Next generation CAR T cells targeting HER2-positive tumors

Abstract

Despite significant advancements in anti-HER2 therapies in recent decades, primary or acquired resistances persist, along with associated adverse effects due to widespread HER2 expression in normal tissues, such as the heart or lungs. Therefore, the development of more effective and safer treatments for HER2-positive tumors, especially in advanced and metastatic stages, remains a significant unmet clinical need. Although redirecting T lymphocytes with bispecific antibodies (TCBs) or chimeric antigen receptors (CARs) has shown success in certain hematological cancers, its efficacy against solid tumors remains limited, partly due to the scarcity of tumor-specific antigens (TSAs). p95HER2, a truncated form of HER2 frequently expressed in tumors with HER2 overexpression, is a promising TSA for the development of targeted immunotherapies. This thesis presents the development of second-generation CAR T cells targeting p95HER2, which exhibited robust activity against p95HER2-expressing cell lines both in vitro and in vivo. However, efficacy against patient-derived xenografts (PDXs) was limited. To enhance their efficacy, we equipped these CAR T cells with bispecific T cell engagers targeting CD3 and HER2 (TECH2s), whose affinity was modulated to bind cells that overexpress HER2 but not those expressing normal levels of the protein. This strategy, known as "next-generation CAR T cells", named p95HER2.CAR-TECH2Me, demonstrated highly potent antitumor activity in p95HER2-/HER2-positive PDXs with no effect on cells expressing physiological levels of HER2, showcasing its potential as a safe and effective immunotherapeutic strategy against a subset of patients with HER2-positive tumors.

Date of Award	3 Apr 2024
Original language	English
Supervisor	Joaquin Vicente Arribas Lopez (Director)