A Permanent Cure? New Therapy Aims to Create a “Living Factory” of Cancer-Fighting T Cells.
LOS ANGELES, CA — In a major step forward for cancer immunotherapy, a new clinical trial has successfully demonstrated a novel approach that uses genetically engineered hematopoietic stem cells (HSCs) to create a persistent, self-renewing supply of tumor-fighting T cells in human patients with advanced solid tumors. The “tandem” cell therapy directly addresses a critical challenge of current immunotherapies: the lack of long-term persistence and functionality of the transferred T cells, which often leads to patient relapse.
The groundbreaking study, published in Nature Communications, was led by a team of researchers at the University of California, Los Angeles (UCLA), and is registered under ClinicalTrials.gov identifier NCT03240861.
The Tandem Approach: A Continuous Supply of Immune Fighters
The novel protocol was designed to overcome the limitations of traditional adoptive cell transfer (ACT) therapies, which often lose efficacy as the infused T cells undergo terminal differentiation and exhaustion in the body. The tandem therapy sequence was as follows:
- Initial T-cell infusion: Patients first received an infusion of their own peripheral blood mononuclear cells (PBMCs), which were transduced with a retroviral vector encoding the NY-ESO-1 T-cell receptor (TCR). This initial dose is intended to provide an immediate anti-tumor effect.
- Stem Cell ‘Factory’: Next, patients received an infusion of their own hematopoietic stem cells (HSCs), engineered with a lentiviral vector carrying the same NY-ESO-1 TCR. Unlike retroviral vectors, lentiviral vectors can efficiently transduce quiescent and non-dividing cells like HSCs, providing a stable, long-term source of gene expression. This process aims to create an “internal immune factory” that can produce new, cancer-hunting T cells for months, if not years, after treatment.
The engineered HSCs were also equipped with a modified herpes simplex virus gene, sr39TK. This gene served a dual purpose: it acted as a non-invasive tracking marker for imaging the cells’ engraftment in the bone marrow using a specialized PET tracer, [18F]-FHBG, and also as a safety “suicide gene” to eliminate the cells in the event of unanticipated toxicity. This is the first time this reporter/suicide gene system has been successfully utilized to monitor engineered HSCs in human subjects.
Promising Clinical Outcomes and Key Findings
The pilot trial was small and its primary goal was to assess safety and feasibility. It enrolled five patients with relapsed or refractory metastatic solid tumors expressing the NY-ESO-1 antigen. Three patients ultimately received both infusions. The results were encouraging:
- Safety and Feasibility: The administration of both the retroviral transgenic TCR-T cells and the lentiviral transgenic TCR HSCs was deemed safe and feasible, with no grade 3 or greater adverse events attributed to the engineered HSCs.
- Antitumor Activity: The therapy led to initial tumor regression activity. Two of the three patients who received the full treatment (NYSCT-03 and NYSCT-05) demonstrated a reduced tumor size.
- Functional T-cell Progeny: The T cell progeny from the engineered HSCs were shown to provide circulating transgenic NY-ESO-1 TCR-T cells. These cells displayed tumor-antigen-specific anti-tumor functionality without any evidence of anergy or exhaustion.
- Engraftment Confirmed: PET scans successfully visualized the engraftment of the transgenic HSCs, and the persistence of lentiviral-derived T cells in the bloodstream correlated with the imaging findings.
The study’s findings, particularly in patient NYSCT-03, who showed a positive clinical response, demonstrated that T cell progeny from the engineered HSCs successfully engrafted and continued to expand after the initial T-cell infusion had declined. Single nuclei sequencing from this patient confirmed that a substantial fraction of circulating nucleated cells contained lentiviral signatures (46.9%) and represented a diverse range of myeloid and lymphoid cell types.
Challenges and Future Implications
The study, which took over a decade of laboratory development, is not without its challenges. The medical fragility of patients with advanced sarcoma and the logistical burden of the treatment, including multiple leukapheresis procedures and an extended manufacturing timeline, limited its broader application. The death of one patient (NYSCT-03) due to an opportunistic cytomegalovirus (CMV) infection during their immunologic reconstitution also highlights the risks inherent to the approach.
However, the researchers are optimistic about the future of this therapeutic modality. The successful generation of functional, tumor-targeted T cells from engineered HSCs opens the door for a new generation of immunotherapies. This approach could be expanded to target other diseases, such as HIV-1, or to generate other types of immune cells, like CAR-T cells, from a similar self-renewing source. The study’s findings provide a crucial proof-of-concept for a new generation of immunotherapies designed for sustained, long-term disease control. As Dr. Antoni Ribas noted, it took a team of more than 30 dedicated academic researchers and over a decade to bring this concept to patients.
References
- Nowicki, T.S., Naser Al Deen, N., Peters, C.W., et al. (2025) ‘Human cancer-targeted immunity via transgenic hematopoietic stem cell progeny’, Nature Communications, 16(5599).
