Innovative Immunotherapy for HER2-Positive Breast Cancer: Harnessing Engineered B Cells

Background

Breast cancer, particularly the subtype overexpressing the HER2 gene, presents a significant unmet medical need due to severe therapeutic challenges. Roughly 15-20% of all breast cancer cases exhibit overexpression or amplification of HER2, a tyrosine kinase receptor. Current treatments using monoclonal antibodies (MoAbs) and antibody-drug conjugates (ADCs) targeting HER2 have improved outcomes, yet metastatic HER2-positive breast cancer still poses an almost incurable condition. Treatment limits stem from therapeutic resistance due to acquired mutations, alongside ineffective tumor microenvironment (TME) interaction. While T cell-based adoptive immunotherapy offers potential, its use has been curtailed by severe safety concerns such as cytokine release syndrome (CRS).

Technology Overview

This invention involves engineering B cells to target HER2 antigens, creating a novel approach to cellular adoptive immunotherapy. The technology employs CRISPR/Cas9-mediated gene editing to integrate trastuzumab’s antigen-binding fragment (Fab) into the endogenous B cell receptor (BCR), enabling these cells to recognize and attack HER2-positive cancer cells. Unlike current options, this method not only leverages the established efficacy of monoclonal antibodies but also introduces local antitumor activity, minimizing systemic toxicity.

Initial proof-of-concept studies suggest that engineered B cells may effectively infiltrate tumors, activate local T cell responses, and reduce metastatic disease burdens:

• Design and Functionality: Engineered B cells were constructed using CRISPR/Cas9 technology to incorporate HER2-specific Fab from trastuzumab. Specificity and activation were confirmed through binding assays and cytokine production, demonstrating direct targeting and killing of HER2-positive cancer cells.
• Animal Models: In HER2-positive tumor-bearing mouse models, these engineered B cells showed effective tumor infiltration and engagement, leading to reduced tumor size and indication of extended survival rates.
• Safety and Immune Response: Studies highlighted a favorable safety profile with minimal adverse systemic effects and activated secondary immune responses, enhancing overall antitumor effects.

Applications

1. Cancer Immunotherapy: Specifically targeting HER2-positive breast cancer.
2. Combination Cancer Treatment: Use alongside chemotherapy or other immunotherapeutic agents.
3. Diagnostic Tools: As a method of enhancing tumor response assessment.

Advantages

• Targeted Action: Precisely directed toward HER2 antigens, providing specificity unattainable by conventional therapies.
• Reduced Toxicity: Decreased risk of cytokine release syndrome due to controlled B cell activation.
• Broad Applicability: Potential use in various solid tumors beyond breast cancer.
• Enhanced Immune Response: By facilitating T cell activation, offers a dual-action attack on cancer cells.