Translational Immunomics in Hematological Neoplasms

PI: Bruno Paiva

Objectives:

1. To develop a complete immunophenotypic characterization of tumor cell precursors (including single cell level analysis) in healthy individuals of advanced age and in premalignant stages of MM (MGUS and smoldering MM) and AL to discover new markers involved in malignant transformation.
2. To study the role of circulating tumor cells (CTCs) and common progenitor cells (CPCs) in the dissemination from benign to malignant stages.
3. To discover the role of the immune system as a driver and Achilles heel of malignant transformation.

Objectives: 

• To compare the genomic profile of bone marrow mesenchymal stromal cells (MSCs) from healthy donors with those at diagnosis (in AL and MM).
• To investigate the genomic profile and biomarkers of BMMSCs at the time of diagnosis (AL and MM), at the time of MRD and at the time of relapse in both diseases.

Our general objective is to study and to know in depth both the complete transcriptome (especially the one referring to long non-coding RNAs (lncRNAs)), the altered epigenome and the aberrant metabolism of tumor plasma cells of monoclonal gammopathy of uncertain significance and multiple myeloma. This objective pursues the aim to better understand the biology of the disease and to detect new targets for the development of new therapeutic strategies for the treatment and improvement of the quality of life of these patients.

Objectives:

• Analysis of the complete transcriptome of lncRNAs of multiple myeloma tumor cells, in the context of the humoral immune response, and functional study of lncRNAs altered in this disease.
• Design and validate new RNA-based therapeutic strategies for the treatment of multiple myeloma.
• Analysis of the epigenome of the tumor plasma cell of monoclonal gammopathy of uncertain significance and multiple myeloma, both in mouse models and primary samples, and the functional study of its alteration in this disease.
• Detection and functional studies on essential and synthetic lethal metabolic genes in multiple myeloma.
• Synthesize and validate new small molecules directed against genetic and metabolic targets for the treatment of multiple myeloma.

PI: Bruno Paiva

Objectives:

• Define the genome and proteome of MRD vs diagnostic clones to understand the molecular signature of ultra-chemoresistant cells that allow them to resist therapy.
• To understand the relevance of molecular and immunological signatures of MRD clones on patient survival.
• Optimize MRD and liquid biopsy strategies to monitor treatment efficacy: i) is sustained MRD negativity a surrogate for operational cure; ii) role of immune surveillance in MRD+ patients; iii) role of immune surveillance in MRD+ patients.

PI: Bruno Paiva 

Objectives:

• Analyze the mechanisms of action and synergy of efficacy in tumor cells and immune system.
• Implement new generation biomarkers to monitor clinical trials.

Objectives:

We have generated a series of experimental models in genetically modified mice that recapitulate the main biological and clinical features of multiple myeloma (MM), including the progressive development of a precursor phase of the disease in the bone marrow (resembling monoclonal gammopathy of uncertain significance MGUS) that eventually progresses to clinically symptomatic MM.

These experimental models include the main genetic lesions detected in patients with MM, allowing them to be sub-classified into genetic risk groups (standard, intermediate, and high). Our preliminary data show that malignant plasma cells in mice are very similar to cells from patients with the disease, both phenotypically and molecularly, in the different genetic risk subgroups.

We also observed that the bone marrow microenvironment in which disease develops in mice includes a progressive increase in infiltrating CD8 T lymphocytes, with effector phenotype and PD-1 expression. In this context, depletion of these T subpopulations accelerates the development of MM, suggesting a role of the immune system in the development of the disease.

The overall objective of the present project is to define the immune biology and the response to immunotherapy strategies in the different genetic risk subgroups in MM, and is based on the preliminary results obtained through the development and characterization of experimental murine models.

In the present project we will continue the study of such models using high resolution cellular and molecular analysis techniques, which have been developed in our hemato-oncology department, and the results will be analyzed with integrative methods of computational biology.

The specific objectives are the following:

1. Determine the molecular mechanisms that converge to promote the progressive transformation of plasma cells in the different experimental models.
2. Characterize the role of the immune system in the progressive transition between MGUS and MM phase in different experimental models.
3. To evaluate the response to different combinations of targeted therapeutic agents and immunotherapy in the experimental models.
4. Characterize the mechanisms of therapeutic response and resistance to immunotherapy in the tumor plasma cell and bone marrow microenvironment.
5. The mouse results will be analyzed in the context of human pathology, with the aim of defining the immune biology of MM development with unprecedented resolution, which will hopefully contribute to the experimental design of future clinical trials of MM patients.