Targeted T-cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial

Area of Science:

• Oncology
• Immunotherapy
• Cellular Therapy

Background:

• Metastatic breast cancer remains a significant challenge, necessitating novel therapeutic strategies.
• Immunotherapy offers a promising avenue for enhancing the body's own defense against cancer.

Purpose of the Study:

• To evaluate the safety, maximum tolerated dose (MTD), and feasibility of anti-CD3 × anti-HER2 bispecific antibody (HER2Bi) armed anti-CD3-activated T cells (ATC) in patients with metastatic breast cancer.
• To assess T-cell trafficking, immune responses, time to progression, and overall survival (OS) in a phase I immunotherapy trial.

Main Methods:

• A 3+3 dose escalation design was employed, administering infusions of HER2Bi-armed ATC combined with low-dose IL-2 and granulocyte-macrophage colony-stimulating factor.
• Patients received escalating doses of armed ATC (5, 10, 20, or 40 × 10^9 cells per infusion).
• Leukapheresis products were used to expand and arm ATC with HER2Bi for infusion.

Main Results:

• No dose-limiting toxicities were observed, and the MTD was not reached.
• Technical feasibility was confirmed, with the ability to generate large numbers of ATC (up to 160 × 10^9) from a single leukapheresis.
• Administered ATC persisted in circulation for weeks, trafficked to tumors, and induced anti-tumor immune responses, including increased immunokines and Th1 cytokines.
• Median OS was 36.2 months, with longer survival observed in HER2-positive patients (57.4 months).

Conclusions:

• HER2Bi-armed ATC infusions are safe and feasible, demonstrating the potential to induce anti-tumor responses and vaccinate patients against their tumors.
• The observed immune activation and promising survival data provide a strong rationale for advancing to phase II clinical trials.
• This approach holds promise for both HER2-positive and HER2-negative metastatic breast cancer.