A Novel B7-H6–Targeted IgG-Like T Cell–Engaging Antibody for the Treatment of Gastrointestinal Tumors

Abstract

Purpose: Advanced stage gastrointestinal cancers represent a high unmet need requiring new effective therapies. We investigated the anti-tumor activity of a novel T-cell engaging antibody (B7-H6/CD3 ITE) targeting B7-H6, a tumor-associated antigen that is expressed in gastrointestinal tumors. Experimental Design: Membrane proteomics and immunohistochemistry analysis identified B7-H6 as tumor- associated antigen in gastrointestinal tumor tissues with no to very little expression in normal tissues. The anti-tumor activity and mode of action of B7-H6/CD3 ITE was evaluated in in vitro co-culture assays, in humanized mouse tumor models, and in Colorectal Cancer Precision Cut Tumor Slice Cultures. Results: B7-H6 expression was detected in 98 % of colorectal, 77 % of gastric cancer, and 63 % of pancreatic cancer tissue samples. B7-H6/CD3 ITE-mediated redirection of T cells towards B7-H6-positive tumor cells resulted in B7-H6-dependent lysis of tumor cells, activation and proliferation of T cells, and cytokine secretion in in vitro co-culture assays, and infiltration of T cells into tumor tissues associated with tumor regression in in vivo CRC models. In primary patient-derived Colorectal Cancer Precision Cut Tumor Slice Cultures, treatment with B7-H6/CD3 ITE elicited cytokine secretion by endogenous tumor infiltrating immune cells. Combination with anti-PD-1 further enhanced the activity of the B7-H6/CD3 ITE. Conclusions: These data highlight the potential of the B7-H6/CD3 ITE to induce T-cell re-directed lysis of tumor cells and recruitment of T cells into non-inflamed tumor tissues leading to anti-tumor activity in in vitro, in vivo, and human tumor slice cultures which supports further evaluation in a clinical study.

Fatty acid metabolism is related to the immune microenvironment changes of gastric cancer and RGS2 is a new tumor biomarker

“…The liver is the most frequently affected organ by hematogenous metastases of gastric cancer tumors, after liver metastasis, the survival rate was only 20% ( 3 ) The development of neoadjuvant chemotherapy and immunotherapy for gastric cancer treatment in recent years has led to improvements in the diagnosis and prognosis of gastric cancer to a certain extent, yet further improvement is still necessary ( 4 ). To this end, new tumor markers, therapeutic targets, and treatment strategies need to be developed ( 5 ). Previous studies have shown that the occurrence, proliferation, and metastasis of tumors are closely related to their microenvironment.…”

The expression and function of theB7family inHelicobacter pyloriinfection and gastric carcinogenesis process

“…132 However, other studies showed B7-H6 expression was detected in 33/43 of GC cases (77%) and a novel T cell-engaging antibody (B7-H6/CD3 ITE) targeting B7-H6 induced T cell-redirected lysis of tumor cells and recruitment of T cells into noninflamed tumor tissues. 133 A significant correlation between B7-H6 expression levels and OS rate has been found. 62 Thus, additional studies are necessary for clarity on the effects of B7-H6 on GC.…”

“…Additionally, B7‐H6 expression was observed in only a few samples, indicating that it lacks utility as a prognostic marker for GC, and B7‐H6 expression did not influence the prognosis of patients with GC 132 . However, other studies showed B7‐H6 expression was detected in 33/43 of GC cases (77%) and a novel T cell–engaging antibody (B7‐H6/CD3 ITE) targeting B7‐H6 induced T cell–redirected lysis of tumor cells and recruitment of T cells into noninflamed tumor tissues 133 . A significant correlation between B7‐H6 expression levels and OS rate has been found 62 …”

“…120 Inversely associated with tumor progression. 122 B7-H6 (−) Expressed in GC cases (77%) 133 Targeting B7-H6 led to antitumor activity. 133 B7-H7 (−) Upregulated 142 Negative prognostic role.…”

Role of B7 family members in glioma: Promising new targets for tumor immunotherapy

“…6 Clinical meanings and functions of B7-H6 in gliomas B7 homolog 6 (B7-H6), also called NCR3LG1, is a kind of the immune checkpoints of the B7 family and plays the role of an endogenous/co-stimulatory ligand. This gene encodes a 454-aalong type I transmembrane protein of which the predicted molecular mass is 51 kDa (93). The B7-H6 extracellular region contains both an IgV-like and an IgC-like domain.…”