The Science behind the Next Generation of Cancer Vaccines

Connecting clinical research with the biology of treatment response

Prof. Michele Maio (Professor of Medical Oncology – University of Siena and National Center researcher in Spoke 2) has played a longstanding role in the development of immuno-oncology in Italy and internationally. As Director of the Center for Immuno-Oncology at the University Hospital of Siena and President of the NIBIT Foundation, he has contributed both to clinical research on immunotherapies and to approaches designed to overcome resistance to treatment.

Siena is one of the Italian centers participating in the INTerpath-001 Phase 3 trial evaluating intismeran autogene in combination with pembrolizumab. The study uses a personalized approach: tumor tissue is collected from each patient and analyzed so that a vaccine can be designed to encode a set of neoantigens specific to that patient’s tumor.

Understanding how to stimulate an immune response is only one part of the challenge. Researchers must also understand why tumors sometimes evade that response. This question is central to a study published in Science Advances on 7 August 2026, involving Prof. Maio together with Prof. Elisabetta Ferretti (Professor of General Pathology – Sapienza University of Rome), Prof. Michele Ceccarelli (Professor of Computational Oncology – University of Miami and University of Naples Federico II), and researchers from the Universities of Siena, Naples and Miami, Sapienza University, the NIBIT Foundation and other major research Institutions.

The Science Advances paper, “Transposable elements and homotypic niches drive immune dynamics and resistance in melanoma epigenetic-based immunotherapy,” investigates how melanoma cells can change their biological state and evade immune attack. The researchers identified mechanisms involving tumor-cell plasticity and highlighted NFATC2 and β-catenin as potential therapeutic vulnerabilities.

Prof. Michele Maio — University of Siena, Spoke 2 explains “The progress we are seeing today in personalized cancer vaccines is the result of many years of research aimed at understanding how tumors interact with the immune system but also to the clinical availability of antibodies to immune checkpoint(s) inhibitors such as pembrolizumab that potentiate patients’ anti-tumor immune response. Clinical research, biomarker discovery and the study of mechanisms of resistance are all pieces of the same puzzle. The opportunity to translate this knowledge into increasingly personalized treatments is a powerful example of how sustained investment in research can ultimately benefit patients.”

A broader Italian research network

The study also highlights the collaborative nature of contemporary biomedical research. Prof. Elisabetta Ferretti, member of the National Center Board of Directors and Spoke 2 researcher at Sapienza University of Rome, has contributed to work on biomarkers and mechanisms associated with response to immunotherapy in melanoma. Her previous research with Prof. Maio and others has focused on circulating and molecular biomarkers capable of predicting how individual patients respond to immunotherapy—an essential element of the move toward more personalized cancer treatment.

The latest Science Advances study brings together this expertise with computational analysis and clinical research, showing how discoveries emerge from the interaction of different disciplines and institutions.

Prof. Elisabetta Ferretti — Sapienza University of Rome, Spoke 2 highlights that “Personalized cancer treatment depends not only on developing new therapies, but also on our ability to understand which patients are most likely to benefit from them. Our work on circulating biomarkers and mechanisms of response to immunotherapy contributes to this goal. The emerging field of personalized mRNA vaccines is another important step toward tailoring cancer treatment to the biological characteristics of each individual patient.”

Building the evidence behind personalized cancer treatment

In 2024, Professors Ferretti, Di Giacomo and Maio were among the authors of the review, “Immunotherapy in melanoma: Can we predict response to treatment with circulating biomarkers?” examining the potential of circulating biomarkers—including DNA, RNA, proteins and circulating cells—to predict and monitor patients’ responses to immune checkpoint inhibitors in melanoma. The work underscored the importance of reliable biomarkers for guiding increasingly personalized treatment decisions.

In the ongoing effort to identify biomarkers capable of predicting response to immunotherapy in patients with melanoma, Professors Ferretti, Di Giacomo, Maio and Ceccarelli further advanced this field with their May 2026 publication, “Circulating EV-microRNAs Are Dynamic Biomarkers of Resistance to Therapeutic Immunomodulation in Metastatic Melanoma.”

Professors Maio, Ceccarelli and Di Giacomo were also among the researchers behind the study “Tumor DNA methylation subtypes predict immunotherapy outcomes in pleural mesothelioma patients in the NIBIT-EPI-MESO study,” published in Nature Genetics in April 2026 that investigated DNA methylation patterns as predictors of response to immunotherapy in patients with pleural mesothelioma. The study identified distinct molecular subtypes associated with different patterns of immune response, survival and treatment benefit, demonstrating how molecular profiling can help explain differences in patients’ responses to immunotherapy.

These publications, supported by and involving National Center scientists, illustrate the broader impact of National Center research: scientific advances do not occur in isolation, but build progressively across studies, disciplines and institutions. Research into biomarkers, tumor biology, immune response and computational analysis generates knowledge that can contribute to the development and refinement of increasingly personalized approaches to cancer treatment—including the new generation of individualized mRNA-based therapies now entering the clinical spotlight.