Armored for Victory: Reprogramming CAR T Cells Against Neuroblastoma

For children with high-risk neuroblastoma, survival rates remain below 50%, even after intensive therapy (1). AACR-funded studies are exploring innovative approaches to improve these outcomes. CAR T cell therapy has transformed treatment for hematological malignancies, but its success in solid tumors, such as neuroblastoma, has been far more elusive (2). While early-phase trials targeting GD2 and GPC2 molecules have shown promise, the immunosuppressive tumor microenvironment (TME) remains a formidable barrier (3). With support from the 2023 AACR-AstraZeneca Career Development Award for Physician-Scientists, in Honor of José Baselga, Kristopher Bosse, MD is leading a project to develop immunocompetent preclinical models to uncover why CAR T cells falter in neuroblastoma, and to design strategies to overcome these hurdles.

“Most preclinical studies use immunocompromised models but conducting experiments in mice with competent immune systems is critical, as they may best recapitulate what happens in patients,” said Dr. Bosse, physician-scientist at the Children’s Hospital of Philadelphia. “The host immune system is really potently toxic to CAR T cells,” he explained. “It is critical to understand the culprits in the TME and develop ways to circumvent these. This award allowed us to take a deep dive looking at how the host immune system negatively impacts GPC2 CAR T cells in neuroblastoma.”

Dr. Bosse’s findings, published in Molecular Therapy (3), reveal that myeloid-derived suppressor cells (MDSCs) represent a major barrier to CAR T cell activation, proliferation and cytotoxicity in neuroblastoma and offer insights to guide the rational design of CAR T cells capable of reprogramming the immunosuppressive TME. Using syngeneic, immunocompetent models, Dr. Bosse’s team demonstrated that GPC2 CAR T cells slightly delayed tumor growth and initially reshaped the neuroblastoma TME toward activation, as evidenced by recruitment of endogenous T cells and M1-type macrophages. While this immune activation was transient, the presence of immunosuppressive MDSCs was more persistent. These cells were elevated from the outset and remained enriched over time, likely driven by early induction of MDSC-recruiting chemokines such as CXCL1 and CXCL2. Collectively, these findings uncover a critical mechanism of immune escape that would not have been detectable in traditional immunodeficient models.

Building on this discovery, Dr. Bosse’s team armored GPC2 CAR T cells with the chemokine receptor CXCR2 to improve trafficking and persistence—genetically enhancing them to migrate toward chemokine CXCL1/2 gradients. This engineered approach offered a dual benefit of improved tumor homing and competitive inhibition, which reduced MDSC infiltration and led to significantly improved tumor control and survival in preclinical models. Importantly, these next-generation CAR T cells maintained their cytotoxicity and metabolic fitness, paving the way for clinical translation.  

CXCR2-engineered lymphocytes are already under investigation in a phase I/II trial for advanced melanoma (NCT01740557). Dr. Bosse’s findings expand the therapeutic potential of CXCR2 armoring for CAR T cells in neuroblastoma and align with prior studies demonstrating benefits of either direct CXCR2 blockade with antibodies or CXCR2 engineering in other tumor models (4). Future work will explore additional armoring strategies and combination approaches to sustain immune activation and overcome immunosuppressive mechanisms. Further studies will also address limitations of current syngeneic models, including species-specific differences in chemokine signaling, by incorporating humanized systems to better predict patient response. “We have several next-generation GPC2 CAR T cell strategies that we are working on right now,” said Dr. Bosse. “It is likely that we will need several armoring strategies and/or dual targeting CARs to achieve durable efficacy in the clinic.”

If you are a physician-scientist committed to advancing cancer research from bench to bedside, consider applying for the AACR-AstraZeneca Career Development Award for Physician-Scientists. This program provides critical funding to accelerate translational research and improve patient outcomes. Learn more about current and upcoming funding opportunities on our Research Funding Page.

References

1. Matthay KK, Maris JM, Schleiermacher G, Nakagawara A, Mackall CL, Diller L, et al. Neuroblastoma. Nat Rev Dis Primers. 2016;2:16078. doi:10.1038/nrdp.2016.78
2. Daei Sorkhabi A, Mohamed Khosroshahi L, Sarkesh A, Mardi A, Aghebati-Maleki A, Aghebati-Maleki L, et al. The current landscape of CAR T-cell therapy for solid tumors: Mechanisms, research progress, challenges, and counterstrategies. Front Immunol. 2023;14:1113882. doi:10.3389/fimmu.2023.1113882
3. Giudice AM, Roth SL, Matlaga S, Cresswell-Clay E, Mishra P, Schürch PM, et al. Reprogramming the neuroblastoma tumor immune microenvironment to enhance GPC2 CAR T cells. Mol Ther. 2025;33(9):4552–4569. doi:10.1016/j.ymthe.2025.05.025
4. Jin L, Tao H, Karachi A, Long Y, Hou AY, Na M, et al. CXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors. Nat Commun. 2019;10(1):4016. doi:10.1038/s41467-019-11869-4