Quantitating the Impact of Plerixafor

Overview

The primary objective of this study is to conduct a proof of concept pilot study that will provide a preliminary evaluation of the safety of plerixafor alone or in combination with bortezomib on plasma cell mobilization, Human Leukocyte Antigen (HLA) antibody levels and toxicity profile in sensitized patients awaiting kidney transplantation. The secondary objective of this study is to conduct additional analyses of the study regimen on HLA antibody levels using multiple different assays and statistical analysis.

The investigators have previously demonstrated that proteasome inhibition (with bortezomib) provides effective antihumoral therapy for antibody-mediated rejection (AMR) and for desensitization in kidney transplant recipients and candidates. These studies have also demonstrated that plasma cell populations exhibit significant heterogeneity. Newly produced plasma blasts and plasma cells, whether from a primary or anamnestic immunologic response, during an acute AMR, are very sensitive to proteasome inhibitor-based therapy. Of the plasma cell populations we have examined, those that demonstrate the greatest degree of resistance to proteasome inhibitor therapy are those that reside within bone marrow niches. These long lived bone marrow niche resident plasma cell (LLBMNRPC) populations demonstrate a significant degree of resistance to bortezomib therapy. This concept of plasma cell niche providing long term survival signals is supported by substantial literature from murine models. A number of signals are involved that derive from the plasma cell niche which are thought to contribute to long lived plasma cell survival including CXC-chemokine receptor 4 (CXCR4)/chemokine (C-X-C motif) ligand 12 (CXCL12) interactions, Interleukin-6 (IL-6), B cell activating factor (BAFF), and cluster of differentiation 44 (CD44). In addition, a number of cells have been demonstrated to be involved in the plasma cell niche in either human or murine models, including eosinophils, osteoclasts, bone marrow reticular cells, amongst others. Interruption of CXCR4/CXCL12 interactions with plerixafor has been used to induce cluster of differentiation 34+ (CD34+) bone marrow stem cell mobilization into the peripheral blood. Since the CXCR4/CXCL12 interaction is also thought to be responsible for plasma cells homing to the bone marrow niche, it has been hypothesized that plerixafor may also provide systemic mobilization of bone marrow niche resident plasma cells, or alternatively, may induce a local mobilization from the bone marrow niche of plasma cells. Given that previous studies have indicated that mobilization of long lived plasma cells is thought to result in short term (less than 72 hour) survival of long lived plasma cells, this represents a significant potential for enhancement of proteasome inhibitor-based plasma cell targeting therapies. Indeed, a previous abstract from the oncology literature has provided preliminary evidence that combined plerixafor and bortezomib therapy may be of use in mobilizing the malignant myeloma cell from its bone marrow niche, thereby enhancing sensitivity to bortezomib. The purpose of the proposed study is to conduct a proof of concept and preliminary safety evaluation of plerixafor alone and also combined therapy with plerixafor and bortezomib. The investigators have prospectively conducted a meticulous assessment of bortezomib-related toxicities in both the transplant recipient AMR and the transplant candidate desensitization populations and recently published this in Transplantation. This experience, which now includes over 100 treated patients, indicates that the toxicity profile of bortezomib is quite comparable to that which is observed in the myeloma population. The investigators' preliminary analysis of plerixafor and bortezomib based toxicities demonstrates that there is no significant degree of overlap in the toxicities and no significant reasons to have concerns regarding combinatorial toxicities a priori. The investigators' extensive phase I/II study of bortezomib-based desensitization with and without rituximab-based memory B-cell depletion and/or plasmapheresis has provided a substantial experience as a first line approach for first generation plasma cell targeted therapies for desensitization in kidney transplant candidates. The current proposal is the first in the initiation of second generation plasma cell targeting protocols which have substantial potential for applications beyond kidney transplant candidates. These types of regimens may also lend themselves to AMR and desensitization in kidney transplant recipients and also in heart and other solid organ transplant recipients. It is also possible that such second generation plasma cell targeted protocols may also be of use for desensitization in kidney transplant, heart transplant, and other solid organ transplant populations. Finally, these plasma cell targeted therapies may also be of use in autoimmune diseases where autoantibodies are thought to represent a major pathogenetic factor.

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