Serum proteome modulations upon treatment provides biological insight on response to treatment in relapsed mantle cell lymphoma

Abstract

Background: The possibility to monitor patient's serum proteome during treatment can provide deepened understanding of the biology associated with response to specific drugs. Non-invasive serum sampling provides an opportunity for sustainable repetitive sampling of patients, which allows for more frequent evaluation of the biological response and enhanced flexibility in treatment selection in contrast to tissue biopsies. Aim: To pin-point biologically relevant changes in pre-and on-treatment serum proteome samples in relapsed mantle cell lymphoma (MCL) patients, leading to insight into mechanisms behind response to treatment in sub-groups of patients. Methods: Pre-and on-treatment serum samples from relapsed MCL patients treated with a triple combination therapy of rituximab, ibrutinib and lenalidomide were available for the study, together with detailed clinicopathological information. A microarray technology targeting 158 serum proteins using 371 antibody-fragments was used to compare the serum proteome at the two time-points. Results: Proteins modulated by the treatment were shown to be associated to a MCL sub-group with ATM/TP53 alterations, which emphasizes the importance of treatment stratification. Absolute values of serum protein levels in on-treatment samples were highly variable and showed no correlation to outcome. To circumvent the challenge of variability in absolute serum protein levels, the velocity of change of individual serum proteins was used to identify proteins associated with clinical response. Increased values of TGF-β1, CD40 and complement component 4 comparing pre-and on-treatment samples were associated with remaining minimal residual disease (MRD) and increased BTK was associated with short progression-free survival (PFS). Conclusion: We show that the genetic sub-type of MCL affects the biological response to treatment in serum and that the change in defined serum proteins reveals the biology associated with clinical response.

Characterization of Human B Cell Hematological Malignancies Using Protein-Based Approaches

“…Assessment of the healthy B cell pool of patients to find disease mechanisms [128] DLBCL Evaluation of the intertumoral and intratumoral heterogeneity [129] Identification of clinically relevant interactions between tumor-associated macrophages and blood endothelial cells [130] Finding proteins overexpressed in relapsed and refractory patients [131] Comparison of major immune subsets in DLBCL and double-hit lymphoma [132] Identification of differences in immune cell compartments across various stages of MM and healthy individuals [133] Description of the immune tumor microenvironment in patients with MGUS and MM at diagnosis and post-initial therapies [134] Analysis of the immune checkpoint signature and regulation [135] Characterization of NK cells in newly diagnosed cases [136] Understanding of the molecular and cellular complexities underlying disease heterogeneity and prognosis [137] Provision of insights into the mechanism of action of daratumumab and the anti-PD-L1 monoclonal antibody atezolizumab [138] MM Employment of protein profiling as a tool for prognosis and treatment stratification [139] Other Tools RRPA CLL Prediction of survival outcomes based on the proteomic signature [140] Protein Microarrays FL Identification of antibodies that distinguish lymphoid follicles in FL and benign follicular hyperplasia [141] MCL Monitoring of patient serum proteomes to identify treatment-modulated proteins linked to the presence of minimal residual disease [142] Western Blot MCL Definition of the pathologic hallmark of MCL as a tool for the diagnosis [143] araCTP, Next, we describe the basis of the main protein-based strategies employed for studying B cell malignancies.…”

“…Specific proteins, such as TGF-β1, CD40, and complement component 4, were linked to the presence of minimal residual disease in the treated samples. Elevated BTK levels were also associated with shorter PFS [142]. In another study, LC-MS/MS analysis of salivary samples before, during, and after chemotherapy provided valuable insights into the dynamics of the disease and response to treatment [99].…”