Advanced therapies often begin with a scientific question. In some cases, that question evolves over years of research, collaboration and clinical development into a therapeutic strategy capable of reaching patients.

One example developed in Spain is Celyvir, an advanced therapy medicinal product designed for the treatment of advanced cancer.

What is Celyvir?

Celyvir is a therapy based on mesenchymal cells carrying an oncolytic adenovirus inside them. Its therapeutic approach combines two complementary mechanisms of action.

The first is the direct activity of the oncolytic virus, which is capable of infecting and eliminating tumour cells while causing minimal impact on healthy tissue.

The second mechanism involves the activation of an anti-tumour immune response. As tumour cells are destroyed through viral infection, the treatment may stimulate immune activity capable of recognising and attacking tumour sites throughout the body, including metastatic disease.

This systemic immune response is considered one of the most promising aspects of the therapy, particularly in patients with advanced or disseminated cancer.

The origins of the project

The development of Celyvir began nearly two decades ago through collaboration between researchers working in paediatric oncology, translational medicine and oncolytic virotherapy.

One of the key challenges identified early in development was the limited efficacy of systemic administration of oncolytic viruses alone. Researchers therefore explored the possibility of using cells as delivery vehicles capable of transporting the virus to tumour sites.

Mesenchymal cells became the preferred option partly because clinical experience with these cells already existed in other therapeutic contexts, which facilitated early development.

The first versions of the therapy used mesenchymal cells obtained directly from the patients themselves through bone marrow aspirates.

Moving from research to regulated development

As the project progressed beyond preclinical research, development entered a new stage defined by manufacturing and regulatory requirements.

At that point, the therapy was no longer only a research concept, but a medicinal product intended for human use. This required the implementation of manufacturing conditions compliant with regulatory standards applicable to advanced therapy medicinal products.

Development therefore involved: interaction with regulatory authorities, adaptation to GMP manufacturing requirements, and the creation of an authorised production environment within a hospital setting.

Support from Fundación Genoma España contributed to the establishment of the infrastructure necessary to manufacture the therapy under appropriate regulatory conditions.

Early clinical development

The first clinical studies focused on paediatric and adolescent patients with advanced cancer who had already undergone multiple previous lines of treatment.

From the beginning, the therapy was designed as a systemic treatment administered intravenously through repeated doses.

Initial development concentrated primarily on neuroblastoma, although later studies expanded to include other extracranial tumours and, more recently, certain paediatric brain tumours.

One of the most relevant observations during these early stages was the favourable tolerability profile of the treatment, particularly in heavily pretreated patients.

Signs of therapeutic benefit were also observed in some patients, despite these being early-phase studies primarily designed to evaluate safety.

Moving from patient-derived cells to donor-derived approaches

One of the limitations identified during early development was the time required to manufacture the therapy using each patient’s own cells. For some patients with advanced disease, the manufacturing period represented a significant challenge.

Development therefore evolved towards an allogeneic version of the therapy based on cells obtained from healthy donors. This approach aims to reduce manufacturing times and make treatment more rapidly available when needed.

This newer version is currently being evaluated in clinical trials involving:

• Paediatric extracranial tumours
• Paediatric brain tumours
• Melanoma with liver metastases

What has been learned so far?

Years of clinical development have provided important insights into how the therapy behaves across different tumour types and treatment settings.

Neuroblastoma appears to be one of the tumour types showing greater benefit, while adenovirus replication during treatment may help predict therapeutic response.

Current research is also exploring how Celyvir could potentially be combined with other therapeutic approaches, including radiotherapy and additional treatment strategies, with the aim of improving efficacy.

At the same time, ongoing development is focused on optimising the mesenchymal cells themselves, either during manufacturing or through additional modification strategies intended to enhance therapeutic performance.

A long-term development pathway

The development of advanced therapies rarely follows a linear process. Celyvir has evolved progressively through preclinical research, regulatory adaptation, manufacturing development and clinical evaluation.

Its trajectory also reflects many of the broader challenges associated with advanced therapy development: long development timelines, complex manufacturing requirements, evolving regulatory frameworks and the need to continuously adapt scientific strategies based on emerging clinical data.

At the same time, it illustrates how translational research developed within academic and hospital environments can progressively move towards clinical application through sustained collaboration and long-term development efforts.