The trial focuses on solid tumours for which CAR T-cell treatment remains far less developed than it is for leukaemia, lymphoma and multiple myeloma. Among the representative cancers named in the protocol are neuroblastoma, glioma and osteosarcoma. These diseases can carry aggressive biological features, respond poorly to conventional treatment and frequently relapse despite intensive therapy. Patients whose disease returns or proves resistant to existing approaches have few effective options, particularly when standard agents have been exhausted. TARGETS therefore addresses both a scientific problem—the limited success of CAR T cells against solid tumours—and a clinical one—the shortage of promising treatments for patients with advanced refractory disease.

GD2 is a ganglioside, a class of molecules composed of sugars linked to a fatty component, and it is expressed by a variety of tumours. Its presence can make it useful as a target, but the effectiveness of an immune treatment depends on more than simply recognising the molecule. A CAR is a synthetic receptor that gives a T cell the ability to detect a specified surface antigen and trigger an immune attack when that antigen is encountered. The investigational product described in TARGETS uses a newly engineered second-generation CAR directed against GD2, combining the antigen-binding machinery of the receptor with intracellular signalling designed to activate the modified T cell.

All participants will receive autologous CAR T cells, meaning that the therapeutic cells are manufactured from each patient’s own immune cells rather than supplied as an off-the-shelf donor product. Before treatment, investigators will collect peripheral blood through leukapheresis, isolate the relevant cells and engineer them to express the anti-GD2 receptor. Manufacturing will follow Good Manufacturing Practice requirements, while broader trial procedures will adhere to Good Clinical Practice principles and the Declaration of Helsinki. The approach is personal to each participant but also complex: it requires coordinated blood collection, specialist cell processing, quality testing and transport before the finished product can be returned for administration.

Before the CAR T cells are infused, patients will receive lymphodepleting chemotherapy. This preparatory treatment reduces the number of lymphocytes in the blood and creates space for the engineered cells to expand, while modifying the immune environment to support their persistence and activity. The CAR T product is then administered intravenously. Because the trial involves a newly engineered construct and is the first clinical evaluation of this particular product, investigators will combine intensive inpatient observation after infusion with longer follow-up. The study plans to monitor participants for up to four years, allowing researchers to capture both immediate toxicities and potential longer-term immune effects.

Safety is the primary focus of the first part of TARGETS. The investigators will use a conventional 3+3 dose-escalation scheme across three planned dose levels. In this design, small groups of participants receive an initial dose, and additional patients are enrolled only when the observed toxicities permit escalation. The process helps identify a dose-limiting toxicity and establish the maximum tolerated dose while balancing treatment exposure against risk. A Data and Safety Monitoring Board will oversee the study, and the researchers will record adverse events, serious adverse events and other safety signals using recognised clinical-trial criteria.

A basket design can accelerate the evaluation of a targeted therapy across several tumour types because the defining feature is shared biology rather than a single organ. Here, eligibility centres on tumours that express GD2 and have relapsed or refractory disease. The approach allows the same CAR T-cell product to be tested in neuroblastoma, glioma, osteosarcoma and other qualifying solid tumours, while also revealing whether biological responses differ markedly between diseases. At the same time, the small planned cohort of roughly 20 participants means the trial is not designed to provide definitive comparative evidence. Its role is early-stage: establish tolerability, characterize dose-related effects and look for signals that justify larger, disease-focused studies.

The protocol has passed ethics review by the Human Research Ethics Committees of the Faculty of Medicine at Chiang Mai University, the Faculty of Medicine Ramathibodi Hospital at Mahidol University, and the Faculty of Medicine at Prince of Songkla University. Written informed consent will be obtained from participants or, where applicable, their parents or legally authorized representatives before enrollment, and assent will be sought from children in line with local regulations and institutional policies. Several investigators involved in the study also report a Thai petty patent covering a GD2-specific CAR T-cell receptor. The work was supported by Genomics Thailand and the Health Systems Research Institute, with partial support from Chiang Mai University.

CAR T cells are not a routine treatment for relapsed GD2-positive solid tumours, and the publication describes a study protocol rather than clinical results. No efficacy figures or conclusions about tumour shrinkage are therefore available from this research. The central scientific question is whether a second-generation anti-GD2 receptor can produce a tolerable and potentially useful immune response in a difficult group of cancers. TARGETS will provide early safety data, define a workable dose and offer a first look at whether engineered T cells can shrink established tumours. If those early signals prove encouraging, they could provide the foundation for larger trials designed around the tumour types most likely to benefit.

Editorial clarification: This article describes a published trial protocol, not treatment results or independent confirmation that recruitment has started. “First-in-human” refers to this particular investigational product.

Subject of Research: A phase I/IIa basket trial of autologous anti-GD2 CAR T cells for relapsed or refractory GD2-positive solid tumours

Article Title: A basket trial of autologous Anti-GD2 chimeric antigen receptor (CAR) T Cells in patients with relapsed or refractory GD2-positive solid tumors (TARGETS): study protocol for a phase I/IIa multicenter open-label trial

Article References: Koonrungsesomboon, N., Anurathapan, U., Chaiyawat, P., Dukaew, N., Kittilukkana, A., Orrapin, S., Choed-amphai, C., Sathitsamitphong, L., Charoentum, C., Hongeng, S., Sripornsawan, P., Sangkhathat, S., Preedagasamzin, S., Atjanasuppat, K., Jittorntrum, B., Suanpan, K., Suthapot, P., & Pruksakorn, D. (2026). A basket trial of autologous Anti-GD2 chimeric antigen receptor (CAR) T Cells in patients with relapsed or refractory GD2-positive solid tumors (TARGETS): study protocol for a phase I/IIa multicenter open-label trial. BMC Cancer. https://doi.org/10.1186/s12885-026-17149-x

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17149-x

Keywords: CAR T cells, GD2, solid tumours, neuroblastoma, glioma, osteosarcoma, immunotherapy, dose escalation, clinical trial, Thailand, basket, trial

The protein in question is PIK3C3, better known in the research world as VPS34. First identified decades ago in yeast cells as a traffic controller that sorts and shuttles proteins to and from the cell membrane, VPS34 later earned fame for a second role: autophagy, the recycling program by which cells break down their own components to survive stress. Because fast-growing tumors depend heavily on autophagy to weather nutrient shortages and to dispose of substances that might otherwise alert the immune system, VPS34 has long been an attractive target for cancer researchers. The new study, published in the journal Autophagy, reveals that its importance extends beyond keeping tumor cells alive — it also determines how easily those cells can be spotted by the body’s defenses.

The key molecule in this story is GD2, a fatty substance with a small sugar chain that decorates the surface of neuroblastoma cells. Anti-GD2 immunotherapy works through lab-made monoclonal antibodies, such as dinutuximab and naxitamab, which are engineered to latch onto GD2 and flag the tumor for destruction by the patient’s own immune cells. The Penn State team, led by corresponding author Hong-Gang Wang, Lois High Berstler Professor of Pediatrics, found that inhibiting VPS34 raised the amount of GD2 displayed on the tumor cell surface. More GD2 means more docking sites for the antibodies — in Wang’s words, the tumor cells become more visible and give the antibodies more to latch onto.

The experimental evidence came from a series of careful measurements. When the researchers blocked VPS34 in cell cultures, they used flow cytometry, a technique that tags specific molecules with fluorescent markers and passes individual cells through a laser to quantify them. The treated cells glowed brighter, indicating elevated surface GD2. Intriguingly, blocking VPS34 increased the total amount of GD2 inside the cells, but the surface pool rose disproportionately, shifting the balance toward the outer membrane where antibodies can reach it. The most exciting finding, Wang noted, was that VPS34 inhibition increased GD2 presentation, making the tumor more visible to the antibody.

Not every result followed the expected script. Because the team’s hypothesis was rooted in autophagy — the idea that starving tumor cells of their recycling machinery would weaken them — they anticipated that the effect would depend on nutrient stress. Yet when VPS34 was blocked in lab cultures, where oxygen and nutrients are plentiful and cells do not rely heavily on autophagy, the tumor cells died anyway, independent of any immunotherapy. This suggested that VPS34’s other, older function — endolysosomal trafficking, the routing of material to different cellular destinations including the membrane — was also at play.

To disentangle the two roles, the researchers ran control experiments targeting ATG14, a protein that partners with VPS34 specifically for autophagy while leaving VPS34’s trafficking duties untouched. Blocking ATG14 produced a dramatically reduced effect on GD2, pointing to endolysosomal trafficking as a central mechanism behind the increased surface display. In mouse models, meanwhile, tumors grew poorly when the team targeted ATG14 and other autophagy genes. The two functions of VPS34, Wang concluded, likely work in tandem to help neuroblastoma cells survive — which means disrupting them strikes the cancer from multiple directions at once.

The therapeutic payoff emerged when VPS34 inhibition was paired with monoclonal antibodies in both cells and mice. The combination outperformed either approach alone. According to first author Jiawen Zhang, a biomedical sciences doctoral student, the brighter cancer cells with elevated GD2 became easier targets not only for the antibodies but for the natural killer cells that bind to them. Once engaged, these NK cells release perforin, a protein that punches holes in the cancer cell membrane, and granzymes, enzymes that pass through those holes and trigger cell death. In both experimental systems, tumor growth was significantly suppressed, and in mice, survival improved. Combining the two therapies, Zhang said, gave better results.

The implications may reach beyond neuroblastoma. High levels of GD2 also appear on melanoma and osteosarcoma cells, but anti-GD2 immunotherapy is currently approved as standard care only for neuroblastoma. Wang suggested that the strategy could potentially be tested in other tumor types that express high GD2 on their surfaces, broadening the relevance of the work well past the pediatric population in which it was conceived. The concept — making tumors more conspicuous by manipulating their internal logistics — could in principle complement antibody-based therapies across several cancers.

Significant hurdles remain before patients benefit. VPS34 inhibitors are still largely confined to pre-clinical studies, and off-target effects frequently complicate experiments in living subjects. What is missing, Wang emphasized, is a clinical-grade VPS34 drug. He expressed hope that the findings will encourage the research community to view VPS34 as an important target and accelerate drug discovery and testing efforts to complement anti-GD2 immunotherapy. The study, he said, provides the pre-clinical evidence and rationale that, once better VPS34 inhibitors are developed, combining them with anti-GD2 antibodies could become an important neuroblastoma treatment strategy.

The research was carried out by a broad Penn State team that included Longgui Chen, research technologist; Todd D. Schell, professor of cell and biological systems; Giselle Saulnier Sholler, Four Diamonds Endowed Chair for Pediatric Oncology Research; Vladimir Spiegelman, THON Chair for Pediatric Cancer Research; and Yoshinori Takahashi, associate professor of pediatrics and of cell and biological systems. Xiaoming Liu, who conducted the research as a doctoral student and has since graduated, also contributed. Funding came from the National Institutes of Health’s National Cancer Institute through awards R01CA222349, R21CA252748 and R01CA304343, along with the Lois High Berstler Research Endowment and Four Diamonds. For families facing high-risk neuroblastoma, the work offers a concrete biological rationale for a combination approach that could turn an elusive cancer into an open target — and a reminder that sometimes the most powerful way to defeat a tumor is simply to make it impossible for the immune system to ignore.

Subject of Research: VPS34 inhibition as a strategy to enhance anti-GD2 immunotherapy in pediatric neuroblastoma

Article Title: Making pediatric cancer more ‘visible’ boosts immunotherapy response

Article References: Making pediatric cancer more ‘visible’ boosts immunotherapy response. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: neuroblastoma, pediatric cancer, immunotherapy, VPS34, GD2, monoclonal antibodies, autophagy, endolysosomal trafficking, natural killer cells, dinutuximab, naxitamab, preclinical study