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Journal of Clinical Oncology, Vol 25, No 24 (August 20), 2007: pp. 3680-3687 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.5718
Treatment With Autologous Antigen-Presenting Cells Activated With the HER-2 –Based Antigen Lapuleucel-T: Results of a Phase I Study in Immunologic and Clinical Activity in HER-2–Overexpressing Breast Cancer
From the University of California, San Francisco, San Francisco, CA; and Dendreon Corporation, Seattle, WA Address reprint requests to John W. Park, MD, UCSF Comprehensive Cancer Center, University of California, San Francisco, 1600 Divisadero St, Box 1710, San Francisco, CA 94115-1710; e-mail: jpark{at}cc.ucsf.edu
Purpose Lapuleucel-T (APC8024), an autologous active cellular immunotherapy, was prepared from peripheral-blood mononuclear cells, including antigen-presenting cells, that were activated in vitro with recombinant fusion protein BA7072. This antigen construct consisted of sequences from intracellular and extracellular domains of human epidermal growth factor receptor 2 (HER-2) linked to granulocyte-macrophage colony-stimulating factor. We conducted a phase I study to evaluate the safety and immunologic activity of lapuleucel-T in patients with HER-2–overexpressing metastatic breast cancer. Patients and Methods Metastatic breast cancer patients whose tumors overexpressed or amplified HER-2 were eligible. Patients underwent leukapheresis and subsequent lapuleucel-T infusion 2 days later at weeks 0, 2, and 4. Patients who achieved a partial response (PR) or had stable disease (SD) lasting through week 48 were eligible for re-treatment using the same protocol and dose as their initial treatment. End points included safety, immunologic activity, and antitumor activity. Results Nineteen patients were enrolled; 18 patients received treatment. Therapy was well tolerated, with no grade 3 or 4 adverse events associated with the treatment. Significant cellular immune responses specific for the immunizing antigen and HER-2 sequences were induced after treatment, as measured by lymphocyte proliferation and interferon gamma enzyme-linked immunospot assay. One patient experienced a PR lasting 6 months. Three additional patients had SD lasting more than 1 year. Conclusion Autologous active cellular immunotherapy with lapuleucel-T was feasible, safe, and well tolerated. The treatment stimulated significant immune responses, which were enhanced after boost infusions. Lapuleucel-T therapy was associated with tumor response or extended disease stabilization in some patients and warrants further investigation.
A variety of active immunotherapies against breast cancer have been studied, including peptide-, protein-, and cell-based vaccines.1-4 Cell-based immunotherapies include those containing autologous antigen-presenting cells (APCs) that are pulsed with a tumor antigen ex vivo. Clinical trials investigating active cellular immunotherapies as cancer treatment have demonstrated induction of immune responses and potential clinical benefits.5-8 For example, an APC-based immunotherapy has been associated with improved survival in the treatment of metastatic prostate cancer.9 Human epidermal growth factor receptor 2 (HER-2) is an attractive target for immunotherapy given its central pathogenetic role in 20% to 30% of breast cancers and its association with an aggressive phenotype.10,11 Substantial clinical efficacy associated with the monoclonal antibody trastuzumab clearly validates HER-2 as a fruitful therapeutic target.12 Pre-existing CD4+ T-cell and antibody-mediated immunity against HER-2 has been described,13 providing further rationale for active specific immunotherapy strategies to augment the anti–HER-2 immune response. In this report, we describe the first clinical experience involving lapuleucel-T (APC8024), a novel cell-based immunotherapy designed to stimulate cellular immune responses against HER-2. Lapuleucel-T was derived from autologous APCs loaded with recombinant antigen comprising extensive HER-2 sequences (HER500) linked to a granulocyte-macrophage colony-stimulating factor (GM-CSF) domain (to target antigen to APCs). This phase I study evaluated the safety and immunologic activity of this therapy in patients with HER-2–overexpressing metastatic breast cancer.
Patients Patients with metastatic (stage IV) breast cancer and a performance status of 0 or 1 were eligible if their tumors were HER-2 positive (HER-2 immunohistochemistry score of 3+, or HER-2 immunohistochemistry score of 2+ with positive fluorescence in situ hybridization showing HER2 amplification). Patients must have experienced tumor progression after treatment with at least one chemotherapy regimen or up to two hormonal therapy regimens for metastatic disease. Chemotherapy or hormone therapy must have been completed  1 month before enrollment, with recovery from all acute adverse effects. All patients were required to have received prior treatment with trastuzumab. Trastuzumab must have been discontinued 6 weeks before enrollment. Otherwise, no prior immunotherapy was allowed. Concurrent bisphosphonate therapy was permitted if begun 30 days before registration. Other eligibility criteria included adequate cardiac, hematologic, renal, and hepatic function and negative serologies for HIV-1/2, human T-lymphotropic virus-1, and hepatitis B and C.
Treatment Plan and Evaluation The treatment regimen consisted of three biweekly leukaphereses and infusions; each infusion was prepared from a single leukapheresis. Lapuleucel-T was administered to three sequential patient cohorts based on the following escalating cell dose levels: 2 x 108, 1 x 109, and 5 x 109 cells. However, if the first leukapheresis failed to harvest the requisite number of cells, the patient was treated at the lower dose level for all three infusions. In this case, the patient was included in the cohort for the actual dose received, and an additional patient was assigned to the higher dose level as a replacement. Patients were monitored for adverse events (AEs) and underwent physical examination and laboratory testing at baseline, weeks 2, 4, 8, and 12, and every 8 weeks thereafter. Multiple-gated acquisition (MUGA) scans were repeated at week 12. Computed tomography of the chest, abdomen, and pelvis and bone scans were performed at week 12, then every 16 weeks. If patients achieved a partial response (PR) or stable disease (SD) persisting through week 48, they were eligible for re-treatment. Consenting patients then received a repeat of the same treatment and evaluation protocol, including the initially assigned cell dose.
Preparation of Lapuleucel-T
Immunologic Evaluation
Proliferation Assay
IFN-
Patients Nineteen patients were enrolled (Table 1). All patients had received prior chemotherapy and trastuzumab for metastatic disease except one patient who had refused these treatments; a protocol exception was made to allow her to participate in this study. No patients were known to be intolerant of trastuzumab. All hormone receptor–positive patients had experienced progression on at least one hormonal treatment before enrollment. The median number of prior chemotherapy regimens was three regimens (mean, 2.9 regimens), with 10 patients having received three prior regimens.
Eighteen patients received study treatment. The one patient who did not receive lapuleucel-T had a positive bacterial culture of her first leukapheresis product and was subsequently determined to have pre-existing infective endocarditis. Six patients were treated at dose level 1 (2 x 108 cells/dose), eight patients were treated at dose level 2 (1 x 109 cells/dose), and four patients were treated at dose level 3 (5 x 109 cells/dose). One patient in dose level 2 received only two of three planned doses of lapuleucel-T therapy because of progressive disease. Three patients assigned to dose level 3 each received significantly less than the planned dose for one of the three infusions (22.4%, 56.4%, and 66.0% of the planned dose). Three patients had SD at 1 year and elected to receive re-treatment with lapuleucel-T, as allowed per protocol, using the same dose and schedule as their initial treatment (two patients at dose level 2 and one patient at dose level 3).
Toxicity
Seven serious AEs (SAEs) were reported in this study. Four SAEs were judged to be unrelated to lapuleucel-T and attributed to underlying disease; these consisted of headache associated with new brain metastasis, increased pleural effusion, post-thoracentesis pneumothorax, and respiratory arrest. The respiratory arrest was the only grade 5 (fatal) SAE. This patient developed increased malignant pleural effusion and parenchymal disease 20 days after the final infusion of lapuleucel-T, received a therapeutic thoracentesis, and suffered respiratory failure 1 day after the procedure. Another SAE, infective endocarditis, was diagnosed after study enrollment but before study treatment. The two SAEs attributed to lapuleucel-T consisted of grade 3 pyrexia and rigors; both SAEs occurred on the same date in the same patient, who was in the dose level 3 cohort. There were no reported cardiac AEs or evidence of cardiac toxicity with lapuleucel-T (Table 3). This includes six patients for whom left ventricular ejection fraction measurements were obtained by MUGA scan both at baseline and in follow-up, generally at 12 weeks. In these six patients, there was no evidence of decline in left ventricular ejection fraction after therapy with lapuleucel-T. Per protocol, serial MUGA scans were not obtained in other patients once they had experienced progression.
Immunologic Activity All patients enrolled onto the study were included in evaluation of immunologic activity. Immunologic response was evaluated against the immunizing antigen, BA7072, as well as HER500, which contains only the HER-2 sequences expressed in a mammalian system. In lymphocyte proliferation studies, baseline response was generally low for most patients (Fig 1A). However, patient 17 showed an HER-2–specific immune response before treatment (HER500 SI of 7.5). After treatment, increased proliferative responses were observed in the study population. Median SI at week 4 and week 8 was 12.3 (range, 1.3 to 841.8) and 60.1 (range, 1.3 to 366.0) for BA7072 at 10 µg/mL, respectively, and 2.9 (range, 0.4 to 212.8) and 7.6 (range, 0.5 to 126.1) for HER500 at 10 µg/mL, respectively. Lapuleucel-T treatment was associated with a significant increase in proliferative response to either BA7072 or HER500 at week 4 (P = .0195 and P = .0371, respectively) and week 8 (P = .0029 and P = .0137, respectively) compared with baseline.
ELISPOT for IFN-  was also performed (Fig 1B). Again, baseline responses were generally low, with the exception of the patient (patient 17) who had the pre-existing HER-2–specific proliferative response; this patient also showed an elevated HER500-specific IFN- ELISPOT response before treatment (118 spots/3 x 105 PBMC). Treatment with lapuleucel-T was associated with a significant increase in IFN- ELISPOT response to BA7072 at week 4 (median, 27 spots/3 x 105 PBMC; P = .0059) and at week 8 (median, 16 spots/3 x 105 PBMC; P = .0010) compared with baseline (median, 0.0 spots/3 x 105 PBMC). Assuming that the PBMC population was 60% T cells, the BA7072-specific T-cell frequency ranged from nondetectable to one in 600 (303 spots/3 x 105 PBMC), with a median of approximately one in 6,000. A trend towards increased immune response to HER500 by IFN- ELISPOT was also noted but did not reach statistical significance. There were no apparent differences in immune response based on cell dose. For the three re-treated patients, immune responses were evaluated before re-treatment and at the same time points after treatment (Figs 2A and 2B). Patient 17, who had pre-existing HER-2–specific immune response, showed variable immune responses after both initial treatment and re-treatment; thus, the impact of immunization in this patient is less clear. For patients 14 and 23, the antigen-specific immune response was increased after both the first and second course of treatment, whether measured by lymphocyte proliferation or ELISPOT. These three patients did not seem to have superior immune responses after their initial therapy compared with the other patients.
Clinical Results Three patients reached the 52-week follow-up point without disease progression (Table 4). Fifteen other patients withdrew before week 52; 10 patients withdrew as a result of disease progression; one patient died as a result of disease progression; one patient received other therapy before progression; one patient received other therapy for suspected progression; one patient received only two infusions as a result of disease progression; and one patient was lost to follow-up.
In the 18 treated patients, the median time to disease progression was 12.1 weeks (range, 2.1 to 94.0+ weeks). Regression of a supraclavicular mass in one patient was classified as PR based on Response Evaluation Criteria in Solid Tumors. This PR lasted approximately 6 months, at which time, disease progression was noted. Three patients experienced disease stabilization of 1 year with no other cancer therapy other than ongoing bisphosphonate treatment. Of note, all of these patients had experienced progression of bone metastases during prior trastuzumab and bisphosphonate therapy. Two of these patients were hormone receptor negative as well as HER-2 positive. Two other patients experienced shorter periods of disease stabilization (up to 20 weeks). Two of the three re-treated patients remained in SD at the time of study closure at 94.0+ and 76.6+ weeks. The third re-treated patient developed progressive disease 74.9 weeks after the first infusion of lapuleucel-T.
Although active specific immunotherapy has yet to become part of standard cancer treatment, recent advances in tumor immunology and immunotherapy have led to more sophisticated and promising strategies. This phase I study evaluated the safety and immunologic activity of lapuleucel-T, a novel active cellular immunotherapy consisting of APCs activated with a recombinant fusion protein (BA7072) containing HER-2 sequences. In contrast to the toxicities associated with many other cancer treatments, lapuleucel-T seemed to be generally well tolerated. The most common AEs reported in this study were pyrexia (74%), rigors (58%), fatigue (37%), injection site bruising (37%), nausea (37%), dyspnea (32%), headache (32%), citrate toxicity (26%), and arthralgia (26%). Most of these events were mild, of short duration, and occurred soon after infusion. The overall toxicity profile was similar to that reported for sipuleucel-T in men with advanced prostate cancer,9 although pyrexia, nausea, injection site bruising, and dyspnea may have been more frequent in this study. The immunotherapy technology involved autologous APCs activated with recombinant antigen in vitro. By including extensive sequences from both extracellular and intracellular domains of HER-2 along with GM-CSF, the antigen construct was designed to elicit immunity to multiple sites along the HER-2 molecule. Studies of native immune responses in breast cancer patients indicate that HER-2 may function naturally as an immunogen during tumorigenesis.13,19,20; for example, one vaccine study reported that five (11%) of 45 patients with HER-2–overexpressing cancers showed pre-existing immunity.21 The cellular immune responses observed in this study are consistent with other studies demonstrating that HER-2–specific immune responses can be elicited in patients with HER-2–overexpressing malignancies. Disis et al3,22 reported responses in patients immunized with HER-2 peptides (SI, 2.1 to 59) or protein (SI, 1.4 to 15.8). Immunization with a class I restricted peptide resulted in slightly lower proliferative responses (SI, 0.8 to 10.9).23 Analysis of the frequency of T cells with specificity for a HLA-A2–restricted peptide, E75, demonstrated that up to 3% of CD8+ T cells were HER-2 specific after treatment.24 Although comparison of immune response data across different trials is speculative, particularly without standardization of methodology,25 the median SIs noted in the present study seem comparable to those reported in these other studies. We did not observe differences in immune response between cell dose cohorts; however, the number of patients per cohort was small. A lack of correlation between HER-2 protein dose and immune response has also been recently reported.3 It is encouraging to observe induction and boosting of immune responses in this highly pretreated, metastatic population because it has been suggested that late-stage patients may be particularly difficult to treat via active immunotherapy.26 Evidence of anticancer activity in this trial included a PR in one patient and long-term disease stabilization lasting 1 year or more in three patients. These observations are suggestive of clinical benefit, particularly given the aggressive phenotype characteristic of HER-2–overexpressing breast cancers, as well as the fact that these patients had experienced progression on prior standard therapies including trastuzumab. It is notable that the patients achieving prolonged SD had bone-only metastatic disease. Because bone-only disease in HER-2–overexpressing patients is not necessarily indolent, this observation is consistent with benefit from anti–HER-2 immunotherapy in this subset. These results confirmed that this active cellular immunotherapy approach is feasible in advanced breast cancer patients who were able to receive immunologically active vaccination derived from autologous pheresis product. Although only one of four patients in the highest dose cohort (dose level 3) actually received the intended dose, all three dose levels were associated with immunologic activity, and patients showing apparent clinical benefit included those in both dose level 2 (three patients) and dose level 3 (one patient). It is anticipated, in phase II trials, that the highest dose level tested will not be further evaluated. Another issue encountered in this study was vascular access. Patients nevertheless tolerated all study-related procedures, including pheresis catheter placement. Future studies may be able to incorporate alternative vascular access strategies for pheresis. Future studies could also potentially include immunization of patients earlier in the disease process, as well as combination with other anti–HER-2 therapies. Preclinical evidence suggests that antibody-dependent cellular cytotoxicity may be an important component of trastuzumab's anticancer activity27; if so, combining trastuzumab with active anti–HER-2 immunotherapy may augment this mechanism. The antiproliferative activity of trastuzumab and small-molecule kinase inhibitors, such as lapatinib,28 may also benefit from induction of anti–HER-2 immune responses. We conclude that a novel APC-based immunotherapy directed against HER2, lapuleucel-T, is feasible, safe, and well tolerated. This approach induced specific T-cell immune responses and showed evidence of anticancer activity including objective response and durable disease stabilization. Further clinical studies of this promising approach are warranted.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: Lori A. Jones, Dendreon Corp; Jami Breen Wollan, Dendreon Corp; Robert Sims, Dendreon Corp Leadership: N/A Consultant: N/A Stock: Lori A. Jones, Dendreon Corp; Jami Breen Wollan, Dendreon Corp; Robert Sims, Dendreon Corp Honoraria: N/A Research Funds: John W. Park, Funds, Dendreon Corp Testimony: N/A Other: N/A
Conception and design: John W. Park, Laura J. Esserman, Lori A. Jones Provision of study materials or patients: John W. Park, Michelle E. Melisko, Laura J. Esserman Collection and assembly of data: John W. Park, Michelle E. Melisko, Laura J. Esserman, Lori A. Jones, Jami Breen Wollan, Robert Sims Data analysis and interpretation: John W. Park, Michelle E. Melisko, Laura J. Esserman, Lori A. Jones, Jami Breen Wollan, Robert Sims Manuscript writing: John W. Park, Michelle E. Melisko, Lori A. Jones, Jami Breen Wollan, Robert Sims Final approval of manuscript: John W. Park, Michelle E. Melisko, Laura J. Esserman, Lori A. Jones, Jami Breen Wollan, Robert Sims
We acknowledge the contributions of study coordinator Marina Kenzer, the University of California, San Francisco General Clinical Research Center, and the expert medical writing assistance of Robert Hill.
Supported in part by Grant No. U54 CA90788 from the National Institutes of Health; and by Grants No. NCI P50-CA 58207, U54-CA90788, U01 CA111234-01, and the Lauder fund. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Avigan D, Vasir B, Gong J, et al: Fusion cell vaccination of patients with metastatic breast and renal cancer induces immunological and clinical responses. Clin Cancer Res 10:4699-4708, 2004 2. Svane IM, Pedersen AE, Johnsen HE, et al: Vaccination with p53-peptide-pulsed dendritic cells, of patients with advanced breast cancer: Report from a phase I study. Cancer Immunol Immunother 53:633-641, 2004[CrossRef][Medline] 3. Disis ML, Schiffman K, Guthrie K, et al: Effect of dose on immune response in patients vaccinated with an her-2/neu intracellular domain protein–based vaccine. J Clin Oncol 22:1916-1925, 2004 4. Disis ML, Goodell V, Schiffman K, et al: Humoral epitope-spreading following immunization with a HER-2/neu peptide based vaccine in cancer patients. J Clin Immunol 24:571-578, 2004[CrossRef][Medline] 5. Small EJ, Fratesi P, Reese DM, et al: Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. J Clin Oncol 18:3894-3903, 2000 6. Hsu FJ, Benike C, Fagnoni F, et al: Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med 2:52-58, 1996[CrossRef][Medline] 7. Morse MA, Deng Y, Coleman D, et al: A phase I study of active immunotherapy with carcinoembryonic antigen peptide (CAP-1)-pulsed, autologous human cultured dendritic cells in patients with metastatic malignancies expressing carcinoembryonic antigen. Clin Cancer Res 5:1331-1338, 1999 8. Nestle FO, Alijagic S, Gilliet M, et al: Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 4:328-332, 1998[CrossRef][Medline] 9. Small EJ, Schellhammer PF, Higano CS, et al: Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:3089-3094, 2006 10. Kallioniemi OP, Holli K, Visakorpi T, et al: Association of c-erbB-2 protein over-expression with high rate of cell proliferation, increased risk of visceral metastasis and poor long-term survival in breast cancer. Int J Cancer 49:650-655, 1991[Medline] 11. Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177-182, 1987 12. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001 13. Disis ML, Calenoff E, McLaughlin G, et al: Existent T-cell and antibody immunity to HER-2/neu protein in patients with breast cancer. Cancer Res 54:16-20, 1994 14. Czerniecki BJ, Carter C, Rivoltini L, et al: Calcium ionophore-treated peripheral blood monocytes and dendritic cells rapidly display characteristics of activated dendritic cells. J Immunol 159:3823-3837, 1997[Abstract] 15. Nagorsen D, Keilholz U, Rivoltini L, et al: Natural T-cell response against MHC class I epitopes of epithelial cell adhesion molecule, her-2/neu, and carcinoembryonic antigen in patients with colorectal cancer. Cancer Res 60:4850-4854, 2000 16. Asai T, Storkus WJ, Whiteside TL: Evaluation of the modified ELISPOT assay for gamma interferon production in cancer patients receiving antitumor vaccines. Clin Diagn Lab Immunol 7:145-154, 2000[CrossRef][Medline] 17. Russell ND, Hudgens MG, Ha R, et al: Moving to human immunodeficiency virus type 1 vaccine efficacy trials: Defining T-cell responses as potential correlates of immunity. J Infect Dis 187:226-242, 2003[CrossRef][Medline] 18. Mwau M, McMichael AJ, Hanke T: Design and validation of an enzyme-linked immunospot assay for use in clinical trials of candidate HIV vaccines. AIDS Res Hum Retroviruses 18:611-618, 2002[CrossRef][Medline] 19. Sotiropoulou PA, Perez SA, Iliopoulou EG, et al: Cytotoxic T-cell precursor frequencies to HER-2 (369-377) in patients with HER-2/neu-positive epithelial tumours. Br J Cancer 89:1055-1061, 2003[CrossRef][Medline] 20. Rentzsch C, Kayser S, Stumm S, et al: Evaluation of pre-existent immunity in patients with primary breast cancer: Molecular and cellular assays to quantify antigen-specific T lymphocytes in peripheral blood mononuclear cells. Clin Cancer Res 9:4376-4386, 2003 21. Disis ML, Knutson KL, Schiffman K, et al: Pre-existent immunity to the HER-2/neu oncogenic protein in patients with HER-2/neu overexpressing breast and ovarian cancer. Breast Cancer Res Treat 62:245-252, 2000[CrossRef][Medline] 22. Disis ML, Gooley TA, Rinn K, et al: Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines. J Clin Oncol 20:2624-2632, 2002 23. Murray JL, Gillogly ME, Przepiorka D, et al: Toxicity, immunogenicity, and induction of E75-specific tumor-lytic CTLs by HER-2 peptide E75 (369-377) combined with granulocyte macrophage colony-stimulating factor in HLA-A2+ patients with metastatic breast and ovarian cancer. Clin Cancer Res 8:3407-3418, 2002 24. Peoples GE, Gurney JM, Hueman MT, et al: Clinical trial results of a HER2/neu (E75) vaccine to prevent recurrence in high-risk breast cancer patients. J Clin Oncol 23:7536-7545, 2005 25. Keilholz U, Weber J, Finke JH, et al: Immunologic monitoring of cancer vaccine therapy: Results of a workshop sponsored by the Society for Biological Therapy. J Immunother 25:97-138, 2002[Medline] 26. Salazar LG, Disis ML: Cancer vaccines: The role of tumor burden in tipping the scale toward vaccine efficacy. J Clin Oncol 23:7397-7398, 2005 27. Clynes RA, Towers TL, Presta LG, et al: Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 6:443-446, 2000[CrossRef][Medline] 28. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733-2743, 2006 Submitted December 27, 2006; accepted May 21, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
.05). PBMC, peripheral-blood mononuclear cell.
