Therapeutic effects of CSF1R-blocking antibodies in multiple myeloma

Abstract

Our previous studies showed that macrophages (MФs), especially myeloma-associated MФs (MAMs) induce chemoresistance in human myeloma. Here we explored the potential of targeting MФs, by using colony-stimulating factor 1 receptor (CSF1R)-blocking mAbs, to treat myeloma. Our results showed that CSF1R blockade specifically inhibited the differentiation, proliferation and survival of murine M2 MФs and MAMs, and repolarized MAMs towards M1-like MФs in vitro. CSF1R blockade alone inhibited myeloma growth in vivo, by partially depleting MAMs, polarizing MAMs to the M1 phenotype, and inducing a tumor-specific cytotoxic CD4+ T cell response. Similarly, genetically depleting MФs in myeloma-bearing MMDTR mice retarded myeloma growth in vivo. Furthermore, the combination of CSF1R blockade and chemotherapy such as bortezomib or melphalan displayed an additive therapeutic efficacy against established myeloma. Finally, a fully human CSF1R blocking mAb, similar to its murine counterpart, was able to inhibit the differentiation, proliferation and survival of human MФs. Thus, this study provides the first direct in vivo evidence that MΦs and MAMs are indeed important for myeloma development and progression. Our results also suggest that targeting MAMs by CSF1R blocking mAbs may be promising methods to (re)sensitize myeloma cells to chemotherapy and promote anti-myeloma immune responses in patients.

Tumor-Associated Macrophages in Hematologic Malignancies: New Insights and Targeted Therapies

“…A similar effect was recently observed in AML where CSF1R inhibition reduced paracrine growth signals from the TME, resulting in reduced leukemic cell viability [76]. In MM, blocking CSF1R with antibody or depleting macrophages both led to reduced tumor growth and sensitized myeloma cells to chemotherapy in vivo [77]. The antitumoral effects of CSF1 blockade was also observed in mantle cell lymphoma where treatments with GW2580, a CSF1R inhibitor reduced lymphoma cell survival, irrespective of their sensitivity to ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor [78].…”

CSF‐1R inhibition disrupts the dialog between leukaemia cells and macrophages and delays leukaemia progression

“…A recent study reported that CSF‐1R inhibitors exhibited anti‐tumour activity in AML by blocking paracrine signals from support cells 21 . Moreover, the effect of CSF‐1R inhibitors has been also shown in multiple myeloma and in CLL 19,22 . BLZ945 is a CSF‐1R inhibitor that selectively binds to CSF‐1R expressed on TAMs and inhibits the proliferation of TAMs 32‐34 .…”

“…Recent studies have shown that CSF‐1R blockage by inhibitors or antibodies improves the efficacy of chemotherapy in multiple solid tumours, such as glioma, cervical and mammary tumour 17,18 . Furthermore, targeting CSF‐1R has been proven effective on haematopoietic malignancies, such as multiple myeloma, chronic lymphocytic leukaemia (CLL) and a subset of AML 19‐23 …”

High CD206 levels in Hodgkin lymphoma‐educated macrophages are linked to matrix‐remodeling and lymphoma dissemination

“…In summary, we hypothesize that the observed in vitro and in ovo regulation of CD206 in Mφ might also occur in vivo and contribute to CD206 abundance in advanced stages of HL. Our data identify CD206 as a potential target for the modulation of Mφ activation in addition to the recently discussed targeting of the CSF1R (Luo et al, 2006;Mart ın-Moreno et al, 2015;Pham et al, 2018;Pyonteck et al, 2013;Ries et al, 2014;Wang et al, 2018;Zhu et al, 2014). Inhibition of the Jak/STAT pathway targets not only lymphoma cells directly, but may also affect lymphoma-educated Mφ development and/or activity.…”