Protective tumor microenvironments can induce resistance to otherwise effective antibody-based anticancer therapies. Adding the chemotherapeutic cyclophosphamide to the treatment can render resistant leukemia cells sensitive to immunity-mediated killing by remodeling the tumor cell surroundings in the bone marrow (Cell 156, 560–602, 2014).

Using a humanized mouse model of acute lymphoblastic leukemia treated with alemtuzumab (anti-CD52 antibody), Christian Pallasch and his colleagues have shown that infiltration of cancer cells into the bone marrow creates a specific protective niche that blocks phagocytosis of antibody-targeted tumor cells. An RNAi screen in vivo demonstrated that increased expression of certain molecules in leukemic cells inhibits their engulfment by macrophages. In an attempt to overcome resistance, the authors combined cyclophosphamide with the antibody, a strategy that induced a secretory phenotype that triggers release of CCL4, IL-8, VEGF and TNF-α from leukemic cells and almost eliminated disease in the bone marrow. This cytokine secretion increased infiltration of macrophages into the bone marrow niche and their phagocytic activity. Notably, this synergistic effect was also seen in other leukemia mouse models.

Bone marrow biopsies from patients with leukemia confirmed macrophage abundance in the bone marrow after the combination treatment. Although the treatment window during which this combination therapy is effective is very small, the findings suggest conventional therapy could be used to induce innate immune killing and boost efficacy of targeted therapies.