Neoadjuvant CD40 Agonism Remodels the Tumor Immune Microenvironment in Locally Advanced Esophageal/Gastroesophageal Junction Cancer

Author:

Soto Maira12ORCID,Filbert Erin L.2ORCID,Yang Hai34ORCID,Starzinski Stephanie34ORCID,Starzinski Alec34ORCID,Gin Marissa34ORCID,Chen Brandon34ORCID,Le Phi34ORCID,Li Tony34ORCID,Bol Brandon34ORCID,Cheung Alexander34ORCID,Zhang Li3456ORCID,Hsu Frank J.12ORCID,Ko Andrew346ORCID,Fong Lawrence346ORCID,Keenan Bridget P.346ORCID

Affiliation:

1. 1Pyxis Oncology, Inc., Boston, Massachusetts.

2. 2Apexigen America, Inc, San Carlos, California (now a fully owned subsidiary of Pyxis Oncology, Inc.).

3. 3Cancer Immunotherapy Program, University of California, San Francisco, California.

4. 4Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.

5. 5Department of Epidemiology and Biostatistics, University of California, San Francisco, California.

6. 6Division of Hematology/Oncology, University of California, San Francisco, California.

Abstract

Abstract Sotigalimab is an agonistic anti-CD40 mAb that can modulate antitumor immune responses. In a phase II clinical trial of sotigalimab combined with neoadjuvant chemoradiation (CRT) in locally advanced esophageal/gastroesophageal junction (E/GEJ) cancer with the primary outcome of efficacy as measured by pathologic complete response (pCR) rate, the combination induced pCR in 38% of treated patients. We investigated the mechanism of action of sotigalimab in samples obtained from this clinical trial. Tumor biopsies and peripheral blood samples were collected at baseline, following an initial dose of sotigalimab, and at the time of surgery after CRT completion from six patients. High dimensional single-cell techniques were used, including combined single-cell RNA-sequencing and proteomics (CITEseq) and multiplexed ion beam imaging, to analyze immune responses. Sotigalimab dramatically remodeled the immune compartment in the periphery and within the tumor microenvironment (TME), increasing expression of molecules related to antigen processing and presentation and altering metabolic pathways in myeloid cells. Concomitant with these changes in myeloid cells, sotigalimab treatment primed new T cell clonotypes and increased the density and activation of T cells with enhanced cytotoxic function. Sotigalimab treatment also induced a decrease in the frequency of Tregs in the TME. These findings indicate that a single dose of sotigalimab leads to enhanced antigen presentation that can activate T cells and induce new T cell clones. This restructuring of the TME provides elements which are critical to the development of effective antitumor immune responses and improved clinical outcomes.

Funder

HHS | NIH | National Cancer Institute

Apexigen America, Inc.

UC | UCSF | Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco

HHS | NIH | U.S. National Library of Medicine

Publisher

American Association for Cancer Research (AACR)

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