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Originally published as JCO Early Release 10.1200/JCO.2008.19.2393 on November 24 2008 © 2009 American Society of Clinical Oncology.
Measuring Granulocyte and Monocyte Accumulation at Malignant Lymphoma Sites
Department of Radiology and Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA
Department of Internal Medicine, Hematology/Oncology and Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA
Department of Internal Medicine, Hematology/Oncology, Stanford University, Stanford, CA
Mayo Clinic Foundation, Rochester, MN To the Editor: We were encouraged by the single-center study reported by Cartron et al1 showing that granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances the efficacy of rituximab, with an increased complete response (CR) rate compared with rituximab monotherapy. As expected, the authors showed that GM-CSF significantly increased WBC, neutrophil, and monocyte counts. However, no significant differences in the mean pre- or post-therapy counts of these cells were found between CR and non-CR patients. Moreover, the ratios of these cell counts after versus before treatment were not significantly different between CR and non-CR patients. These findings may be surprising and could cast some doubt about the role of the increase in effector cells in enhancing the antitumor effects of rituximab that are mediated by antibody-dependent cellular cytotoxicity, particularly because in vitro studies typically demonstrate a clear-cut correlation between the effector-cell-to-target ratio and percent tumor cell lysis induced by antibody-dependent cellular cytotoxicity. However, we would like to point out that the authors did not determine the magnitude of accumulation of the investigated effector cells at the tumor sites, but rather only their blood levels. One approach that may enable at least a semiquantitative determination of the magnitude of accumulation of effector cells at the tumor sites before and after combined rituximab and GM-CSF therapy in patients with follicular lymphoma involves radiolabeling of autologous granulocytes and/or mononuclear WBC populations with indium-111–labeled oxine. This technique has been shown to be feasible in normal patients and patients with benign conditions as well as various malignancies, including lymphoma (Fig 1).2-6 We believe that quantifying the magnitude of radiolabeled effector-cell accumulation at the tumor sites could reveal a better correlation between effector-cell levels and response (eg, CR v non-CR) after treatment with rituximab compared with measurements of blood levels of these cells.
The expected variability in intratumoral macrophage or granulocyte accumulation between tumors of different patients or even within the same patient is likely to be relevant to the study by Cartron et al.1 Ultimately, what might be important is the accumulation of effector cells at the tumor site both before and after combined rituximab and GM-CSF therapy, rather than the circulating effector-cell levels. For example, if, over a certain time period, a tumor accumulates 0.01% of the circulating peripheral-blood mononuclear cell (PBMC) count per gram of tissue in a patient with a blood PBMC count of 3,000/µL, its per-mass accumulation of PBMCs will be much greater than a tumor in a patient with a blood PBMC count of 6,000/µL but with only 0.001% of circulating PBMCs accumulating per gram of tumor. A three-fold increase in PBMC count through GM-CSF in both cases will not change anything in this relationship, and even a four-fold increase in PBMC count in the latter patient versus only a two-fold increase in the former after GM-CSF will not eliminate, although it will attenuate, the advantage of higher accumulation of PBMCs at the tumor site in the former patient, despite substantially higher circulating PBMC count in the latter both before and after therapy. Such or similar scenarios are likely to explain the lack of correlation between baseline or post-therapy circulating monocyte or granulocyte counts and response, and also the lack of correlation between the ratio of post- versus pretherapy cell count and response. Indirect evidence for the importance of intratumoral levels of effector cells is illustrated in the finding by Canioni et al7 that rituximab is able to circumvent the unfavorable outcome of patients with follicular lymphoma with high amounts of intratumoral macrophages. It might also be interesting to speculate that the patients most likely to benefit from GM-CSF in combination with rituximab may be those who demonstrate considerable accumulation of granulocytes and/or monocytes at their tumor sites before treatment or after a single test dose of GM-CSF, emphasizing the potential usefulness of effector-cell imaging in this setting. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
NOTES published online ahead of print at www.jco.org on November 24, 2008 REFERENCES
1. Cartron G, Zhao-Yang Lu, Baudard M, et al: Granulocyte-macrophage colony stimulating factor potentiates rituximab therapy in patients with relapsed follicular lymphoma: Results of a phase II study. J Clin Oncol 26:2725-2731, 2008 2. Heyns AP, Pieters H, Steyn AC: Isolation and labeling with In-111 of a viable population of blood monocytes, in Sinzinger H, Thakur ML (eds): Radiolabeled Cellular Blood Elements. New York, NY, Wiley-Liss, 1990, pp 261-270 3. Virgolini I, Muller Ch, Fitscha P, et al: Radiolabelling autologous monocytes with In-111-oxine for reinjection in patients with atherosclerosis, in Sinzinger H, Thakur ML (eds): Radiolabeled Cellular Blood Elements. New York, NY, Wiley-Liss, 1990, pp 271-280 4. Schmidt KG, Rasmussen JW, Wedebye IM, et al: Accumulation of indium-111–labeled granulocytes in malignant tumors. J Nucl Med 29:479-484, 1988 5. Weiblen BJ, Forstrom L, McCullough J: Studies of the kinetics of Indium-111–labeled granulocytes. J Lab Clin Med 94:246-255, 1979[Medline] 6. Juweid ME, Wiseman G, Witzig T, et al. Assessment of peripheral blood mononuclear cell (PBMC) trafficking in patients with non-Hodgkin's lymphoma prior to and following therapy. Eur J Nucl Med Mol Imaging 33:223s, 2006 (abstr) 7. Canioni D, Gilles S, Mounier N, et al: High numbers of tumor-associated macrophages have an adverse prognostic value that can be circumvented by rituximab in patients with follicular lymphoma enrolled onto the GELA-GOELAMS FL-2000 trial. J Clin Oncol 26:440-446, 2008
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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