NT-I7 Boosts CAR T-Cell Expansion, Persistence, and Anti-Tumor Activity in Preclinical Study

A multisite phase 1 clinical trial for NT-I7 is underway in patients with relapsed/refractory large B-cell lymphoma.

A long-acting human IL-7, NT-I7, fused with hybrid Fc (rhIL-7-hyFc) was shown to enhance the proliferation, persistence, and cytotoxicity of human CAR T cells in xenogeneic mouse models and murine CAR T cells in syngeneic mouse models, leading to long-term tumor-free survival, according to results from a preclinical study recently published in Nature Communications.1 These results indicate that NT-17, which is being developed by NeoImmuneTech, could prove useful in improving suboptimal CAR T-cell activity.

In murine models of both acute myeloid leukemia and B-cell lymphoma, NT-17 significantly prolonged survival by enhancing the efficacy of CAR-T therapy. Additionally, NT-17 allowed for a 5-fold reduction in the number of CAR T-cells needed at the time of infusion to prolong survival.2

“Enhancement of CAR T cell activity has the potential to improve patient outcomes by reducing target positive relapse in patients with CD19+ B cell malignancies,” the investigators wrote.1

The study utilized sophisticated mouse models of B-cell lymphoma and acute myeloid leukemia and an immune competent syngeneic mouse model of acute promyelocytic leukemia.2 NT-17 was shown to protect CD19-targeting CAR –T-cells from cell death, which promoted their proliferation in the presence of CD19+ tumor cells. While CAR T-cells that expanded in the presence of NT-I7 were less differentiated, it was noted that they possessed equivalent effector cytokine secreting abilities.2

“Importantly, we did not see any evidence of toxicity with the combination of mCART19 and rhIL-7-hyFc in the immunocompetent mice,” the investigators noted.1 “Additionally, murine CAR T-cell numbers in immunocompetent mice did not reach the astronomical levels seen with human CAR T-cells in NSG mice after rhIL-7-hyFc. The NSG model provides proof of principle that this reagent is effective on human CAR T-cells in vivo, but the lack of endogenous lymphocytes in these mice is likely responsible for the massive expansion of CAR T-cells, and in human subjects, the kinetics of CAR T-cell expansion is expected to be more akin what was seen in the immunocompetent mice.”

Se Hwan Yang, PhD, president and chief executive officer of NeoImmuneTech, Inc., said in a statement, “Those results demonstrate the broad applicability of NT-I7 for cellular therapy, in addition to its well-documented benefits as a long-acting human IL-7 that has the potential to amplify T cells across the subsets, boost the immune system, and enhance the anti-tumor response in people with hematologic malignancies and solid tumors.”2

A multisite phase 1b clinical trial (NCT05075603) is currently underway to pursue the results of this study further, and will investigate NT-I7 with CD19-targeting CAR T-cells for the treatment of relapsed/refractory large B-cell lymphomas. NT-I7 will be administered via intramuscular injection following tisagenlecleucel (tisa-cel; Kymriah, Novartis) infusion. Primary outcome measures include safety and tolerability with end points such as incidence, nature, and severity of adverse events and the maximum tolerated dose. Secondary outcome measures include preliminary anti-tumor activity of NT-I7 with end points such as overall response rate, duration of response, progression-free survival, and overall survival.

REFERENCES
1. Kim MY, Jayasinghe R, Devenport JM, et al. A long-acting interleukin-7, rhIL-7-hyFc, enhances CAR T cell expansion, persistence, and anti-tumor activity. Nature Communications. 2022; 13(3296). doi:10.1038/s41467-022-30860-0
2. A study in Nature Communications reports that NeoImmuneTech's NT-I7 enhances CAR-T cell expansion, persistence and anti-tumor activity. News release. NeoImmuneTech, Inc. June 14, 2022. https://www.prnewswire.com/news-releases/a-study-in-nature-communications-reports-that-neoimmunetechs-nt-i7-enhances-car-t-cell-expansion-persistence-and-anti-tumor-activity-301567985.html