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1046 A long-acting and Beta-intensified IL-2 analog, HM16390, significantly alters tumors to an immune favorable environment to potentiate PD-1 blockade
  1. Jaehyuk Choi,
  2. Jinyoung Kim,
  3. Seongju Jeong,
  4. Yuyon Kim,
  5. Sang Hyun Park,
  6. Sungmin Bae,
  7. Daejin Kim and
  8. In Young Choi
  1. Hanmi Pharm. Co., Ltd, Hwaseong-si, Gyeonggi-do, Republic of Korea
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Anti-PD-1 is most widely used immune checkpoint inhibitors (CPIs) in cancer immunotherapy. However, the response to CPIs depends on the phenotype of the tumor microenvironment (TME). Cold tumor, also known as immune-excluded or -desert tumors, have shown a poor response to PD-1 blockers due to an absence of effector T cells in the TME. Here, we investigated the tumor-infiltrating immune cells composition after HM16390 treatment and the synergistic activity after combination with anti-PD1 in poorly immunogenic tumor syngeneic mice model.

Methods B16F10 mice were sacrificed on days 1, 3, and 8 after a single subcutaneous administration of HM16390 or 5 consecutive days via intraperitoneal injections of aldesleukin. The tumor-infiltrating immune cell profile including CD8+ T cells and regulatory T cells (Treg) was assessed by flow cytometry as well as immunofluorescence staining. To investigate synergistic anti-tumor effect in combination with anti-PD1, B16F10 mice were repeatedly given once a week of HM16390 or 5 consecutive days per week of aldesleukin with or without twice a week of anti-PD-1, and tumor growth and survival were monitored up to 49 days.

Results The tumor-infiltrating CD8+/Treg ratio was upregulated by approximately 74 by treatment with HM16390, whereas it was only 6.1 in the aldesleukin-treated group on day 8. The Ki-67 expression was significantly upregulated on tumor-infiltrating CD8+ T cells following HM16390 treatment. Interestingly, while aldesleukin significantly upregulated Ki-67 expression on Tregscompared to the vehicle, HM16390 did not induce Ki-67 expression on Tregs during the observation period. Significantly increased pro-inflammatory molecules such as GrzB and IFN-γ were also observed in the HM16390-treated group compared to aldesleukin (p<0.01 and p<0.001, respectively). Next, we investigated synergistic anti-tumor effects in combination with anti-PD-1 in B16F10 mice. After four weeks of treatment, 25% of the B16F10 mice showed a complete response to treatment with HM16390, and this increased significantly to 88% when combined with anti-PD1. However, none of the mice showed a complete response to treatment with the aldesleukin/anti-PD1 combination. The median overall survival with aldesleukin alone was 22.5 days and increased to 34.5 days when combined with anti-PD-1. HM16390 monotherapy showed similar results to the aldesleukin combination group (37.5 days), and all animals survived up to the end of the study in combination with anti-PD1.

Conclusions HM16390 efficiently inhibited tumor growth and prolonged survival rate through the significant increase of tumor-infiltrating cytotoxic lymphocytes. This favorable immune alteration in tumors by HM16390 potentiates anti-tumor effect of PD-1 blockade.

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