Table 2.
Preclinical studies of IL-15 IN combination immunotherapy and cancer.
| IL-15 agent | Combination agent | Study | Best response to IL-15 | Reference |
|---|---|---|---|---|
| rhIL-15 | Rituximab | Mouse graft EL4 transfected with human CD20 | Prolongation of survival increase in ADCC | Zhang et al. (62) National Cancer Institute, NIH |
| rhIL-15 | Alemtuzumab | Mouse xenograft with ATL cell line | Prolongation of survival increase in ADCC | Zhang et al. (62) National Cancer Institute, NIH |
| RLI | HCT human colon carcinoma B16F10 | NK mediated reduce tumor growth overcoming limited effect of IL-15 | Bessard et al. (60) | |
| RLI anti-GD2 | SC EL4, metastatic N x S2 Neuroblastoma | Better murine survival than anti-G2D or RLI alone | Vincent et al. (61) | |
| RLI anti-CD20 | Human B cell lymphoma in SCID mice | Prolonged survival of mice beyond that of RLI or anti-CD20 alone | Vincent et al. (55) | |
| rhIL-15 | Cetuximab | Triple negative breast cancer cell line EGFR expression Hbbr with KRAS mutation 50:1 effector target | Increase in TBMC, ADCC against cell lines from 28 to 34% without IL-15 to 71% with this increase in NK expression and activation of receptors | Roberti et al. (63) Centro de Investigaciones Oncológicas, Buenos Aires, Argentina |
| ALT-803 | Anti-CD20 | Primary human B cell lymphoma and B cell lines. Two human NK xenografts in NOD/SCID mice | Significant increase in degranulation, IFNα production, decrease in tumor cells, and ADCC by human NK cells against B cell lymphoma. Increase mouse survival. | Rosario et al. (64) Johns Hopkins Medicine, Baltimore, Maryland |
| IL-15 | Rituximab | CLL cells γc−/− mice | Enhanced cytotoxicity against CLL cells with overcome TGFβ mediated immunosuppression. | Moga et al. (65) Department of Immunology Hospital Santa Creu i Sant Pau, Barcelona, Spain |
| ALT-803 fused to Rituximab 2B8T2M | B-cell lymphoma cells xenograft to SCID/NOD mice | 2B8T2M better cytokines, better survival of mice with xenografts better depletion of B cells in monkeys. | Liu et al. (66) Alto BioScience Corp, Miramar, Florida | |
| rhIL-15 0.25 mcg/day daily 5x/week for 4 weeks | Anti-CD40 | TRAMP-C2 graft in mice | Prolongation of survival of mice with xenograft. Development of tumor specific CD8 T cells. | Zhang et al. (67, 68) National Cancer Institute, NIH |
| ALT-803 | Anti-gp75, TA99 anti-PD-L1 | Mice bearing B16F10 | Prolong survival through activation of NK cells and expansion of CD8+CD44high T cells. Addition of anti-PD-L1 further increases antitumor activity. | Chen et al. (56) University of South Carolina Medical School |
| TriKE bispecific NK cell engaged against CD16 modified IL-15 crosslinker. | Cr51 release degranulation vs. carcinoma cell lines. | TriKE with IL-15 when compared to BiKE without IL-15 showed enhanced ADCC with improved activation and survival of NK cells. | Schmohl et al. (58) University of Minnesota Medical School | |
| rhIL-15 | Anti-CTLA-4 Anti-PD-L1 | Mouse TRAMP-C2 prostate, CT26 colon carcinoma models. | Simultaneous inhibition of two regulatory 7-cell inhibitory checkpoints enhanced IL-15 efficacy in murine tumor models. | Yu et al. (69, 70) National Cancer Institute, NIH |
| IL-15 sIL-15Rα/Fc | Anti-PD-1 | HT-29 xenograft in NOD/SCID mice. | Tumor growth inhibition. | Zhao et al. (71) Shanghai University |
| IL-15/IL-15Rα armed oncolytic virus | Anti-PD-1 | MC38 colon mouse carcinoma or ID8 ovarian cancer models. | CD8 T cell mediated by IL-15 armed oncolytic virus. Antitumor immunity was dramatically improved by addition of anti-PD-1 | Kowalsky et al. (72) University of Pittsburgh School of Medicine |
| ALT-803 (N-803) | Anti-PD-L1 | 4TI Triple negative breast and MC38 colon tumor bearing mice | ALT-803 enhanced anti-PD-L1 antitumor efficacy by increasing CD8 T cell effector function. | Knudson et al. (73) National Cancer Institute, NIH |