LIGHT enhanced bispecific antibody armed T-cells to treat immunotherapy resistant colon cancer.

Abstract

Increased tumor infiltrating lymphocytes (TIL) are associated with improved patient responses to immunotherapy. As a result, there is interest in enhancing lymphocyte trafficking particularly to colon cancers since the majority are checkpoint blockade-resistant and microsatellite stable. Here, we demonstrate that activated T-cells (ATC) armed with anti-CD3 x anti-EGFR bispecific antibody increases TIL and mediate anti-tumor cytotoxicity while decreasing tumor cell viability. Furthermore, treatment induces endogenous anti-tumor immunity that resisted tumor rechallenge and increased memory T-cell subsets in the tumor. When combined with targeted tumor expression of the tumor necrosis factor superfamily member LIGHT, activated T-cell proliferation and infiltration were further enhanced, and human colorectal tumor regressions were observed. Our data indicate that tumor-targeted armed bispecific antibody increases TIL trafficking and is a potentially potent strategy that can be paired with combination immunotherapy to battle microsatellite stable colon cancer. SIGNIFICANCE: Enhancing trafficking of tumor infiltrating lymphocytes (TILs) to solid tumors has been shown to improve outcomes. Unfortunately, few strategies have been successful in the clinical setting for solid tumors, particularly for "cold" microsatellite stable colon cancers. In order to address this gap in knowledge, this study combined TNFSF14/LIGHT immunomodulation with a bispecific antibody armed with activated T-cells targeted to the tumor. This unique T-cell trafficking strategy successfully generated anti-tumor immunity in a microsatellite stable colon cancer model, stimulated T-cell infiltration, and holds promise as a combination immunotherapy for treating advanced and metastatic colorectal cancer.

• Authors: Guilin Qiao, Lyonell B Kone, Evan H Phillips, Steve Seung-Young Lee, Grace E Brown, Salman R Khetani, Archana Thakur, Lawrence G Lum, Bellur S Prabhakar, Ajay V Maker
• Journal: Oncogene (Oncogene) Vol. 41 Issue 14 Pg. 2054-2068 (04 2022) ISSN: 1476-5594 [Electronic] England
• PMID: 35177811 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2022. The Author(s).

Chemical References

• Antibodies, Bispecific
• CD3 Complex

Topics

• Antibodies, Bispecific (pharmacology, therapeutic use)
• CD3 Complex
• Colonic Neoplasms (drug therapy)
• Humans
• Immunotherapy
• T-Lymphocytes