As the theme of this year’s VHIO Scientific Report indicates, 2023 marked myriad milestones at our Institute. This year’s report celebrates the incorporation of eight new research groups and the arrival of leading investigators who have joined VHIO over the past 12 months, as well as many well-deserved promotions of renowned VHIO researchers and clinical investigators as leaders of newly established groups across our programs. To discover more about these teams, I invite you to glance through the fold out section opening this year’s report and browse the corresponding program pages.

Based on our strategic plan, we have been busy implementing and developing several new technologies, platforms and facilities, including new VHIO infrastructures and premises that will enable us to further deliver on our research priorities. 

In addition to the amazing support that we receive from our institutional supporters and Patrons, Institutional Programs, VHIO’s many other supporters, funding entities, agencies and individuals, a number of important institutional awards this year will help us to expand our research in some of the most promising and emerging fields in precision oncology, some of which I highlight here in my foreword to this report.

In 2023, the AstraZeneca José Baselga Innovative Disruption (J-BID) Program provided support to four VHIO groups leading projects with great potential for groundbreaking discovery in our understanding of cancer. The legacy of José, VHIO’s Founding Director, continues to inspire us all, including the next generation of cancer researchers and clinical investigators. Honoring his legendary career and exceptional contributions to research, as well as the care of patients the world over, this program embodies the spirit of disruptive innovation that epitomized José’s work and extraordinary vision. 

At VHIO, we believe in team science of excellence. In collaboration with many other leading research centers and groups, both nationally and internationally, VHIO teams and talents published 435 scientific articles, including many in the most prestigious scientific and medical journals, as corresponding, senior or co-authors in 2023. 

As I reflect on the breadth of peer-review articles published by our researchers and clinicians this year, I take this opportunity to express once again my heartfelt thanks to each and every one of them for their dedication and commitment that continue to make a difference in our ongoing fight against cancer. 

I cannot possibly do justice to all our contributions to translational cancer science and clinical research over the past year, but here are a few that have particularly caught my eye.

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LIF as a novel drug target in immuno-oncology

Results of a preclinical study led by Joan Seoane, published in Clinical Cancer Research ⁽¹⁾, highlig hted the promise of leukemia inhibitor factor (LIF) as a novel drug target for cancer immunotherapy. Data showed that MSC-1—now AZD0171*, a monoclonal antibody developed by Joan’s team and VHIO-born spin-off Mosaic Biomedical—combined with anti-PD1 achieved a strong anti-tumor response and durable disease-free survival in mouse models of various tumor types.

The investigators studied the mechanism of action of MSC-1 and found that the compound’s main targets are the tumor-associated macrophages (TAMs). Data pointed to high levels of LIF expression as a predictor of poor prognosis and that LIF contributed to the immunosuppressive nature of macrophages as a driver of tumor growth through the deactivation of the immune response to cancer. MSC-1 converts immunosuppressive TAMs into immunostimulatory cells, reactivating the immune system against the tumor. Their work identified LIF as a therapeutic target and provided biomarkers to select the patients that may benefit from MSC-1 therapy. 

Their discoveries build a platform for the clinical testing of MSC-1.The group’s preclinical data were validated in a phase I study ⁽²⁾, led by VHIO, through the characterization of biopsies before and after treatment. Using these patient samples, the researchers observed how MSC-1 modulated the tumor microenvironment and confirmed their preclinical results, as MSC-1 re-educated immunosuppressive TAMs into immunostimulatory macrophages and induced immune T-cell infiltration in tumors.

*Mosaic Biomedicals was acquired by Medimmune/AstraZeneca in 2020.

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Myc inhibition in melanoma and the unveiling of a prognostic gene signature

Results of a study led by Laura Soucek, and research associate and co-corresponding author Mariano F. Zacarías-Fluck in Genes & Development ⁽³⁾ showed how expression of the first-in-class MYC inhibitor Omomyc disrupted MYC activity in preclinical melanoma models and altered gene expression profiles. This activity reduced cancer proliferation and progression.

Reducing MYC’s transcriptional footprint via transgenic expression of Omomyc achieved a significant reduction in tumor growth and metastatic capacity, independently of the driver mutation, recapitulating the transcriptional profile of patients with good prognoses. These findings suggest that Omomyc’s inhibition of MYC could improve outcomes in patients with melanoma, although further evaluation will be required in clinical trials. 

Developed by VHIO-born spin-off Peptomyc, a company co-founded by Laura in 2014, the first Omomyc-derived compound, OMO-103, is the most clinically advanced MYC inhibitor to date, having successfully completed a phase I clinical trial in October 2022. A phase Ib trial began this year evaluating OMO-103 in metastatic pancreatic ductal adenocarcinoma in combination with standard of care chemotherapy.

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Deciphering cell cycle dynamics in cancer

The upregulation of the cell cycle kinase MASTL has been identified in multiple tumor types and is associated with a poor prognosis. While showing potential therapeutic value in some malignancies including breast cancer, the MASTL kinase remains poorly understood.

Results of a study directed by Marcos Malumbres, published in The EMBO Journal ⁽⁴⁾, described a new function for MASTL in regulating the feedback loops that control AKT activity downstream of mTOR. Data suggest that MASTL inhibition could represent a promising and selective drug target for specific anticancer therapy as well as the treatment of metabolic diseases, including obesity‐induced diabetes. 

As MASTL does not participate in the central AKT‐mTOR axis, MASTL inhibition can be considered a first-in-class therapeutic strategy aimed at controlling the activity of the AKT oncogene, without the toxicities associated with 

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Unravelling the genomic basis of tumorigenesis and the key role of the immune system the blockade of central mTOR‐S6K kinases.

Two studies led by Francisco Martínez-Jiménez, published concurrently in Nature ⁽⁵⁾ and Nature Genetics ⁽⁶⁾, have advanced insights into the genomic differences between primary and metastatic tumors. Directed by corresponding author Edwin Cuppen, Director of the Hartwig Medical Foundation (The Netherlands), the investigators quantified the impact of these alterations on cancer drug resistance toward developing more effective and personalized therapies. 

They generated the largest repository of whole genome sequencing (WGS) data from more than 70 tumor types, including more than 7,000 unpaired primary and metastatic tumor samples. In the Nature paper, they described the overall genomic differences observed and showed that these discrepancies are highly dependent on tumor type and exposure to previous therapies. 

The pan-cancer scope of this study led them to identify which processes are shared between tumor types and quantified their prevalence. Results of the second study exposed the genomic alterations that enable tumors to evade attacks from the immune system, as well as their prevalence in primary and metastatic tumors. The prevalence of genetic immune escape is highly variable across tumor types. In some cancers, only a single mechanism is present while in others, several processes are affected. Few differences were observed between primary and metastatic tumors, suggesting that immune evasion is acquired relatively early in tumor development.

This is the first time that a WGS dataset has been generated for primary and metastatic tumors of this magnitude. These data are publicly available for research and provide a new global resource for advancing research into the biology and evolution of cancer and the development of new anti-cancer therapies.

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Exposing the genomic features of early-onset pancreatic cancer

Illustrative of VHIO’s interest in tackling early-onset cancer, results of a VHIO-led study published in European Journal of Cancer (EJC) ⁽⁷⁾, first authored by Florian Castet, a Clinical Investigator in our Upper Gastrointestinal and Endocrine Tumors Group, indicate that patients with early-onset pancreatic cancer (EPOC) have unique clinical and molecular features and could derive particular benefit from precision oncology-based approaches. 

The incidence of EPOC is increasing sharply and the molecular characteristics of pancreatic cancer in people 50 years or under are poorly defined. A team led by Teresa Macarulla, in collaboration with Tian Tian and her group’s translational laboratory, performed a comparative, single-center, retrospective analysis of clinical, germline, and genomic features in 139 EOPC (≤50 years) patients and compared them with a control group of 197 average-onset pancreatic cancer patients (AOPC, ≥70 years). 

No significant differences in overall survival (OS) were observed between EOPC and AOPC patients across all disease stages, and EOPC were enriched in KRAS^WT tumors and potentially targetable alterations. EOPC patients who received targeted therapies exhibited a longer OS compared with those patients who did not.

Further advancing insights into the unique features of EOPC will ultimately help to identify novel molecular targets and develop new, more effective therapeutic options in this patient population. 

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Cancer immunotherapy: novel targets, biomarkers, platforms and combination treatment

In addition to a preclinical study led by Joan Seoane that I highlighted earlier, I take this opportunity to mention six other studies in the realm of cancer immunotherapy.

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Non-canonical proteins as candidate targets

A study directed by Alena Gros delved into the identification of non-canonical peptides and their importance in cancer immunosurveillance. This work represents a first step toward exploiting them therapeutically to develop novel of immune-based strategies in oncology. Published in Clinical Cancer Research ⁽⁸⁾, the investigators leveraged HLA-I immunopeptidomics, to identify peptides presented on HLA-I in patient-derived tumor cell lines of melanoma, gynecological, and head and neck cancers. 

They discovered more than 500 peptides derived from allegedly non-coding proteins, representing from 0.3-3.3% of the peptides eluted from the cell lines and explored their ability to elicit T cell responses. They evaluated the presence of spontaneous pre-existing T-cell responses in cancer patients, targeting these tumor antigens as well as other conventional candidates. Some of these non-canonical proteins were common across tumor types and could be naturally presented by cancer cells and recognized by T-cells. Importantly, their results also demonstrated that these candidate antigens can be tumor-specific, as they were naturally presented by cancer cells but rarely detected in healthy cells. The findings demonstrated that tumor-specific non-canonical proteins could potentially provide an alternative source of tumor antigens and represent interesting targets for the development of T-cell therapies. 

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Tumor mutational burden as a predictive biomarker of response to immunotherapy in non-small cell lung cancer

The IMpower010 randomized, multicenter phase III study was designed to assess the efficacy and safety of the immune checkpoint inhibitor atezolizumab as adjuvant therapy in patients with resected, high-risk early-stage non-small-cell lung cancer (NSCLC). First authored by Enriqueta Felip, results of the first interim analysis of overall survival, published in Annals of Oncology ⁽⁹⁾, indicated a positive trend favoring atezolizumab in the PD-L1 subgroup analyses, primarily driven by PD-L1 expression of tumor cells of ≥50% in the stage II-IIIA subgroup. To identify patients most likely to benefit from this immunotherapy as adjuvant treatment, the investigators continued to analyze IMPower010 data to identify novel biomarkers of response.

Results of subsequent exploratory analysis, presented by Enriqueta at the 2023 International Association for the Study of Lung Cancer World Conference on Lung Cancer (WCLC), suggested that tumor mutational burden (TMB) is not a predictive marker of response in this population. Data from their subgroup investigations showed that the improvement in disease-free survival (DFS) versus best supportive care was similar for both the TMB-high and TMB-low populations. The findings did however demonstrate that improvement with adjuvant atezolizumab was greater in the PD-L1 subgroup of patients compared with the PD-L1-negative subgroup, irrespective of TMB status. 

These results are of value in more precisely matching immunotherapy for the treatment of this patient population.

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The power of three: triplet drug combination slows disease progression in patients with advanced kidney cancer

Co-authored by Cristina Suarez, results of the phase III COSMIC-313 trial were published in The New England Journal of Medicine ⁽¹⁰⁾. Led by Toni Choueiri at the Dana-Farber Cancer Institute in Boston, this global, multi-center study was designed to evaluate the efficacy of adding tyrosine kinase inhibitor cabozantinib to immunotherapy with nivolumab and ipilimumab as a triplet treatment strategy versus contemporary standard of care with nivolumab plus ipilimumab as the control arm.

COSMIC-313 included 855 previously untreated patients with advanced or metastatic renal cell carcinoma, 428 of whom received the triplet experimental combination, and 427 who were treated with the standard immunotherapy doublet.

Results showed that patients treated with the triplet had a 27% lower risk of disease progression or death compared to those who received the two immunotherapy drugs. The overall response rate in the specified intention-to-treat population was 43% with the triplet combination compared to 36% with the standard two-drug immuno-oncology combination.

Despite increased toxicity observed in those patients receiving the experimental treatment, these findings show a clear progression-free survival benefit. Further analysis will show if these initial data translate in improved overall survival to identify those patients who could benefit from this three-drug combination.

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VIGEX pan-cancer platform to guide patient selection for personalized immunotherapy

Published in the Cell Press journal Med ⁽¹¹⁾, a VHIO core study directed by Ana Vivancos and Elena Garralda, has preliminarily validated the VIGex gene expression signature as a tool for classifying solid tumors. Based on the expression level of genes involved in the adaptive immune response, this panel could also serve as a predictor of response to immunotherapy.

Developed in-house at VHIO, this platform has been designed to classify solid tumors into three categories based on the inflammatory status of the tumor microenvironment: hot, intermediate-cold and cold. PD-1/PD-L1 checkpoint inhibitors (ICIs) have been shown to work best against hot tumors, while they generally fail to yield benefit in the treatment of cold tumors.

First authored by Alberto Hernando-Calvo, a Clinical Investigator of Elena Garralda's Group, data showed that the inflammatory status of the tumor microenvironment, scored by the VIGex signature, varied depending on the origin of the primary tumor and anatomic site of metastases, with liver metastases showing an immunosuppressive tumor microenvironment. This last observation justifies the worse immunotherapy outcomes observed in patients with liver metastases across histologies. 

The predictive power of VIGex was initially observed in a cohort of 98 refractory solid tumors from patients treated in early phase immunotherapy clinical trials performed at VHIO’s UITM-CaixaResearch. The investigators subsequently validated the test in a metanalysis with more than 800 tumor samples from previously published studies with clinical and gene expression datasets available to the scientific community.

In the initial validation cohort of patients treated with immunotherapy agents under development in early phase clinical trials, the authors observed better responses in those patients with tumors classified as hot. The investigators also generated a pan-cancer biomarker platform that integrated VIGex categories with the gene expression levels of immunotherapy targets in early phase drug development.

This tool shows promise in improving the selection of patients most likely to benefit from immuno-oncology across tumor types and different immune-based treatments. As part of an existing international collaboration, the VIGex signature will be applied to data from an immunotherapy clinical trial conducted at the Princess Margaret Cancer Centre in Toronto and used as a biomarker in a prospective clinical trial of the European Organisation for Research and Treatment of Cancer (EORTC), funded by the Spanish Association Against Cancer (AECC), for head and neck cancer patients treated with immunotherapy.

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PET-based radiomics: predicting patient responses to CAR T-cell therapy in blood cancer

Illustrative of team science at VHIO, a proof-of-concept study led by Raquel Perez-Lopez and co-senior author Pere Barba, a Lead Investigator of our Experimental Hematology Group, explored the potential of positron emission tomography (PET)-based radiomics to predict treatment outcomes with chimeric antigen receptor (CAR) T-cell therapy in patients with large B-cell lymphoma (LBCL).

While CAR T-cell therapy is a promising treatment option for patients with relapsed or refractory LBCL, only a subset of patients will derive long-term benefit. Aimed at improving patient selection for CAR T-cell therapy, the investigators conducted a single-center study including over 90 patients who received CAR T-cell infusion from 2018-2021.

Published in eJHaem ⁽¹²⁾, results showed that a radiomics signature including 4 PET-based parameters outperformed conventional PET biomarkers. In their multivariable analysis, a high radiomics score also correlated with longer progression free survival and overall survival. These findings could help to stratify patients for treatment with CAR-T cell therapy in this patient population.

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Accelerating the production of more effective CAR-T cell therapy

Co-authored by Pere Barba, results published in Cancer Discovery ⁽¹³⁾ showed that the next generation chimeric antigen receptor (CAR) T cell manufacturing platform—T-charge™—reduced the ex vivo culture time of a novel autologous CD19-directed CAR-T cell therapy to about 24 hours, taking less than two days to manufacture the final product.

Directed by corresponding author Michael J. Dickinson at the Peter MacCallum Cancer Centre and Royal Melbourne Hospital, the investigators reported preclinical data from mouse models of non-Hodgkin lymphoma and showed how this new manufacturing process generated a more effective product, leading to improved results with enhanced in vivo expansion and antitumor activity at lower doses than traditionally manufactured T-cell-based therapies.

Interim analysis of a first-in-human phase I clinical study demonstrated the preliminary antitumor efficacy of YTB323, a novel autologous CD19-directed CAR-T cell therapy, manufactured using this novel platform in a cohort of patients with relapsed/refractory diffuse large B cell lymphoma.

The investigators observed that treatment with T-charge-processed CAR-T cells, at doses 25 times lower than CAR-T therapy approved for these tumors, showed a promising overall safety profile and a response rate of between 75 and 80%. The preservation of T-cell stemness in the product also translated into promising early clinical activity with a desirable safety profile.

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Advancing the frontiers of liquid biopsy in oncology

The promise of ctDNA testing in prostate cancer

Co-authored by Joaquin Mateo, genomic profiling analysis of data from the phase III PROfound study, published in Clinical Cancer Research ⁽¹⁴⁾, supported the use of plasma-derived circulating tumor DNA (ctDNA) detected by liquid biopsy for the identification of BRCA1, BRCA2, and ATM alterations in patients with metastatic castration resistant prostate cancer (mCRPC). Led by Kim N. Chi at BC Cancer in Vancouver, the researchers investigated the sensitivity and specificity between matched tumor tissue and circulating tumor DNA (ctDNA) testing using samples from patients screened for the PROfound study.

Using an investigational next-generation sequencing (NGS) assay based on FoundationOne®Liquid CDx, they found that this test yielded biomarker results for a high proportion of samples (81%). Results demonstrated that plasma-derived ctDNA can greatly complement tissue testing in identifying patients most likely to benefit from treatment with PARP inhibitors. The investigators observed that although tumor tissue testing remains the gold standard, liquid biopsies could be particularly useful for patients who do not have sufficient or suitable tumor tissue for genomic analyses, or when tumor tissue analysis fails to provide a result. 

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Liquid biopsy in breast milk as a potential new tool for early diagnosis of breast cancer in the postpartum period

Illustrative of our collaborative translational efforts, a study led by Cristina Saura showed that circulating tumor DNA (ctDNA) can be detected through liquid biopsy in breast milk from women with breast cancer who were diagnosed during pregnancy or postpartum. First results of this pioneering study, published in Cancer Discovery ⁽¹⁵⁾, could offer a potential new technique for the early diagnosis of breast cancer in the postpartum period.

The investigators collected breast milk and blood samples from 15 patients diagnosed with breast cancer during pregnancy or postpartum who were breast feeding. Using next-generation sequencing and droplet digital PCR, they found ctDNA of tumor origin in breast milk. Notably, they detected mutations present in those patients with breast cancer in the samples of breast milk of 13/15 patients analyzed. In the blood samples collected at the same time, ctDNA was only identified in one of them. 

For the first time, the investigators have shown that breast milk from this particularly sensitive population of young women and mothers with breast cancer carried sufficient levels of ctDNA to be detected by liquid biopsy, even prior to diagnosis by image. To confirm the utility of this novel, non-invasive liquid biopsy test as a new potential tool for breast cancer screening for healthy women, a prospective study is now underway to collect breast milk samples from 5,000 healthy women worldwide who became pregnant at the age of 40 or above, or at any age who carry mutations that confer an increased risk of breast cancer. 

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BRAF mutations in blood serve as a biomarker of response to anti-BRAF/EGFR combinatory therapies

Illustrative of our leading role in advancing liquid biopsy for guiding treatment strategies in oncology, a VHIO-led study directed by Elena Élez explored the value of BRAF-V600E mutation detected in blood by liquid biopsy as a prognostic biomarker in metastatic colorectal cancer (mCRC). 

To optimize the clinical management of patients with BRAF-mutant mCRC treated with anti-BRAF/EGFR combinatory therapies, the investigators prospectively evaluated a cohort of patients who had received treatment with a BRAF inhibitor plus anti-EGFR therapy (with or without a MEK inhibitor) in clinical trials and in real-world practice. Published in Annals of Oncology ⁽¹⁶⁾, the results showed that that high expression patterns of BRAF correlated with poorer outcomes compared with patients with low BRAF expression levels. Analysis of the predictive value of these findings revealed that patients with high BRAF expression levels derived most benefit from triplet therapy. The identification of mutations in the BRAF gene detected in blood using non-invasive liquid biopsy technologies could serve as predictive biomarker of response and therefore help to identify patients most likely to benefit from treatment with combined BRAF-targeted therapies and refine patient stratification.

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Rethinking clinical trial design for rare tumors

A Comment article authored by César Serrano and colleagues in Nature Medicine ⁽¹⁷⁾ proposed a rethink of using placebos in phase III clinical studies for rare tumors. To understand the natural history of placebo-treated metastatic gastrointestinal stroma tumor (GIST), the investigators conducted pooled meta-analyses of selected phase III clinical studies performed between 2003 and 2020. The authors suggested new directions for the optimization of clinical trial design for GIST and other rare cancers to facilitate the development and approval of new therapies for patients with limited treatment options. 

For the regulatory approval of a new agent or combination, current randomized controlled trials compare experimental therapy with the best treatment option available---usually the standard-of-care for a given tumor type or subgroup of patients. For rare cancers, when no active therapy is available as a comparator, placebo is administered in the control group. Conventional study design typically demands high numbers of participants to reach conclusive results, which poses a significant challenge in rare cancers, and is suited to more common tumor types.

In their meta-analyses, the researchers studied the results in the placebo groups of five landmark clinical trials in GIST, and showed that the patients who received placebo exhibited poorer outcomes compared to those treated with experimental therapy. These outcomes led them to propose a rethink of using placebos in phase III randomized studies in metastatic GIST and other rare cancers. Instead, they recommend the use of synthetic control arms designed with data from previous clinical studies or systematic collection of real-world data as comparators, but only when compelling clinical efficacy has been clearly shown in the early phases of drug development. 

This suggested shift in clinical trial design for rare cancers must naturally involve patients, investigators, sponsors, and regulatory agencies. Future discussions regarding the removal of placebo and the introduction of a given external comparator, where appropriate, will need to carefully balance all considerations as we seek to improve outcomes for patients with rare malignancies.

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The promise of an antibody-drug conjugate as biomarker-driven monotherapy in chemotherapy-resistant ovarian cancer

The phase II multi-center and single-arm SORAYA study evaluated the efficacy and safety of the antibody-drug conjugate (ADC) mirvetuximab as monotherapy in more than 100 patients with platinum-resistant ovarian cancer (PROC) with high folate receptor alpha (high-FRα) expression who had received one to three prior therapies, including bevacizumab. Results of this landmark study, first authored by Ursula A. Matulonis at the Dana-Farber Cancer Institute in Boston, with Ana Oaknin as a co-author, were published in the Journal of Clinical Oncology ⁽¹⁸⁾. 

This is the first trial of an ADC to demonstrate a meaningful clinical benefit in a biomarker-selected population of patients with PROC. At a median follow-up of 13.4 months, overall response rate (ORR) was 32.4% with a median duration of response of 6.9 months. The confirmed ORR in this study was more than double compared with that of single-agent chemotherapies reported in previous trials in this setting. Clinical benefit was observed in all prespecified subgroups, including patients who had received one to three prior lines of therapy, irrespective of whether they had received previous treatment with a PARP inhibitor. 

Considering the lack of effective therapies and poor prognosis for patients in this setting, mirvetuximab shows promise as a biomarker-driven, standard-of-care treatment option in this difficult-to-treat population. 

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Targeting epigenetic modulators in salivary gland cancer

Directed by Principal Investigator Irene Braña, a first-in-human phase I, open-label and multicenter trial evaluated the protein arginine methyltransferase 5 (PRMT5) inhibitor JNJ-69619178 in patients with advanced solid tumors or non-Hodgkin lymphomas. The primary objectives of this study were two-fold: to assess the safety of this novel, selective and potent small molecule inhibitor, and identify a recommended phase II dose. This study included thirty-two patients with salivary gland cancers, the vast majority of whom were enrolled in this study at Vall d’Hebron.

Published in Clinical Cancer Research ⁽¹⁹⁾ and first authored by Maria Vieito, a CORE Phase I Investigator of VHIO’s Research Unit for Molecular Therapy of Cancer (UITM) – CaixaResearch and Early Clinical Drug Development Group, the results showed preliminary antitumor activity in patients with adenoid cystic carcinoma (ACC) and reported an overall responses rate of 11.6%.

ACC is one of the most common types of salivary gland cancer. Although these tumors are slow growing, they are highly resistant to chemotherapy and eventually lead to a fatal outcome, underscoring the need to identify and develop more effective and targeted therapies against this disease. While the identification of biomarkers in response to PRMT5 inhibition will be key to advancing drug development, these initial results point to the promise of a new therapeutic avenue by targeting epigenetic modulators in salivary gland cancers.

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Genetic counseling programs to address the medical and psychological impact of incidental cancer-related exome results in patients with non-oncological diseases

Published in the Journal of Medical Genetics ⁽²⁰⁾, a case-control, retrospective study led by Judith Balmaña in collaboration with our colleagues at the Vall d’Hebron Research Institute (VHIR), reported on the clinical and psychological implications of secondary and incidental findings (SF/IF) in cancer susceptibility genes after exome sequencing in patients with rare, non-oncological disorders without a personal or family history of cancer. 

The investigators analyzed exome sequencing results from 533 patients who were tested for non-oncological pathologies at Vall d’Hebron’s Department of Clinical and Molecular Genetics (January 2018–September 2020), which yielded a 2.1% cancer-related SF/IF. These findings led to 20 individuals enrolling in a cancer surveillance program, 20% of whom were subsequently diagnosed with cancer, the majority presenting with early-stage disease.

While secondary findings can be helpful in the early detection of cancer, the researchers observed a significantly higher psychological impact in these individuals compared to patients who are routinely tested due to a personal or family history of cancer. This underscores the importance of tailored genetic counselling programs to help patients cope with secondary findings, as well as the development of new genetic delivery models and frameworks to lessen the psychological burden.

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New technologies, platforms and facilities in 2023

While our VHIO talents continue to drive progress against this devastating disease, we are always looking to develop and implement novel technologies and platforms. These efforts are crucial as we continue to advance precision medicine in oncology. 

As examples this year, we continue to pioneer liquid biopsy for the monitoring and tracking of disease—and crucially, to enable us to predict cancer’s next move and response to anticancer therapies. Driven by our comprehensive Molecular Prescreening Program, powered by one of our devoted patrons, the Fundación FERO, we have introduced the VHIO360 panel. In partnership with Guardant Health, our liquid biopsy technology enables tumor molecular profiling from blood samples. These efforts have also resulted in the molecular profiling of 1,968 cancer patients’ tumors, representing a significant increase over previous years.

Thanks to FERO’s Institutional Advanced Molecular Diagnostics Program (DIAMAV), our molecular prescreening efforts continue to occupy a top spot in oncogenomics in Europe, as we deliver on the promise of personalized therapy for an increasing number of cancer patients. 

Our ongoing CaixaResearch Advanced Oncology Research Program, supported by the ”la Caixa” Foundation, also a VHIO patron and longstanding supporter of our activities, enables our Research Unit for Molecular Therapy of Cancer (UITM) – CaixaResearch to leverage ‘big-data’ derived insights, integrate cutting-edge platforms, and deploy machine learning applications in cancer prognosis and prediction, all for the development of individually tailored and targeted therapies. 

Our new transversal and pioneering platform —UNIQUE – UNderstanding cancer through sIngle cell seQUEncing (also supported by the ”la Caixa” Foundation)—represents a powerful tool that will help us to unravel complex biological processes in cancer, develop new therapies and biomarkers. Designed to explore gene expression in tumor tissue and blood samples, enabling the characterization of expression patterns in individual cells, UNIQUE integrates three state-of-the-art single-cell technologies. This platform will consolidate VHIO as a reference hub in single-cell analysis and create new opportunities for advancing the clinical management of cancer patients.

2023 marked the start of the second edition of our Comprehensive Program of Cancer Immunotherapy and Immunology (CAIMI-II), supported by another of our wonderful patrons, the Fundación BBVA. Among many highlights this year, we have externally validated our VIGex signature for immunotherapy as a predictive tool to refine patient selection for early-phase clinical trials and strengthened our Advanced Therapies Program. We have also advanced insights for the development of personalized, minimally invasive T-cell therapies guided by whole-genome sequencing (WES) analysis of circulating free DNA (cfDNA), aiming to expose neoantigens. 

Thanks to the successes of CAMI-I and now CAMI-II, we continue to generate new insights into the mechanisms of resistance and response to cancer immunotherapies, opening new avenues for the development of immune-based treatment strategies. 

Since 2022, VHIO is accredited as a Severo Ochoa Center of Excellence (2022-2026). As one of our Institutional Programs, this award strengthens our research programs and groups in advancing cancer discovery and precision medicine in oncology. This prestigious distinction also reflects our Institute’s important contributions to cancer discovery and precision medicine at a global level. 

The new transversal Severo Ochoa Digitalization Unit (SOUND) is at the nexus of digital health and data science for research, clinical applications and patient-centered medicine. Since it was established in 2022, SOUND has launched the cVHIO portal for cancer genomics adapted to research data at VHIO. Reflecting our growing activities in this area, our Business Development, Innovation and Systems team now incorporates expertise in information systems to further advance our data infrastructures and capabilities. 

The support we receive from the Asociación Española Contra el Cáncer – AECC Excellence Program – Advanced Therapies Accelerator Program, now launched as one of our Institutional Programs, will help to establish VHIO as an international reference in the creation of new gene and cell products, advance existing ones in our pipeline, and increase Europe’s prominence in this emerging field. 

To accelerate the development of academic gene and cell therapy products, in parallel with translational and clinical research, we are planning the construction of a clean room, envisaged in 2024. This facility will allow the rapid and efficient development of new products, and upon successful evaluation, their transfer to centers for larger-scale production. 

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New builds

The unwavering support received from another of our patrons, the Fundació Privada CELLEX (CELLEX Private Foundation), has been instrumental in strengthening our collaborations, accelerating our efforts in cancer research, and fortifying our research infrastructures. Among many other facilities at Vall d’Hebron, it financed the construction of our state-of-the-art CELLEX Building, finalized in 2015, representing the hub of preclinical and translational research at VHIO. By financing the renovation of the first floor at CELLEX, fully completed this year, our eight new groups are now housed with the valuable space to grow and pursue emerging research areas.

As this report goes to print, we have opened our new building, the Saturnino Center. Providing 900.5 m² new space, this area is equipped with cutting-edge facilities and is dedicated to strengthening innovation and technology at VHIO. Representing a thriving new hub in the realm of bioinformatics and computational sciences, our Academic CRO teams, Bioinformatics Unit, Cancer Computational Biology, Computational Immunogenomics, Oncology Data Science (ODysSey), and Radiomics Groups have already moved in.

Another exciting development has been the purchase of land for a new VHIO build. Spanning 1,400 m², this plot, situated adjacent to our CELLEX Building, will enable us to sustain our growth in preclinical and translational research and deliver on future priorities and action points set out in our strategic plan. 

Watch this space! 

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Institutional recognitions and awards

In recognition of multidisciplinary integrated cancer care, translational and clinical cancer research of excellence at the Vall d'Hebron University Hospital (HUVH), Vall d’Hebron Institute of Oncology (VHIO), and Vall d’Hebron Research Institute (VHIR), I am delighted to report that Vall d’Hebron and the Universitat Autònoma de Barcelona (UAB) have been accredited by the Organisation of European Cancer Institutes (OECI) as a Comprehensive Cancer Centre through its Accreditation and Designation (A&D) Programme. 

In addition to the support received from the Asociación Española Contra el Cáncer – AECC Excellence Program – Advanced Therapies Accelerator Program, to develop academic gene and cell therapy products, our efforts in the emerging field of gene and cell therapies will be further strengthened thanks to funding received as part of the CERTERA (Consorcio Estatal en Red para el desarrollo de Medicamentos de Terapias Avanzadas) national network for Advanced Therapy Medicinal Products (ATMPs). This consortium, set within the framework of the Strategic Project for Economic Transformation and Recovery (known as PERTE) for Cutting-Edge Healthcare, aims to foster collaboration between national research centers, including Vall d’Hebron, with VHIO and the Vall d’Hebron Research Institute (VHIR) as project partners. 

In the realm of ATMPs, our team also obtained international funding from the European Commission for two collaborative projects: PragmaTIL and JOIN4ATMP.

Also enabling us to expand our activities as we pursue new directions in oncology, we obtained significant funding through the Instituto de Salud Carlos III – ISCIII (Carlos III Health Institute) Acción Estratégica en Salud 2023 (Strategic Action in Health 2023) call for R+D+I projects. The support from ISCIII, a public research body of the Spanish Ministry of Science, Innovation and Universities, will enable several VHIO groups to continue to conduct transformative translational and clinical research in precision medicine.

Accredited as a Health Research Institute (ISS IR-HUVH by ISCIII, the Vall d’Hebron University Hospital obtained significant funding through the FORTALECE program, which aims to strengthen pre-existing lines of research and innovation in the IIS and promote the generation of cutting-edge scientific knowledge to improve health and address the main health challenges in society. The awarded project —TACTIC: TACkling healthcare challenges through disruptive science, novel Therapies and systems medICine—will be co-led by consolidated groups at VHIO and VHIR to develop new perspectives for personalized and precision medicine in cancer, cardiovascular and neurological disorders and rare diseases—from childhood to adulthood. 

In addition to all these research highlights and developments, so many other activities and initiatives shaped our year of strategic expansion, celebration of new directions, and the dawn of precision oncology. I invite your to browse the pages that follow to discover more about who we are, what we do, and how we did it in 2023.

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The Last Word

As I write each year, as VHIO’s Director, I am honored to lead and work with our many cancer research talents and dedicated healthcare professionals in oncology. In partnership with many other investigators and partners across the globe, including our (co) lead and participation of powerful international consortia of excellence and alliances, our multidisciplinary, preclinical, translational and clinical teams work together to improve outcomes for cancer patients. 

But we must continue to push forward. As this report goes to print, I was invited to join forces with more than 50 leading representatives of the global scientific and research community, including three Nobel Prize Winners, to co-sign a “letter to the world” ⁽²¹⁾ calling for urgent investment to help accelerate a new golden age of cancer research. This letter calls for more support for life-saving research to beat this disease. As highlighted, by 2040, the number of cancer diagnoses globally is expected to increase by 50%, representing an unthinkable amount of sorrow and suffering for families across the world. The time for change is now. 

At VHIO, we are united by our intense desire to reduce the devastating burden this disease inflicts on society. We are grateful that this solemn commitment is also shared by our amazing Institutional Supporters and Patrons —Generalitat de Catalunya, Fundació Privada CELLEX, Fundación FERO, ”la Caixa” Foundation, and the Fundación BBVA— as well as the Severo Ochoa Center of Excellence, AECC Excellence and the AstraZeneca José Baselga Innovative Disruption (J-BID) programs, in addition to VHIO’s many other supporters, funding entities, agencies and individuals. I must also mention the many fundraising, public outreach and patient engagement activities organized and celebrated throughout the year. These experiences further inspire and encourage us to continue to make important progress against cancer. 

With our strategic expansion and continued focus on new directions and future horizons in precision oncology, all of which have defined our year in 2023, I firmly believe that we will be reporting bigger successes in thwarting this disease through 2024 and beyond.

We can, and will, do even better.

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References

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21. A ‘letter to the world’, an initiative led by Cancer Research UK (CRUK).