Enhanced CTLA-4 blockade anti-tumor immunity with APG-157 combination in a murine head and neck cancer

Daniel Sanghoon Shin; Saroj Basak; Mysore S Veena; Begoña Comin-Anduix; Arjun Bhattacharya; Tien S Dong; Albert Ko; Philip Han; Jonathan Jacobs; Neda A Moatamed; Luis Avila; Matteo Pellegrini; Marilene Wang; Eri S Srivatsan

doi:10.1002/cam4.7212

Enhanced CTLA-4 blockade anti-tumor immunity with APG-157 combination in a murine head and neck cancer

Cancer Med. 2024 May;13(9):e7212. doi: 10.1002/cam4.7212.

Authors

Daniel Sanghoon Shin¹, Saroj Basak¹, Mysore S Veena¹, Begoña Comin-Anduix^{2

3

4}, Arjun Bhattacharya^{5

6}, Tien S Dong⁷, Albert Ko², Philip Han², Jonathan Jacobs⁷, Neda A Moatamed⁸, Luis Avila, Matteo Pellegrini^{5

6

9}, Marilene Wang¹⁰, Eri S Srivatsan¹¹

Affiliations

¹ Department of Medicine, Division of Hematology-Oncology, VAGLAHS/David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, California, USA.
² Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
³ Parker Institute for Cancer Immunotherapy, Los Angeles, California, USA.
⁴ Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California, USA.
⁵ Department of Chemistry and Biochemistry and the Institute for Quantitative and Computational Biology, UCLA, Los Angeles, California, USA.
⁶ Department of Louise M. Darling Biomedical Library and The Institute for Quantitative and Computational Biology, UCLA, Los Angeles, California, USA.
⁷ Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
⁸ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
⁹ Department of Molecular, Cellular and Developmental Biology, UCLA, Los Angeles, California, USA.
¹⁰ Department of Surgery, VAGLAHS and Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
¹¹ Department of Surgery, VAGLAHS/David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Abstract

Background: A phase I clinical study for patients with locally advanced H&N cancer with a new class of botanical drug APG-157 provided hints of potential synergy with immunotherapy. We sought to evaluate the efficacy of the combination of APG-157 and immune checkpoint inhibitors.

Methods: CCL23, UM-SCC1 (human), and SCCVII (HPV-), MEER (HPV+) (murine) H&N cancer cell lines were utilized for in vitro and in vivo studies. We measured tumor growth by treating the mice with APG-157, anti-PD-1, and anti-CTLA-4 antibody combinations (8 groups). The tumor microenvironments were assessed by multi-color flow cytometry, immunohistochemistry, and RNA-seq analysis. Fecal microbiome was analyzed by 16S rRNA sequence.

Results: Among the eight treatment groups, APG-157 + anti-CTLA-4 demonstrated the best tumor growth suppression (p = 0.0065 compared to the control), followed by anti-PD-1 + anti-CTLA-4 treatment group (p = 0.48 compared to the control). Immunophenotype showed over 30% of CD8+ T cells in APG-157 + anti-CTLA-4 group compared to 4%-5% of CD8+ T cells for the control group. Differential gene expression analysis revealed that APG-157 + anti-CTLA-4 group showed an enriched set of genes for inflammatory response and apoptotic signaling pathways. The fecal microbiome analysis showed a substantial difference of lactobacillus genus among groups, highest for APG-157 + anti-CTLA-4 treatment group. We were unable to perform correlative studies for MEER model as there was tumor growth suppression with all treatment conditions, except for the untreated control group.

Conclusions: The results indicate that APG-157 and immune checkpoint inhibitor combination treatment could potentially lead to improved tumor control.

Keywords: APG‐157; head and neck cancer; immune checkpoint inhibitors; microbiome; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
CTLA-4 Antigen* / antagonists & inhibitors
Cell Line, Tumor
Disease Models, Animal
Female
Head and Neck Neoplasms* / drug therapy
Head and Neck Neoplasms* / immunology
Head and Neck Neoplasms* / pathology
Humans
Immune Checkpoint Inhibitors* / pharmacology
Immune Checkpoint Inhibitors* / therapeutic use
Mice
Programmed Cell Death 1 Receptor / antagonists & inhibitors
Tumor Microenvironment* / drug effects
Tumor Microenvironment* / immunology

Substances

CTLA-4 Antigen
Immune Checkpoint Inhibitors
Programmed Cell Death 1 Receptor
Ctla4 protein, mouse

Grants and funding

I01 BX005588/BX/BLRD VA/United States