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methods allow the study of multicellular interactions between human stromal cells and HSC.46
Targeting the tumor microenvironment
Targeting the tumor microenvironment in B-cell lymphomas
Other ways to target the tumor microenvironment in B- cell malignancies have been exemplified by research in Dr. Gribben’s laboratory and take advantage of the fact that lymphoma cells live in an immune cell-enriched microenvi- ronment. However, immune cells do not function normally because CLL or lymphoma cells reduce the F-actin immune synapse formation in tumor-infiltrating T cells. Nonetheless, impaired T-cell function can be therapeutical- ly reverted by the immunomodulatory drug lenalidomide.47 which has recently been approved for the treatment of lym- phoma. In a subsequent study, the inhibitory B7-related molecules CD200, CD274 (PD-L1), CD276 (B7-H3) and VD270 (HVEM) were identified as key mediators of the T- cell synapse defect.48 Consequently, the PD1-PDL1 axis has emerged as a highly promising target in CLL and lym- phoma.49,50 These results have been extrapolated to solid tumors, in which PD1 expression has become both a bio- marker and a therapeutic target.
Engineering T cells to overcome the immunosuppressive tumor microenvironment
Engineered T cells can be used to overcome the immuno- suppressive tumor microenvironment. Generating tumor- specific lymphocytes has proven challenging given that many tumors are not very immunogenic. A revolutionary approach in immunotherapy is to combine the variable regions of antibodies (which recognize epitopes shared by tumors) with the constant regions of the T-cell receptor to generate chimeric antigen receptor (CAR) T cells.51 This approach has been improved recently by adding co-stimu- latory domains. CD19-specific CAR-T cells have provided impressive results in acute lymphoblastic leukemia, with reported cure of chemorefractory disease. Some lessons learned from these studies are: (i) chemotherapy is essen- tial; (ii) it is critical to include a co-stimulatory domain; (iii) targeting a single antigen may enable immune escape; and (iv) significant toxicities (neural, cytokine storm) should be avoided in the future by improving the specificity and effi- cacy of the approach (to reduce the number of CAR-T cells infused). However, despite the impressive positive results of CD19-specific CAR-T cells in acute lymphoblastic leukemia, AML has proven more difficult to treat. In this regard, integrated transcriptomics and proteomics have not identified single candidate targets in AML, although combi- natorial strategies have been proposed.52,53
Targeting altered metabolism in the leukemia microenvironment
It is now clear that the bone marrow microenvironment rewires energy metabolism in AML; however, targeting metabolic vulnerabilities in AML has proven challenging given the high degree of metabolic adaptation in AML cells. One key driver of metabolic reprograming in the leukemic bone marrow microenvironment is hypoxia. Most tumors are typically hypoxic, as cancer cells avidly consume oxy- gen and blood vessels become progressively compressed or obstructed by the growing tumor mass. Cancerous tissue in
both solid and liquid tumors develops chronic hypoxia, which is associated with resistance to therapy and immune suppression.54 However, the role of (low) oxygen in the pro- gression and chemoresistance of leukemia remains contro- versial. Recently, a hypoxia-activated prodrug (TH-302) was tested in models of AML in vivo.55 TH-302 is able to eliminate cancer cells residing in hypoxic microenviron- ments. Hypoxic niches were increased in a syngeneic AML murine model, but AML cells surviving chemotherapy could be targeted by TH-302, which improved mouse sur- vival. On the other hand, metabolic reprogramming was previously reported to become more dependent on glyco- lysis. However, recent findings have challenged this view by showing that many tumors rely primarily on OXPHOS. Although targeting OXPHOS clinically presents some obstacles, drugs such as IACS-010759, a highly effective and selective small-molecule inhibitor of complex I of the mitochondrial electron transport chain, can reduce tumor burden in experimental models of brain cancer and AML.56
Interferon in myeloproliferative neoplasms
Connected with the effects of IFN-α on HSC and their microenvironment described above, studies by Dr. Kiladjian and others have shown that IFN-α is one of very few drugs capable of reducing the mutant allele burden in myeloproliferative neoplasms. Ropeginterferon triggered a dose-dependent anti-proliferative effect in JAK2V617F- mutated cell lines, whereas it did not affect the differentia- tion of normal CD34+ cells.57 One possibility might be to combine IFN with JAK inhibition, since the latter does not seem to modify the allele burden, but does dampen inflam- mation. IFN has been shown to induce molecular histopathological responses in myelofibrosis but it also induces immune and inflammatory toxicity. Ruxolitinib may offset IFN toxicity and the combination of these two drugs might enhance the molecular and histopathological response rate. However, it is possible that the anti-JAK1 activity of ruxolitinib might antagonize IFN signaling. These issues remain to be investigated in future studies.
CXCR4 inhibitors
The CXCL12-CXCR4 axis regulates bone marrow hom- ing, retention, proliferation and egress of HSC and also affects the traffic of leukocytes. In particular, CXCR4 expres- sion in HSC is necessary to keep these cells in the CXCL12- enriched bone marrow microenvironment. Dr. Peled and others have shown that efficient blockade of CXCR4 mobi- lizes HSC from the bone marrow into the circulation. Plerixafor (AMD3100) is a first-generation CXCR4 antago- nist which has low affinity for the receptor. It is approved for HSC mobilization (but only in combination with granu- locyte colony-stimulating factor) for the treatment of multi- ple myeloma and non-Hodgkin lymphoma. The new-gener- ation CXCR4 inhibitor BL8040 binds CXCR4 with higher affinity (1-2 nM) than AMD3100 (84 nM).58 In addition, whereas AMD3100 rapidly dissociates from CXCR4, BL8040 behaves as an inverse agonist and has a slow off- rate, causing more sustained CXCR4 inhibition. CXCR4 directly or indirectly stimulates tumor growth and regulates stromal cell adhesion-mediated drug resistance to chemotherapy. BL8040 can induce the mobilization of AML cells into the circulation and promote AML differentiation and apoptosis. A synergistic effect can be observed in com- bination with FLT3 or BCL-2 inhibitors,59 suggesting that combination therapies could be useful in AML.
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haematologica | 2019; 104(10)