, immune stimulation, and anti-tumor efficacy of iv and sc injection routes of ALT-803 in C57BL/6 mice were compared. The half-life of ALT-803 was 7.5 h for iv versus 7.7 h for sc with the maximal detected serum concentration of ALT-803 to be 3926 ng/ml at 0.5 h time-point following iv injection versus 495 ng/ml at 16 h post sc injection. Biodistribution studies indicated that sc ALT-803, similarly to iv ALT-803 as previously reported, has a greater tissue distribution and longer residence time in lymphoid tissues compared to recombinant IL-15. Notably, ALT-803 when administered either iv or sc induced comparable proliferation and activation of CD8 T and NK cells and resulted in similar reductions of tumor burden. A toxicity study of mice receiving multiple injections of ALT-803 for 4 weeks by iv or sc routes revealed equivalent immune-related changes. The gradual absorbance into the blood stream and lower maximal blood levels of ALT-803 in sc-injected mice, along with similar anti-tumor efficacy support the administration of ALT-803 by sc injection in patients with various malignancies and infectious diseases.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916319 | PMC |
| http://dx.doi.org/10.1016/j.cyto.2017.12.003 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
N-803, an IL-15 Superagonist Complex as Maintenance Therapy After Allogeneic Donor Stem Cell Transplant for Acute Myeloid Leukemia or Myelodysplastic Syndrome; A Phase 2 Trial.
Transplant Cell Ther
December 2024
Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
Article Synopsis
- * In a Phase 2 trial with 20 patients in complete remission, N-803 was administered subcutaneously at day 60 after transplant, leading to enhanced NK cell proliferation and antitumor responses without causing significant immune exhaustion.
- * Patients receiving more than 4 doses of N-803 experienced a significant decrease in relapse rates over two years, supporting its safety and potential efficacy for preventing relapse in AML and MDS after hematopoietic stem cell transplant.
Induction of durable remission by dual immunotherapy in SHIV-infected ART-suppressed macaques.
Science
March 2024
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Article Synopsis
- The study focuses on overcoming the challenge of eradicating the viral reservoir to find a clinical cure for HIV-1 by using a combination of N-803 and broadly neutralizing antibodies (bNAbs) in rhesus macaques that were previously treated with antiretroviral therapy (ART).
- Researchers found that while the treatment induced some immune activation and transient viral levels, it did not significantly lower the viral reservoir. However, about 70% of treated macaques achieved sustained control of the virus after stopping ART.
- The success of viral control was linked to changes in CD8 T cells induced by the combination treatment, suggesting that eliminating the viral reservoir may not be necessary for long-term remission
Quality of Life in the Phase 2/3 Trial of N-803 Plus Bacillus Calmette-Guérin in Bacillus Calmette-Guérin‒Unresponsive Nonmuscle-Invasive Bladder Cancer.
Urol Pract
March 2024
ImmunityBio, Inc, Culver City, California.
Article Synopsis
- In the phase 2/3 QUILT-3.032 study, the combination of the IL-15RαFc superagonist N-803 and BCG effectively achieved durable complete responses in patients with nonmuscle-invasive bladder cancer that did not respond to BCG alone.
- Patient-reported outcomes were assessed through standardized questionnaires at multiple time points, revealing relatively stable scores in physical function and global health throughout the study period.
- The findings suggest that the treatment not only shows efficacy but also indicates a favorable risk-benefit ratio and maintained quality of life for the patients involved.
IL-15 and N-803 for HIV Cure Approaches.
Viruses
September 2023
Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC 20037, USA.
In spite of the advances in antiretroviral therapy to treat HIV infection, the presence of a latent reservoir of HIV-infected cells represents the largest barrier towards finding a cure. Among the different strategies being pursued to eliminate or reduce this latent reservoir, the γc-cytokine IL-15 or its superagonist N-803 are currently under clinical investigation, either alone or with other interventions. They have been shown to reactivate latent HIV and enhance immune effector function, both of which are potentially required for effective reduction of latent reservoirs.
View Article and Find Full Text PDFALT-803 in the treatment of non-muscle-invasive bladder cancer: Preclinical and clinical evidence and translational potential.
Front Immunol
November 2022
Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong, China.
Bladder cancer (BCa) is one of the most common malignant tumors that cause death. Approximately 75%-85% of BCa develop into non-muscle-invasive bladder cancer (NMIBC). Bacillus Calmette-Guérin (BCG) is the gold standard for avoiding cystectomy in the treatment of NMIBC.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!