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Updated: Jun 4, 2025
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
In Vivo Antitumor Activity of the PD-1/PD-L1 Inhibitor SCL-1 in Various Mouse Tumor Models
Tadashi Ashizawa1, Akira Iizuka1, Akari Kanematsu1
1Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.
Background/Aim:
Immune checkpoint blockade has achieved great success as a targeted immunotherapy for solid cancers. However, small molecules that inhibit programmed death 1/programmed death ligand 1 (PD-1/PD-L1) binding are still being developed and have several advantages, such as high bioavailability. Previously, we reported a novel PD-1/PD-L1-inhibiting small compound, SCL-1, which showed potent antitumor effects on PD-L1+ tumors. These effects were dependent on CD8+ T-cell infiltration and PD-L1 expression on tumors. The present study investigated the in vivo antitumor activity of SCL-1 in various mouse syngeneic tumor models.
Materials And Methods:
Twelve syngeneic mice models of tumors, such as colon, breast, bladder, kidney, pancreatic, non-small cell lung cancers, melanoma, and lymphomas, were used for in vivo experiments. Tumor mutation burden (TMB) was analyzed by whole exome sequencing (WES) using reference DNA from mouse blood. The proportion of CD8+ T-cells infiltrating tumors before and after treatment was assessed using flow cytometry and immunohistochemistry (IHC).
Results:
SCL-1 had a markedly greater antitumor effect (11 sensitive tumors and 1 resistant tumor among the 12 tumor types) than the anti-mouse PD-1 antibody (8 sensitive tumors and 4 resistant tumors). In addition, the tumor growth inhibition rate (%) was more closely associated with TMB in the SCL-1 group than in the anti-PD-1 antibody group. Furthermore, in vivo experiments using PD-L1 gene knockout and lymphocyte-depletion technologies demonstrated that the antitumor activity of SCL-1 was dependent on CD8+ T-cell infiltration and PD-L1 expression in tumors.
Conclusion:
SCL-1 has great potential as an oral immunotherapy that targets immune checkpoint molecules in cancer treatment.
Insights
The small molecule SCL-1 demonstrates potent antitumor activity in various mouse models, outperforming anti-PD-1 antibodies. Its efficacy relies on CD8+ T-cell infiltration and programmed death-ligand 1 (PD-L1) expression, highlighting its potential as an oral immunotherapy.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Immune checkpoint blockade is a successful cancer immunotherapy.
- Small molecule inhibitors of programmed death 1/programmed death ligand 1 (PD-1/PD-L1) offer advantages like high bioavailability.
- Previous studies identified SCL-1 as a novel PD-1/PD-L1 inhibitor with antitumor effects dependent on CD8+ T-cells and PD-L1 expression.
Purpose of the Study:
- To investigate the in vivo antitumor activity of the small molecule SCL-1.
- To compare the efficacy of SCL-1 with anti-mouse PD-1 antibody across various syngeneic tumor models.
- To elucidate the mechanisms underlying SCL-1's antitumor effects.
Main Methods:
- In vivo experiments were conducted on twelve syngeneic mouse tumor models.
- Tumor mutation burden (TMB) was analyzed using whole exome sequencing (WES).
- CD8+ T-cell infiltration was assessed via flow cytometry and immunohistochemistry (IHC).
Main Results:
- SCL-1 showed superior antitumor effects compared to anti-mouse PD-1 antibody, with 11 out of 12 tumor types responding.
- Tumor growth inhibition correlated more strongly with TMB in the SCL-1 group.
- Antitumor activity of SCL-1 was confirmed to be dependent on CD8+ T-cell infiltration and PD-L1 expression.
Conclusions:
- SCL-1 exhibits significant potential as an oral immunotherapy agent.
- SCL-1 effectively targets immune checkpoint molecules for cancer treatment.
- The findings support further development of SCL-1 for clinical application.
