Aggressive T cell Lymphomas, integrated clinical and genomic analysis for a precision medicine.

Project Information

PRECISMEDLYM

Grant agreement ID: 882597

DOI

10.3030/882597

Project terminated on 17 April 2022

EC signature date 17 March 2020

Start date 28 September 2020

End date 27 September 2022

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 160 932,48

EU contribution

€ 160 932,48

Coordinated by

INSTITUTO INVESTIGACION SANITARIA FUNDACION JIMENEZ DIAZ
Spain

Periodic Reporting for period 1 - PRECISMEDLYM (Aggressive T cell Lymphomas, integrated clinical and genomic analysis for a precision medicine.)

Reporting period: 2020-09-28 to 2022-09-27

Summary of the context and overall objectives of the project

T-cell lymphoma is a heterogeneous group of aggressive non-Hodgkin lymphomas associated with a poor clinical outcome. T and B-cell lymphomas classification is complex and involved a combination of clinical, histological and immunohistochemical markers, however frequently has a low reproductivity. Importantly, this classification is critical for patient diagnosis and treatment. Although, recent advances in molecular biology techniques have contributed additional tools for providing more accurate diagnosis and new therapeutic targets, nowadays the need for reliable diagnostic and prognostic markers remains partially unmet.

T and B-cell non Hodgkin lymphomas constitute malignant neoplasms with an adverse outcome and low probability of survival. Furthermore, these patients are exposed to high toxicity treatments which are not specific for the different types of diseases. Current integrative clinical and molecular studies are improving the identification of specific subtypes, allowing the recognition of targeted therapy and prognostic markers with a minimum toxicity and maximum clinical benefit for the patients.

The objectives of the PRECYSMEDLYM project were the identification of new molecular biomarkers of prognostic utility in the context of precision medicine; perform an in-depth analysis of cellular subpopulation in microenvironment tumor; design new monoclonal antibodies using the biomarkers previously identified.

Conclusions: The accomplishment of the PRECYSMEDLYM project has allowed the routine application of molecular techniques in clinical patient samples with different types of lymphoma. Moreover, we have provided a better understanding of the pathogenesis of the corresponding lymphoma subtypes, as well as proposed diagnostic, predictive and prognostic molecular signatures.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In PRECYSMEDLYM project we have carried out comparative gene expression (GEP) and next generation sequencing (NGS) analysis of the different histological T and B-cell lymphomas. Firstly, we studied the gene expression of 27 genes associated with R-CHOP response (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) in 197 patients with Diffuse large B-cell lymphoma (DLBCL). We generated a risk score combining the International Prognostic Index with cell of origin and double expression of MYC/BCL2.

Next, we analyzed the GEP and NGS of Peripheral T-cell lymphoma (PTCL) subtypes: angioimmunoblastic T-cell lymphoma, (AITL); PTCL-with T follicular helper phenotype, (PTCL-TFH); PTCL-not otherwise signified, (PTCL-NOS). We identified gene signatures allowing the molecular recognition of risk groups, including TFH, cytotoxic and cellular specific markers. This study also showed mutational significant differences within the three subgroups.

The third studied included GEP in mycosis fungoides (MF) patients in different stages of the disease. The results of this scrutiny revealed that Gene-expression profiling using a customized NanoString platform can be applied to routine paraffin MF samples providing useful data for better understanding of MF genesis and progression. Additionally, MF samples showed an unexpected high degree of inter-tumoral heterogeneity, suggesting an individual molecular signature features.

Thereafter, we analyzed 89 Spanish patients with Extranodal natural killer/T-cell lymphoma, nasal type (ENKTL-NT). We observed EBV, cytotoxic, T-cell receptor, and proliferation gene signatures, and increased expression of the targetable gene pathway which associates PI3K/MTOR/AKT with NF-kB and TGFB. We did not recognize a significant association between clinical presentation, survival and mutated genes.

Finally, we are currently analysis the GEP profile of Merkel cell carcinoma (MCC) patients and the gene mutational landscape of 48 patients.

The results from this study has been published in three open access journal articles, two under review journal articles and one in progress. Furthermore, I have communicated the PRECYSMEDLYM outcome in several International Congress with a Scientific and Medical audiences. As a dissemination strategy, I have also presented this data in clinical and scientific seminars and I have employed the social media to improve the diffusion of the project ongoing, publications and conference attendance (Linkedin, Researchgate, Tweeter, Instagram).

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Non- Hodgkin lymphoma patients present a very low probability of survival and unfavorable prognosis with 5 years relative survival (36-56% depending on ethnic/sex). They constitute a heterogeneous collection of B-, T and NK-cell neoplasm that historically have been classified based on their morphological features. Next Generation Sequencing and Gene Expression analysis has enabled the elucidation of the remarkable complexity of no- Hodgkin lymphomas, however there is still a significant number of uncategorized patients.

Patients treated for Non- Hodgkin lymphoma have a worse prognosis than other types of cancer so may have a higher prevalence of psychological and social morbidity. Furthermore, adjusting to life with these diseases produce a significant impact on patient and patient´s families wellbeing. Beside the social impact, it also has a tremendous economic effect resulting from patient treatment, patient palliative care and shortness of patient´s contribution to the economic society.

The recent advances of targeted therapy have proven that monoclonal antibodies based drugs have significant effect in some of the non- Hodgkin lymphomas (DLCBL, T-cell, etc.). Deepening understanding of the pathogenesis mechanism of non- Hodgkin lymphomas subtypes contribute to recognize new monoclonal antibodies against specific patients reducing therapy resistance and toxicity.

The accomplishment of the PRECYSMEDLYM project has allowed the routine application of molecular techniques in clinical patient samples with different types of lymphoma. Moreover, we have provided a better understanding of the pathogenesis of the corresponding lymphoma subtypes, as well as proposed diagnostic, predictive and prognostic molecular signatures.

Summary project