Improving outcomes in patients' refractory to standard therapies: Dual-Mechanism to Mitigate Antigen Escape for Bridge-to-Transplant Immunotherapy

Abstract

Refractory patients who fail standard therapies have limited options, and NK92-, CD16+NK92-, and CAR-NK92–based approaches are being explored to prolong survival and serve as bridging therapy to transplantation. Because NK92 cells are infused after irradiation, their in vivo persistence and activity are short-lived. We will generate CD16-expressing NK92 cells to enhance cytotoxic potency and broaden applicability by enabling tumor-associated antigen (TAA)–directed, monoclonal antibody–dependent cellular cytotoxicity (ADCC). In parallel, we will engineer “ASSASSIN” cells (CD16+IL12+NK92) and introduce BCMA-specific CARs to create CAR ASSASSIN (CAR+CD16+IL12+NK92) cells capable of dual/bispecific killing via CAR recognition and CD16-driven ADCC. This combinatorial targeting is designed to reduce antigen-escape–mediated loss of efficacy, a key limitation of conventional CAR therapies. To promote more durable immune control despite the transient lifespan of irradiated NK92 cells, IL-12 secretion is incorporated to stimulate the host immune system, aiming to sustain antitumor activity after infused cells disappear. Overall, this study proposes a ready-to-use, IL-12–secreting NK92 platform that can be redirected to multiple tumor antigens within a bridging-therapy framework and may support the development of standardized, flexible, and clinically actionable treatment approaches for time-sensitive therapeutic settings.

Keywords: NK92, CD16, IL-12, BCMA CAR-NK92, Bridging Therapy

DOI: 10.54941/ahfe1007478