Disrupting the food chain in B cell lymphomas: co-operation between CXCR4 antagonists and antibodies

In tissue microenvironments, such as the secondary lymphatic tissues or the bone marrow, lymphoma B cells are nourished by stromal cells, which form protective niches and provide survival- and drug resistance-signals. Once removed from the host environment and placed into culture dishes, most lymphoma cells undergo spontaneous apoptosis, unless they are co-cultured with supportive stromal feeder layers. Such simple, early experiments illustrate the importance of the microenvironment in B cell malignancies, which has become an area of growing translational research. Therapeutic targeting of the microenvironment requires identification and disruption of critical pathways of cross talk between the B cells and their nursing stroma. Given the diversity of non-tumoral cells interspersed with the malignant B cells, such as mesenchymal (actin/SMA +) stromal cells, CD68 + monocytes/macrophages (also called nurselike cells/NLCs or lymphoma-associated macrophages/LAMs) and T cells, it is not surprising that the list of molecules involved in this cross talk, and hence the list of potential targets, is very long. Therefore, it remains a challenge to identify and target the most relevant actors in the microenvironment. To make things more complex, different B cell malignancies may use different pathways for receiving optimal growth support, and even within distinct B cell lymphomas, certain pathways may be more or less relevant in individual patients. For example, B cell receptor (BCR) signaling is a central pathway for promoting disease progression in patients with diffuse large cell lymphoma (DLBCL) [1] and chronic lymphocytic leukemia (CLL) [2]. However, subsets of patients, for example patients with DLBCL with oncogenic CARD11 mutations, or patients with CLL expressing high levels of ZAP-703, display higher levels of BCR signaling and therefore may be more responsive to inhibitors targeting this pathway.

The CXCR4–CXCL12 axis is another critical pathway of B cell cross talk with the environment. CXCR4 is a chemokine receptor expressed on normal and malignant B cells and becomes activated by the chemokine CXCL12, also called stromal cell-derived factor-1 (SDF-1) [4]. Mesenchymal stromal cells, particularly bone marrow stromal cells (BMSCs), constitutively secrete high levels of CXCL12 and thereby attract and retain normal and malignant hematopoietic cells in the tissues. Once the lymphoma cells are attached to BMSCs, they become activated, and become largely resistant to cytotoxic drugs. Consequently, the concept of chemo-sensitization was developed, based on the idea that lymphoma–stroma cross talk needs to be disrupted in order to re-sensitize the neoplastic cells [5]. This can be accomplished by mobilization of the malignant cells from their supportive niches, using antagonists that block a critical tissue homing/retention signals, such as CXCR4.

In this issue of Leukemia and Lymphoma Hu and colleagues present a study entitled “Enhancement of the anti-tumor activity of therapeutic monoclonal antibodies by CXCR4 antagonists,” in which they investigated the activity of two CXCR4 antagonists, plerixafor and GENZ-644494, in B cell lymphoma models in combinations with rituximab or alemtuzumab [6]. The concept of combining CXCR4 antagonists with antibodies is particularly attractive in B cell lymphomas, where such active therapeutic antibodies are available. Also, compared to chemotherapy, antibodies are less myelosuppressive and likely well tolerated in combination with a CXCR4 antagonist. Moreover, B cell antibodies are not particularly active in tissue sites, and their therapeutic activity therefore could greatly benefit from a mobilizing agent. The in vivo data by Hu et al., in which the combination of the CXCR4 antagonists with rituximab or alemtuzumab reduced tumor cell growth and prolonged survival in experimental lymphoma models in immunodeficient mice, are exciting and novel, and in line with a recent in vitro study by Buchner et al. in which the investigators reported that stromal cell contact attenuated rituximab- and alemtuzumab-induced cytotoxicity of CLL cells, which could be overcome by the addition of CXCR4 antagonists [7]. Hu and colleagues also present data demonstrating lymphoma cell mobilization from the tissues into the blood after injection of the CXCR4 antagonist GENZ-644494. Conceptually, this is of great interest, because it illustrates the critical function of CXCR4 as an anchor signal for tissue retention of lymphoma cells. These data corroborate the preliminary data from the ongoing clinical trial in CLL, in which patients treated with plerixafor display robust, transient mobilization of CLL cells into the blood [8]. Interestingly, new orally bioavailable inhibitors of kinases downstream of the BCR display similar clinical effects. Characteristically, these kinase inhibitors induce rapid lymph node shrinkage along with a transient lymphocytosis during the first weeks of treatment, presumably due to mobilization of CLL cells from the tissues into the blood. These new targeted agents are the Syk inhibitor fostamatinib disodium, the Btk inhibitor PCI-32765 and the PI3Kδ inhibitor CAL-101. Inhibition of signaling through CXCR4 and potentially other chemokine receptors and adhesion molecules [9,10] has been proposed as the basis for this remarkable phenomenon. Future research on these agents will need to address the question whether CLL cell mobilization is a prerequisite for the efficacy of these agents, and comparative studies may eventually address the question whether such kinase inhibitors or CXCR4 antagonists are more effective mobilizers and/or drug (chemo- or antibody-) sensitizers.

In summary, the study by Hu et al. corroborates the new therapeutic concept of leukemia/lymphoma cell mobilization and sensitization to B cell antibodies by using CXCR4 antagonists. This innovative concept, already tested in first clinical trials, has not previously been experimentally tested in animal models, and therefore the data in this paper are valuable and provide a roadmap for further pre-clinical development and testing of CXCR4 antagonists in B cell malignancies.

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