The lack of reliable immunocompetent mouse models of multiple myeloma (MM) for mechanistic assessment restricts preclinical immunotherapy research, representing an unmet medical need. A recent study by researchers at the University of Navarra in Pamplona, Spain, represents an excellent example of preclinical research by establishing fifteen genetically engineered mouse models covering the key factors during human MM pathogenesis.
Larrayoz M, et al. performed an integrative analysis including coupled scRNA-seq and TCR-seq to test and predict response to immunotherapy drug combinations. The authors propose a model in which MM is driven by genetically heterogeneous lesions that converge in a common oncogenic axis during progression from precursor states. This genetic axis controls the immune-escape mechanisms that reshape the BM microenvironment during MM development, and conditions immunotherapy outcomes.
“By integrating studies in our mouse models and in samples from patients we are defining cellular and molecular events that originate MM, along with the immunological traits underlying progressive disease development”, says Jose A. Martinez-Climent, senior author of the study.
These pre-clinical models by recapitulating the principal MM genetic and immunological characteristics hold the potential of expanding our knowledge of the biological aspects of the disease during progression. Moreover, these models could accelerate our bench to bedside research effort, leading to the optimization of future immunotherapy clinical trial designs. “Our next step is the “humanization” of selective therapy targets in the mouse cells by replacing endogenous genes by human genes. This strategy allows testing clinical immunotherapy drugs against human protein targets that otherwise cannot be evaluated in murine systems”, explains Martinez-Climent.
As proof-of-concept, the group has already established MM models with humanized BCMA and CD3ε proteins in MM and T cells, respectively, for testing BCMAxCD3 bi-specific antibodies. Such humanization efforts in experimental mice are being supported by a Translational Research Grant from the IMS/Rinney Foundation.
Larrayoz M, et al. Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma Nature Medicine https://doi.org/10.1038/s41591-022-02178-3 (2023)