The tumor microenvironment contributes to malignant cell growth and drug resistance through diverse mechanisms including elaboration of stimulatory cytokines that promote tumor cell proliferation and neoangiogenesis; release by marrow mesenchymal stromal cells of exosomes containing IL6, fibronectin, and microRNAs that support growth of the neoplastic plasma cells;1 adhesion of malignant cells to cellular or matrix components of the microenvironment that confers chemotherapy resistance by upregulating survival and anti-apoptotic pathways;2 and specific genetic alterations in matrix components, such as deletion of Dicer1 in osteoprogenitors or an activating mutation of β-catenin in osteoblasts, that induce development of leukemia.3,4 Now Dr. Christian Pallasch and colleagues at the Massachusetts Institute of Technology in Cambridge, Massachusetts, and the University of Cologne in Cologne, Germany, have identified a mechanism by which the microenvironment confers resistance to antibody therapy. But this story has a happy ending as the investigators have identified a means to overcome the resistance and thereby restore response to treatment.
Monoclonal antibodies, such as rituximab (anti-CD20) and alemtuzumab (anti-CD52), directed against antigens expressed on tumor cells are fundamental components of chemoimmunotherapy regimens used to treat lymphomas and some leukemias. The anti-tumor effects of antibodies are mediated by immunoglobulin activation of the classical pathway of complement and/or by antibody-dependent cell-mediated cytotoxicity (ADCC), which relies on recognition of the Fc portion of the immunoglobulin molecule by natural killer cells and macrophages.
Presence of tumor cells in the bone marrow microenvironment can block macrophage activation and inhibit the ability of macrophages to engulf tumor cells. However, treatment with chemotherapy (CTX) can induce changes that activate the macrophages and promote phagocytosis.Reprinted from Cell, Vol. 156, Pallasch CP, et al, Sensitizing protective tumor microenvironments to antibody-mediated therapy, Page 590-602, Copyright 2014, with permission from Elsevier.
Presence of tumor cells in the bone marrow microenvironment can block macrophage activation and inhibit the ability of macrophages to engulf tumor cells. However, treatment with chemotherapy (CTX) can induce changes that activate the macrophages and promote phagocytosis.Reprinted from Cell, Vol. 156, Pallasch CP, et al, Sensitizing protective tumor microenvironments to antibody-mediated therapy, Page 590-602, Copyright 2014, with permission from Elsevier.
Dr. Pallasch and colleagues developed a murine xenograft model of the aggressive “double-hit” form of non-Hodgkin lymphoma by transfecting human umbilical cord blood progenitor cells with a bcl2/myc construct. Tumor cells in the blood and spleen of these animals were found to be transiently susceptible to the anti-CD52 antibody alemtuzumab, but tumor cells in the bone marrow were resistant to such treatment. Subsequent studies suggested that the resistance was a consequence of a tumor-induced process that rendered macrophages unable to mediate ADCC (Figure). But when cyclophosphamide was given within one day before or after alemtuzumab treatment, efficient phagocytosis was observed along with a reduction in tumor burden (Figure). The combination of cyclophosphamide and alemtuzumab was synergistic, producing a reduction in tumor burden 160-fold greater than that predicted if the effects of the combination were additive, and durable complete responses were observed in the animals treated with the antibody/cyclophosphamide combination. Further analysis revealed that production of the stress-related cytokines IL8, TNFα, VEGF, and CCL4 (together called the “acute secretory activating phenotype” or ASAP), was induced by cyclophosphamide treatment, and that phagocytic activity was dependent on these cytokines. ASAP was also observed to be inducible by treatment with cyclophosphamide and rituximab in murine models of Burkitt lymphoma and BCR-ABL+ ALL.
In Brief
When used as single agents, antibodies are ineffective in eradicating leukemia and lymphoma, but the combination of chemotherapy and antibody can be highly efficacious. The remarkable findings of Dr. Pallasch and colleagues that the tumor microenvironment inhibits macrophage function and that this inhibition can be ameliorated by treatment with chemotherapy (Figure) provides a plausible explanation for the success of chemoimmunotherapy combinations such as fludarabine, cyclophosphamide, and rituximab (FCR); chlorambucil-alemtuzumab; and R-CHOP. Understanding how ASAP is induced may result in rational development of specific pharmacologic modalities with favorable therapeutic profiles such that serious adverse effects (e.g., secondary malignancy) of alkylating agents including cyclophosphamide and chlorambucil can be avoided.
