Abstract 6677: Preliminary immune correlatives from BCA101 trial show favorable modulation of tumor immune microenvironment
Authors: Lizotte Patrick H. , Paik Paul , Niculescu Liviu , Tan Seng-Lai H. , Bohr David , Gharakhani Elham , Reiners Ralf , Salazar Rachel , Varshney Avanish , Krishn Shiv Ram , Nair Pradip , Paweletz Cloud 
Published: April 2023

Abstract
Background: BCA101 is a bispecific antibody targeting EGFR and TGF-β. TGF-β pathway activation is a hallmark of human immune-excluded tumors, and TGF-β expression is associated with resistance to anti-PD-1 blockade. Neutralization of TGF-β removes an immunosuppressive signal that drives accumulation and polarization of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in solid tumors, while EGFR inhibition targets tumor cell-intrinsic oncogenic signaling. Co-targeting of EGFR and TGF-β directly impacts tumor progression while enhancing the immunogenicity of tumors.
Methods: Patients with multiple solid tumor types (CRC, pancreatic, HNSCC, SqNSCLC, and others) were treated with escalating doses of either single agent BCA101 or in combination with anti-PD-1 (pembrolizumab) enrolled on NCT04429542 trial. We performed a variety of immune correlatives on pre- and on-treatment tumor biopsies, including Nanostring-based transcriptomic profiling and IHC for immunophenotypic markers, as well as multiparametric flow cytometric profiling of circulating PBMCs.
Results: Our preliminary evidence suggests that neutralization of TGF-β positively alters the systemic immune state (PBMCs) and tumor immune phenotype (mRNA, IHC). Circulating HLA-DR+ monocytes were significantly increased in on-treatment PBMC samples relative to screening. Pathway analysis of on-treatment tumor biopsies revealed enhanced costimulatory signaling, cytokine and chemokine signaling, immune infiltration, and interferon signaling. Top differentially regulated genes in on-treatment biopsies included CCL21, CXCL9, CXCL11, and CXCL13, which recruit T and NK cells. HDAC11, which negative regulates type-I interferon signaling, was significantly reduced in on-treatment biopsies. Notably, two patients with EGFR-amplified squamous non-small cell lung cancer, who both progressed on first-line immunotherapy treatment, were treated with BCA101 at 1250 mg and 1500 mg qw and achieved a partial response (ongoing for 10 months at the time of the data cutoff) and a prolonged stable disease for 11 months, respectively. They exhibited increased CD8+ T cell infiltration and a reduction in TAMs following treatment.
Conclusions: Increased abundance of circulating HLA-DR+ monocytes following treatment indicated polarization towards a more positive, Th1-like systemic immune state. We observed enhanced immunogenicity of tumors as assessed by a targeted IO transcriptomic analysis. The results of the pathway analysis were supported by IHC on post-treatment biopsies from a subsequent cohort showing enhanced CD8+ T cell infiltration and stable, or reduced expression of TAM marker CD163. These results indicate that neutralization of TGF-β induces a more permissive tumor immune microenvironment.
Citation Format: Patrick H. Lizotte, Paul Paik, Liviu Niculescu, Seng-Lai H. Tan, David Bohr, Elham Gharakhani, Ralf Reiners, Rachel Salazar, Avanish Varshney, Shiv Ram Krishn, Pradip Nair, Cloud Paweletz. Preliminary immune correlatives from BCA101 trial show favorable modulation of tumor immune microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6677.