Preclinical Evaluation of Recombinant Human IL15 Protein Fused with Albumin Binding Domain on Anti-PD-L1 Immunotherapy Efficiency and Anti-Tumor Immunity in Colon Cancer and Melanoma

Abstract

Anti-PD-L1 antibody monotherapy shows limited efficacy in a significant proportion of the patients. A common explanation for the inefficacy is a lack of anti-tumor effector cells in the tumor microenvironment (TME). Recombinant human interleukin-15 (hIL15), a potent immune stimulant, has been investigated in clinical trial with encouraging results. However, hIL15 is constrained by the short half-life of hIL15 and a relatively unfavorable pharmacokinetics profile. We developed a recombinant fusion IL15 protein composed of human IL15 (hIL15) and albumin binding domain (hIL15-ABD) and explored the therapeutic efficacy and immune regulation of hIL-15, hIL15-ABD and/or combination with anti-PD-L1 on CT26 murine colon cancer (CC) and B16-F10 murine melanoma models. We demonstrated that hIL15-ABD has significant inhibitory effect on the CT26 and B16-F10 tumor growths as compared to hIL-15. hIL-15-ABD not only showed superior half-life and pharmacokinetics data than hIL-15, but also enhance anti-tumor efficacy of antibody against PD-L1 via suppressive effect on accumulation of Tregs and MDSCs and activation of NK and CD8+T cells. Immune suppressive factors including VEGF and IDO were also decreased by combination treatment. hIL15-ABD combined with anti-PD-L1 antibody increased the activity of anti-tumor effector cells involved in both innate and adaptive immunities, decreased the TME’s immunosuppressive cells, and showed greater anti-tumor effect than that of either monotherapy.

RETRACTED ARTICLE: Combination therapy with Nab-paclitaxel and the interleukin-15 fused with anti-human serum albumin nanobody as a synergistic treatment for colorectal cancer

“…A novel long-acting IL-15, including an anti-HSA nanobody and a human IL-15, were designed and prepared. Previous data demonstrated the similar in vitro activity and enhanced in vivo stability compared with wild type IL-15 [ 17 ]. In current study, we hypothesized that complementary strategies of combined chemotherapy and with immunotherapy may be effective against colon cancer.…”

“…Colon cancer is relatively resistant to chemotherapy or immunotherapy because the tumor is surrounded by an extracellular fibrotic barrier that is formed by collagen, fibronectin and hyaluronic acid, which prevents the delivery of sufficient chemodrugs and infiltration of the immune effector cells [ 22 , 23 ]. The lack of NK and CD8 + T cells within the TME characterizes colon cancer as a cold tumor so there may be a beneficial effect for immune stimulants that are combined with chemotherapy, so that is challenged by toxic drug becomes a hot tumor when it is infiltrated by active immune effector cells [ 17 , 24 ]. In addition to tumor cells, which are the major target of conventional anticancer therapy, stromal, endothelial and immune cells all play a critical role in the progression, survival and metastasis of tumor cells [ 13 ].…”

“…After 7-day, the mice were assigned into 4 groups: a vehicle control (n = 5), Nab-paclitaxel (300 μg, n = 6), IL-15 fusion protein (10 μg, n = 6) and combined treatment of Nab-paclitaxel and IL-15 fusion protein (n = 6), when the tumor grow to about 110 mm 3 . Tumor volume was assessed via a caliper and calculated as follows: Tumor volume = tumor length × tumor width 2 × 0.523 [ 17 ].…”

“…IL-15 is a potent immune stimulator that is critical for the proliferation and activation of NK and CD8 + T cells [ 17 ]. By acting on T cells, IL-15 stimulates their proliferation and allows them to secrete cytokines that kill tumor cells, such as IFN-γ and TNF-α, which show a variety of biological activities and exert their antitumor effects, making ‘cold’ tumors ‘hot’ [ 17 ]. A novel long-acting IL-15, including an anti-HSA nanobody and a human IL-15, were designed and prepared.…”

Cancer Immunology and Immunotherapies: Mechanisms That Affect Antitumor Immune Response and Treatment Resistance

“…Their modified CAR T cells are better directed to kill malignant B-cells, while sparing the CD19 + HLA-C1 + healthy B Cells. The next study by Hsu et al [ 17 ] developed a recombinant fusion IL15 protein composed of human IL15 (hIL15) and albumin-binding domain (hIL15-ABD) which has been successfully tested with anti-PD-L1 on CT26 murine colon cancer and B16-F10 murine melanoma models. Horn et al [ 18 ] also reported on the use of IL15 as an agonist adjuvant for other cancer immunotherapies.…”