Table 3.
The role of tumor-associated macrophages (TAM) as treatment target in hematologic malignancies.
| Reference | Treatment | Disease | Mechanism of Action | Type of Study | Results |
|---|---|---|---|---|---|
| Benerjee et al. [158] | Trabectedin | CLL | Macrophage killing due to CCL2-CCR2 signalling axis inhibition, antiangiogenic |
Leukemic mouse model Human CLL cells |
Apoptosis trigger MDSC and TAM depletion. M1 shift Memory T-cells increase Increased mice survival |
| Cucè et al. [159] | Trabectedin | MM | Macrophage killing due to CCL2-CCR2 signalling axis inhibition, antiangiogenic |
Human MM cells | Apoptosis trigger VEGF depletion NK cells upregulation |
| Polk et al. [74] | CSF-1R signalling inhibitor |
CLL | CSF-1R signalling Inhibition |
Human CLL cells | NLC depletion Reduced CLL cells Viability |
| Li et al. [160] | BLZ-945 | T-ALL | CSF-1R signalling Inhibition |
Mouse model | Inhibition of BMDMs viability, LAMs polarization blocking and depletion. Combination of CSF-1R inhibitor and VCR increased the survival of T-ALL mice. |
| Komohara et al. [161] | PLX3397 | ATLL | CSF-1R signalling Inhibition |
ATLL cells | Inhibition of ATLL cell proliferation Apoptosis induction |
| Edwards et al. [162] | GW-2580, ARRY-382 | CLL | CSF-1R signaling Inhibition |
Human CLL cells | NLC depletion BCR signaling disruption (together with ibrutinib or idelalisib) |
| Walker et al. [163] | CXCR4 inhibitor plerixafor | T-ALL | CXCR4/CXCL12 axis inhibition | In vitro Xenograft model |
Improved survival (together with ruxolitinib and venetoclax) M1 shift of TAM |
| McClellan et al. [164] | Exposure to myeloid differentiation promoting cytokines |
Ph+ B-ALL | B-ALL blasts reprogram into Macrophage |
In vitro Xenograft model |
Eliminates B-ALL cells leukemogenicity. |
| De Vos et al. [165] | Dacetuzumab | R/R DLBCL | anti-CD40 mAb | Phase II study, 46 patients | Disease control (CR/PR/SD) 37% |
| Liu et al. [166] | Preemptive IFN-α | ALL | TAM reprogramming | 47 B-ALL 21 T-ALL (MRD+ after allo-SCT) |
M1 shift of TAM, 76% of cases became MRD- |
| Mancuso et al. [167] | Artesunate | Leukemia | TAM reprogramming JAK2/STAT3 Downregulation |
Human monocytes, leukemic cells |
Increase in inflammatory monocytes. After contact with monocytes, in vitro apoptosis of leukemic cells increased |
| Kriston et al. [168] | Lenalidomide | CLL | Abrogation of BMSC survival effect | CLL cells | Abrogation of anti-apoptotic effect of BMSCs on CLL cells. |
| Chao et al. [169] | Anti-CD47 mAb | ALL | Enabled phagocytosis of tumor cells by TAM | Mouse model | Induces remissions in ALL-engrafted mice |
| Advani et al. [170] | Anti-CD47 mAb Hu5F9-G4 | R/R DLBCL or FL | Enabled phagocytosis of tumor cells by TAM | Phase 1b-2 study | ORR 50% CR rate 36% |
Abbreviations: CCL, chemokine ligands with C-C motif; CCR, C-C chemokine receptor; CLL, chronic lymphocytic leukemia; MDSC, myeloid-derived suppressor cells; TAM, tumor-associated macrophages; MM, multiple myeloma; VEGF, vascular endothelial growth factor; NK, natural killer; CSF-1R, colony stimulating factor-1 receptor; NLC, nurse-like cells; ALL, acute lymphoblastic leukemia; BMDM, bone marrow-derived macrophages; LAM, leukemia-associated macrophages; VCR, vincristine; ATLL, adult T-cell lymphoma leukemia; BCR, B-cell receptor; CXCR, chemokine receptor; Ph, Philadelphia; mAb, monoclonal antibody; CR, complete response; PR, partial response; SD, stable disease; IFN, interferon; allo-SCT, allogeneic stem-cell transplantation; MRD, minimal residual disease; JAK, Janus kinase, BMSC, bone marrow stromal cells; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; ORR, overall response rate.