Ex-Vivo Testing of Myeloma Cells and Autologous Effector Cells from the Tumor Microenvironment Unveils Differential Response to Daratumumab and Isatuximab
Authors: Marin Constanza , Nicola Maribel , Andino Diego , Bernaschini Maria Laura , Ferreira Gimena , Moyano Alejandro , Ridano Magali , Campestri Reinaldo , Julian Freue , Jarchum Gustavo , Jarchum Sol , Garcia Pablo , García Juan José , Ferrero Maria Cecilia , Seifi Veronica , Remaggi Guillermina , Zaki Tarek Ali , Llorens Candelaria , Gatti Gerardo , Arroyo Daniela , Soria Gastón 
Published: December 2024

Introduction
Therapeutic antibodies have become central tools for the treatment of newly diagnosed and relapsed Multiple Myeloma (MM) patients. Daratumumab (Dara) and Isatuximab (Isa) are naked monoclonal antibodies targeting CD38 that have pleiotropic mechanisms of action (MoAs), including direct cytotoxic activity, Fc-dependent immune-effector mechanisms and immunomodulatory effects mediated by the elimination of CD38+ immune-suppressor cells. It is broadly recognized that the relative contribution of these different MoAs of MM cell killing differs significantly between Dara and Isa, presumably due to different epitopes recognized by each antibody in the CD38 molecule (van de Donk NWCJ et al., Blood 2018). However, it remains unclear how these functional differences may impact on therapeutic outcomes for different patients and, to date, both therapeutic antibodies are prescribed rather interchangeably at the clinic. Therefore, there is a growing clinical interest in novel actionable tools that may help determine which CD38-targeting antibody is more suitable for challenging patients, with a particular focus on relapsed/refractory settings.
OncoPrecision has developed a technology named Patient Micro-Avatars (PMAs) that mimics the tumor microenvironment and promotes the survival of Patient-Derived Cells (PDCs), allowing the ex-vivo testing of myeloma treatments within 7 days (Marin C et al., Blood (2023) 142 (Supplement 1): 5033). Importantly, PMAs not only enable the evaluation of the direct cytotoxic activity of Dara and Isa, but also the contribution of autologous effectors cells to trigger Antibody-Dependent Cellular Cytotoxicity (ADCC), as well as potential unspecific toxicities of these treatments on the non-myeloma cells form the tumor microenvironment.
Results
In this work, we used PMAs to explore the differential responses of Isa and Dara in a cohort of 23 Myeloma patients recruited from multiple healthcare centers in Argentina. We observed that while in most patients Dara and Isa performed similarly, ~15% of patients presented clear differential responses to these therapies. Our data indicates that while the abundance and proficiency of autologous effector cells from the microenvironment are critical to attain a full response to CD38 antibodies, the most striking differences between Dara and Isa responses are determined by intrinsic features of the MM cells from the different patients. This finding is supported by the fact that the effector cells from these patients trigger similar ADCC in a control MM cell line that serves as an internal quality control of system robustness and reproducibility, intrinsic to the co-culture technology through which PMAs are created.
Conclusions
The results of this study illustrate the potential of PMAs to comprehensively evaluate the performance therapeutic antibodies, even when designed for the same target, and how unlocking such actionable insights may serve as a powerful tool to enable greater personalization in therapy selection. Moreover, our exploration of Dara vs Isa using samples from MM patients indicates that these therapeutic antibodies are not always interchangeable, and that the side-by-side evaluation of these agents merits further clinical investigation.