Translational Research in NK Cell Engineering

In an interview with Targeted Oncology, Katy Rezvani, MD, PhD, vice president and head, Institute for Cell Therapy Innovation and Discovery, Department of Institute for Cell Therapy Innovation and Discovery, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the antitumor effectiveness of chimeric antigen receptor-natural killer (CAR-NK) cell therapy.

The research described is fundamentally rooted in science, emphasizing a rigorous, data-driven approach to advancing cellular immunotherapies, specifically using NK cells. A recent discovery tool has yielded a long list of potential targets: genes and regulators that appear to function as negative regulators of NK cell function. This suggests that inhibiting or removing these elements could enhance the cells' anticancer capabilities.

The immediate and necessary next step is the validation of each target. This involves a systematic, one-by-one approach to confirm the initial findings. Researchers must employ precise genetic engineering techniques, such as CRISPR gene editing, to specifically target these identified genes. The goal is to demonstrate that, upon targeting, the NK cells acquire greater fitness and greater potency.

However, potency cannot come at the expense of safety. A critical component of the validation process is ensuring that the enhanced NK cells do not acquire adverse characteristics that could lead to clinical safety concerns. These concerns include, but aren't limited to, uncontrolled proliferation (a hallmark of cancer itself) or the induction of a severe systemic inflammatory response, such as cytokine release syndrome (CRS). This extensive testing must occur both in vitro (in tissue culture) and in vivo (using relevant mouse models) to fully assess the cells' behavior in a complex biological environment.

Beyond safety, specificity of the gene editing is paramount. It is crucial to confirm that the targeting is highly precise, ensuring that there is no off-target editing. Off-target modifications, where the CRISPR system edits unintended DNA sequences, could have unpredictable and potentially harmful consequences. The most important concern throughout this early research is to ascertain the safety of the entire therapeutic approach before moving forward.

Once these new targets are thoroughly validated for both efficacy and safety, the long-term plan would be to translate these strategies to the clinic. The team is already experienced in this translational process, having successfully moved a first-generation CRISPR gene-edited NK cell therapy into a clinical trial.

In this existing trial, they targeted the receptor for TGF-beta, a highly immunosuppressive molecule frequently released by various cancers, including highly aggressive forms like glioblastoma and many other solid tumors. They utilized CRISPR gene editing to knock out the specific receptor. This modification prevents the tumor's immunosuppressive signal from dampening the NK cell response. They have already demonstrated successful on-target editing, confirmed the absence of off-target editing, infused the modified cells into patients, and demonstrated safety.

The next generation strategy is already being developed, which involves a multi-pronged approach: combining CAR engineering (to give NK cells a tumor-specific homing mechanism) and cytokine engineering (to enhance survival and activity) together with the TGF-beta receptor gene editing. The ultimate goal is to apply this successful, comprehensive translational pipeline—from discovery tool to preclinical validation and clinical trial—to the new targets currently being discovered.

Watch more with Dr Rezvani.