Contributions
Abstract: PS1208
Type: Poster Pitch
Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00
Location: Poster area
Background
Immunotherapy with CD19 CAR T cells achieves complete or partial remission in a fraction of patients with B cell malignancies, but disease progression remains common. IL-15 promotes T cell proliferation and survival and may enhance CAR T cell efficacy. However, exploiting native IL-15 is challenging due to its unfavorable pharmacokinetics and tolerability. In contrast, NKTR-255 is a polymer-conjugated IL-15 that retains binding affinity to IL15Rα and exhibits reduced clearance, providing sustained pharmacodynamic responses.
Aims
We investigated the effects of NKTR-255 on human CD19 CAR T cells both in vitro and in an in vivo xenogeneic B cell lymphoma model.
Methods
T cells expressing a CD19/4-1BB/CD3ζ CAR were generated from healthy donors. For in vitro studies, CAR T cells were incubated with NKTR-255 (0-100 ng/mL) with and without CD19 antigen. STAT5 phosphorylation and CFSE dilution were assessed by flow cytometry. For in vivo studies, NSG mice received 5x105 Raji lymphoma cells IV on day (D)-7 and a subtherapeutic dose (0.8x106) of CAR T cells (1:1 CD4:CD8) on D0. NKTR-255 (0.03-0.3mg/kg IV) was administered weekly starting on D-1, 7, or 14. Tumor-free mice were rechallenged with Raji cells. Tumors were assessed by bioluminescence imaging.
Results
In vitro, NKTR-255 led to dose-dependent STAT5 phosphorylation and increased antigen-dependent proliferation of CD8 CAR T cells. In vivo, infusion of NKTR-255 starting at D-1, 7 or 14 increased peak CAR T cell numbers in blood. Raji cells were eliminated from marrow by D14 in mice receiving CAR T cells and NKTR-255 on D7, but not CAR T cells alone. There was superior NKTR-255 dose-dependent tumor control and survival in mice receiving CAR T cells with NKTR-255 compared to CAR T cells or NKTR-255 alone. The benefit of combination therapy with NKTR-255 and CART T cells was greater when NKTR-255 was started by D7. Residual CAR T cells in NKTR-255-treated mice rejected re-challenge of Raji tumor cells administered beyond 5 weeks after CAR T cell infusion.
Conclusion
NKTR-255 administration improves the antitumor efficacy and kinetics of CD19 CAR T cells, supporting advancement into clinical trials of combination therapy with NKTR-255 and approved CD19 CAR T cell products.
Session topic: 24. Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Res
Keyword(s): Immunotherapy, Lymphoma
Abstract: PS1208
Type: Poster Pitch
Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00
Location: Poster area
Background
Immunotherapy with CD19 CAR T cells achieves complete or partial remission in a fraction of patients with B cell malignancies, but disease progression remains common. IL-15 promotes T cell proliferation and survival and may enhance CAR T cell efficacy. However, exploiting native IL-15 is challenging due to its unfavorable pharmacokinetics and tolerability. In contrast, NKTR-255 is a polymer-conjugated IL-15 that retains binding affinity to IL15Rα and exhibits reduced clearance, providing sustained pharmacodynamic responses.
Aims
We investigated the effects of NKTR-255 on human CD19 CAR T cells both in vitro and in an in vivo xenogeneic B cell lymphoma model.
Methods
T cells expressing a CD19/4-1BB/CD3ζ CAR were generated from healthy donors. For in vitro studies, CAR T cells were incubated with NKTR-255 (0-100 ng/mL) with and without CD19 antigen. STAT5 phosphorylation and CFSE dilution were assessed by flow cytometry. For in vivo studies, NSG mice received 5x105 Raji lymphoma cells IV on day (D)-7 and a subtherapeutic dose (0.8x106) of CAR T cells (1:1 CD4:CD8) on D0. NKTR-255 (0.03-0.3mg/kg IV) was administered weekly starting on D-1, 7, or 14. Tumor-free mice were rechallenged with Raji cells. Tumors were assessed by bioluminescence imaging.
Results
In vitro, NKTR-255 led to dose-dependent STAT5 phosphorylation and increased antigen-dependent proliferation of CD8 CAR T cells. In vivo, infusion of NKTR-255 starting at D-1, 7 or 14 increased peak CAR T cell numbers in blood. Raji cells were eliminated from marrow by D14 in mice receiving CAR T cells and NKTR-255 on D7, but not CAR T cells alone. There was superior NKTR-255 dose-dependent tumor control and survival in mice receiving CAR T cells with NKTR-255 compared to CAR T cells or NKTR-255 alone. The benefit of combination therapy with NKTR-255 and CART T cells was greater when NKTR-255 was started by D7. Residual CAR T cells in NKTR-255-treated mice rejected re-challenge of Raji tumor cells administered beyond 5 weeks after CAR T cell infusion.
Conclusion
NKTR-255 administration improves the antitumor efficacy and kinetics of CD19 CAR T cells, supporting advancement into clinical trials of combination therapy with NKTR-255 and approved CD19 CAR T cell products.
Session topic: 24. Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Res
Keyword(s): Immunotherapy, Lymphoma