|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 24, No 36 (December 20), 2006: pp. 5716-5724 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.9129 Phase II Trial of a Toll-Like Receptor 9–Activating Oligonucleotide in Patients With Metastatic Melanoma
From the Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, and Department of Radiology, Medical University of Vienna; Center for Molecular Medicine, Austrian Academy of Sciences, Vienna; Department of Dermatology, Medical University of Graz, Graz, Austria; 3rd Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz; Department of Dermatology, University of Cologne, Cologne; Department of Dermatology, University of Muenster, Muenster; Department of Dermatology, University of Duisburg/Essen, Essen, Germany; and Coley Pharmaceutical Group Inc, Wellesley, MA Address reprint requests to Stephan N. Wagner, Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria; e-mail: stephan.wagner{at}meduniwien.ac.at
PURPOSE: The recent identification of toll-like receptors (TLRs) and respective ligands allows the evaluation of novel dendritic cell (DC) –activating strategies. Stimulation of TLR9 directly activates human plasmacytoid DCs (PDCs) and indirectly induces potent innate immune responses in preclinical tumor models. We performed an open-label, multicenter, single-arm, phase II pilot trial with a TLR9-stimulating oligodeoxynucleotide in melanoma patients. PATIENTS AND METHODS: Patients with unresectable stage IIIb/c or stage IV melanoma received 6 mg PF-3512676 weekly by subcutaneous injection for 24 weeks or until disease progression to evaluate safety as well as clinical and immunologic activity. Clinical and laboratory safety assessments were performed weekly; blood samples for immunological measurements were taken every 8 weeks. Tumor measurements were performed according to Response Evaluation Criteria in Solid Tumors. RESULTS: Twenty patients received PF-3512676 for a mean of 10.9 weeks with a mean of 10.7 injections. Laboratory and nonlaboratory adverse events were limited, transient, and did not result in any withdrawals. Two patients experienced a confirmed partial response; one response is ongoing for 140+ weeks. Three patients experienced stable disease. Immunologic measurements revealed induction of an activated phenotype of PDC, elevation of serum levels of 2',5'-oligoadenylate, a surrogate marker of type I interferon production, and significant stimulation of natural killer cell cytotoxicity (the latter was associated with clinical benefit). CONCLUSION: These results indicate that TLR9-targeted therapy can stimulate innate immune responses in cancer patients, identify biomarkers that may be associated with TLR9-induced tumor regression, and encourage the design of follow-up studies to evaluate the ability of this therapeutic approach to target human cancer.
Toll-like receptors (TLRs) belong to the family of pattern-recognition receptors and comprise 10 members so far identified in humans.1 Among these, TLR9 is expressed primarily, if not exclusively, in plasmacytoid dendritic cells (PDCs) and B cells.2-4 The molecular structure recognized by TLR9 consists of unmethylated deoxycytidylyl-deoxyguanosine (CpG) dinucleotides in particular base contexts (so-called CpG motifs).5 Synthetic oligodeoxynucleotides (ODNs) containing CpG motifs are endocytosed by PDCs, bind to TLR9 presumably in the tubular lysosomal compartment, and after association with adapter molecule MyD88, lead to formation of the interleukin 1 receptor-associated kinase (IRAK)-tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6)-transforming growth factor beta (TGF-ß)-activated kinase 1 complex with activation of mitogen-activated protein kinases and I kappa B (I  B) kinases and subsequent upregulation of transcription factors including nuclear factor kappa B and activator protein 1.1 Activation of this signal transduction cascade ultimately leads to PDC activation with subsequent maturation into professional antigen presenting cells. Simultaneously, antigen macropinocytosis is stimulated, leading to enhanced presentation on class I and II major histocompatibility complex molecules.6 TLR9-activated PDCs express high levels of costimulatory molecules (CD80, CD86) and secrete cytokines such as type I interferons (IFNs) and tumor necrosis factor alpha, as well as T-helper cell type 1–promoting chemokines CXCL-10 and CCL3/4.5 Within hours, secondary effects such as natural killer (NK) cell activation are induced. Early activation of innate immunity may be followed by stimulation of adaptive immunity even in the absence of CD4+ T-cell help.7 Antitumor effects of TLR9-targeted therapies have been described in animal models against various tumor types, including melanoma, after repeated administration as monotherapy or in combination with antigens or antibodies.5 In humans, the safety and activity of TLR9-targeted therapy are poorly understood, and no biomarkers have yet been associated with clinical response. Clinical trials of TLR9-targeted therapy lasting for more than a few weeks have not been reported. Therefore, we performed a clinical trial to assess the clinical and immunologic effects of chronic TLR9 activation with weekly subcutaneous administration of ODN PF-3512676.
Study Design Twenty-six patients were recruited from six centers. All patients provided written informed consent for the study protocol approved by the institutional review boards. Six patients were excluded due to screening failures and 20 patients (Table 1) were treated per protocol. Eligibility criteria were histologically confirmed nonocular melanoma, unresectable clinical stage IIIb/c or IV according to American Joint Committee on Cancer8; measurable disease as defined by Response Evaluation Criteria in Solid Tumors9; an Eastern Cooperative Oncology Group performance status  2; and neutrophils  1,000/µL, platelets 100,000/µL, hemoglobin 10 g/dL, serum creatinine 2.0 mg/dL, bilirubin 1.5 mg/dL, ALT/AST less than 3x upper limit of normal, and partial thromboplastin time (PTT) 40 seconds. Exclusion criteria included prior chemotherapy or immunotherapy, with the exception of up to two different adjuvant immunotherapeutic regimens terminated at least 4 weeks before, (history of) brain metastasis, lactate dehydrogenase more than upper limit of normal, use of systemic glucocorticosteroids/immunosuppressants or anticoagulants (except acetylsalicylic acid 500 mg/d), clinical and/or laboratory evidence of pre-existing autoimmune disease, HIV/active hepatitis B and C infection, or pregnant/lactating females.
Previous phase I trials demonstrated that PF-3512676 doses of up to 0.08 mg/kg provide a consistent increase in serum immune activation markers after subcutaneous administration.10 Objective clinical responses to PF-3512676 monotherapy in cancer patients have occurred at doses of 0.08 mg/kg and higher, with no obvious dose-response. The maximum-tolerated dose of PF-3512676 has not been reached, despite dosing up to 0.81 mg/kg weekly (data on file; Coley Pharmaceutical Group, Wellesley, MA). On the basis of these findings, PF-3512676 was administered in this study at a total dose of 6 mg subcutaneously once weekly in an outpatient setting for 24 weeks or until the development of progressive disease (PD). Primary objectives of this trial were evaluation of antitumor activity and safety of repeated PF-3512676 application. Secondary objectives were descriptions of duration of responses and immune responses induced.
Safety Assessments
Clinical Response Assessments
Active Compound
Immunophenotyping of Peripheral Blood Mononuclear Cells
NK Cell Cytotoxicity Assay NK cell cytotoxicity was determined by the effector-to-target ratio required to kill 20% of target cells and expressed as lytic units (LU20) per 105 NK cells (Current Protocols in Immunology online; http://www.currentprotocols.com/WileyCDA/CPTitle/isbn-0471522767.html). Percentages of CD3–CD56+ NK cells among PBMCs were determined by flow cytometry.
IFN-
Analysis of Regulatory T-Cell Activity
Enzyme-Linked Immunosorbent Assay and Radioimmunoassay
Statistical Analysis
Patient Characteristics Twenty patients were eligible for treatment on this protocol, with demographic characteristics as shown in Table 1. Twelve patients had PD after receiving adjuvant immunotherapy. Thirteen patients had metastatic lesions at more than one body site, with all relevant visceral sites represented (Table 1). Twenty patients received PF-3512676 for a mean of 10.9 weeks with a mean of 10.7 injections. The number of injections per patient ranged from three to 24. One patient with PR has continued to receive therapy in an extension protocol for 140+ weeks.
Toxicity
Clinical Results Responses and their duration are listed in Table 1. A confirmed clinical response occurred in patient 14, who suffered from lung metastasis. This patient had undergone prior surgical resection of the primary tumor and had a single lung metastasis at study entry, but had received no previous adjuvant immunotherapy. The target lesion showed no additional progression after 8 weeks of therapy and significant regression after 16 weeks. No new lesions appeared and no nontarget lesions progressed. This response was confirmed at week 24 and is now ongoing after 140+ weeks of PF-3512676 therapy. Another confirmed clinical response occurred in patient 2, who had developed multiple lymph node and skin/soft tissue metastases. This patient had undergone surgery of lymph node and multiple skin/soft tissue metastases, but had not received any prior adjuvant immunotherapy. At study entry, the patient presented with multiple skin/soft tissue metastases. The target lesion regressed significantly after 8 weeks and completely after 16 weeks of treatment (Fig 1). Simultaneously, several nontarget skin/soft tissue lesions regressed completely. Regression of these lesions was still observed at week 24, although at this time the patient developed new lesions in bone and mucosal tissues.
Three patients experienced SD (patients 3, 5, and 18). All patients had undergone prior surgery of the primary tumor and sentinel lymph node dissection; two patients had received adjuvant immunotherapy (Table 1). Sites of metastasis were lung and lymph nodes, respectively. At week 24, each patient experienced PD at one or more sites. Within the complete patient population, objective regression of metastases was seen in lung, lymph node, and skin/soft tissue, and incomplete responses/SD were observed in the liver.
Biomarkers of Therapy Direct effects on TLR9-expressing target cells were analyzed by flow cytometry. PF-3512676 induced a moderate but consistent increase in proportions of CD86+ blood PDCs (P = .019) and elevation of mean fluorescence intensity (MFI) for HLA-DR (P = .016) on blood PDCs, both features of PDC activation (Figs 2A and 2B). These changes occurred irrespective of clinical response. Changes in absolute or relative PDC counts were not observed.
A marked elevation in the proportion (P = .002) and absolute numbers (P = .002) of CD19+CD38high B cells (early plasma cells) was found during treatment (Figs 2C and 2D).14 Relative and absolute counts or induction of B cells and surface expression of CD80, CD86, and HLA-DR by B cells did not show any correlation with clinical response. Despite the evidence of differentiation of B cells to plasma cells, neither total serum IgG and IgE, nor titers of IgG and IgM against capsid antigen of Epstein-Barr virus changed during treatment (data not shown). Serum type I IFN responses were analyzed because they are important mediators of TLR9 stimulation. However, their detection is complicated by their rapid pharmacokinetics.15 We therefore measured serum levels of 2-5A, a surrogate marker of type I IFN production, which remains elevated in serum for more than a week after induction.16 Serum levels of 2-5A were a median of 1.23 pmol/mL (range, 0.41 to 6 pmol/mL; 20 patients) at week 0, increasing to 2.71 pmol/mL (range, 1.33 to 10.56 pmol/mL; 20 patients) at week 4 (P < .001) and 2.56 pmol/mL (range, 1.27 to 7.69 pmol/mL; 18 patients) at week 8 (P < .001), indirectly confirming sustained induction of type I IFN expression (Fig 2E). The dynamics of 2-5A expression were not associated with clinical response. Indirect effects of TLR9-targeting on antitumor effector cells were analyzed in NK and T cells. PF-3512676 induced a decrease in CD56+CD16+ NK cell numbers (Fig 3A), presumably reflecting NK cell recruitment into tissues. NK cytotoxicity (NKC) showed divergent dynamics: an up to 30.1-fold increase was measured in three of the four patients with PR and SD (week 8/week 0 NKC ratio > 1) and a decrease was observed in seven of the nine patients with PD (P = .019; Fig 3B). In patient 14, the sustained (140+ weeks) clinical response was associated with a sustained increase of NKC (week 54/week 0 ratio) during therapy (Fig 3B, arrowhead). Pre- and post-treatment NK cell numbers and their dynamics did not correlate with clinical response.
IFN-  enzyme-linked immunospot assay with circulating CD8+ T cells from eight patients revealed no clear-cut reactivity to any MDA tested. CD8+ T cell-reactivity was detected against viral antigen CMV pp65 in three of four anti-CMV IgG-seropositive patients at baseline, but frequencies did not increase during treatment (Fig 4).
To screen for regulatory T-cell (Treg) activity, we isolated blood CD4+ T cells from week 0 and week 8 PBMC samples and depleted them for CD25high Treg cells. This technique removed CD4+CD25high Treg cells, but retained CD4+CD25dim activated T-helper cells (Fig 5A, 5B, 5C). Although proliferative responses of nondepleted CD4+ T cells changed little during treatment, those of Treg-depleted CD4+CD25dim/– T cells increased, sometimes dramatically (P = .008; Fig 5D). There was no correlation of proliferative responses of Treg-depleted CD4+ T cells with clinical response. Percentages of blood Treg cells did not change during therapy (median frequency of CD25high cells among CD4+ T cells at week 0, 4.8% [range, 3.3% to 7.7%]; week 8, 5.6% [range, 2.8% to 7.9%]).
TLR9 agonists interact directly with and activate PDCs as indicated by the in vitro upregulation of surface expression of major histocompatibility complex class II and costimulatory molecules including CD86.17 Consistently, we found that PF-3512676 administration to humans results in a moderate but consistent relative increase in the CD86+ subpopulation of PDCs and elevation of HLA-DR MFI on blood-derived PDCs. Once activated, PDCs secrete high levels of type I IFNs.18 Although we could not directly detect increased serum cytokine levels in our patients, presumably because serum samples were collected at time points when the cytokines would be expected to have returned to baseline, the marked elevation of 2'-5'-oligoadenylate serum levels indicates sustained effects of type I IFNs during therapy.10 Type I IFNs are important enhancers of NK cytotoxicity and their induction by PF-3512676 may contribute to our observations on the reduction of NK cell counts in the peripheral blood during treatment, which may reflect NK cell recruitment into tissues following activation and on the increase in NK cytotoxicity in patients with clinical benefit (PR/SD),19 which could represent a potential biomarker for clinical benefit from TLR9 activation. NK cytotoxicity generally has not been evaluated in other TLR9 agonist trials with one exception. When applied intravenously to non-Hodgkin's lymphoma patients, PF-3512676 induced NK cell activity, but without association with clinical outcome.20 This finding is somewhat difficult to interpret, given that intravenous administration of PF-3512676 is not associated with induction of IFN expression, and non-Hodgkin's lymphoma expresses TLR9, which may result in mechanisms of tumor regression different than that of TLR9-negative melanoma. We suggest that NK cell activity should be evaluated in future cancer trials with TLR9 agonists, to confirm or refute our findings. Given that type I IFNs were induced in all patients, other mechanisms apparently contribute to induction of NK cytotoxicity. A candidate molecule is IL-12, which is induced in PDCs through a combination of TLR9 stimulation and CD40 ligation.18 Once loaded with tumor antigens, TLR9-activated PDCs also promote activation of antigen-specific CD8+ T-cell responses.5,7,18,21 When administered with a MDA-derived peptide, PF-3512676 is able to expand MDA-specific CD8+ T cells in vitro and in combination with incomplete Freund’s adjuvant, in melanoma patients.21,22 Even without administration of an antigen, PF-3512676 can induce antitumor T-cell responses in mouse tumor models.23 In our study, PF-3512676 was administered without a defined antigen and we could not find evidence for the induction of MDA-specific CD8+ T-cell responses. One explanation may be the limited number of available K562-HLA transfectants matching patients' haplotypes. Therefore, induced CD8+ T-cell responses may have been missed. Another intriguing but still preliminary explanation may be provided by the Treg cell-depletion experiments. These data suggest that in some patients, TLR9-induced proliferation of CD4+ T cells does not overcome Treg function, even in the presence of an additional antigenic stimulus such as CD3-ligation in vitro or a tumor antigen in vivo. This observation requires additional confirmation, but provides a scientific rationale for a combination of TLR9 agonists and Treg-targeting therapy, notably cytotoxic chemotherapy and Ab-based immunotherapy.24 Additional clinical studies are required to define the complex effects of TLR9 activation in the absence of exogenous antigen (ie, not using a vaccine) on tumor-specific T-cell responses. PF-3512676 treatment also resulted in a marked elevation of circulating CD19+CD38high early plasma cells. This observation was in agreement with the recent description that TLR9 activation can induce memory B cells to proliferate and differentiate into plasma cells.14,25 This effect can be viewed as an in vivo marker of exposure to TLR9 agonists. PF-3512676 has shown activity in patients with renal cell cancer26 and cutaneous T-cell lymphoma,27 and has improved the rate of objective responses in non–small-cell lung cancer patients when added to a taxane/platinum regimen.28 These results and our data provide the rationale to evaluate further the activity of TLR9-induced innate antitumor immune responses in larger phase II and III trials.
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.
We thank A. Chott, Department of Clinical Pathology, Medical University of Vienna, for histopathologic advice; S. Efler and K. Robertson for data management; C. Lefebvre for data monitoring; and B. Volc-Platzer for excellent help with accrual of patients.
Supported by the Austrian National Bank (Grant No. 11062), the Medical-Scientific Fund of the Mayor of the City of Vienna (Grant No. 02529), the Deutsche Krebshilfe (Grant No. 70-2427-Hul), and Coley Pharmaceutical Group Inc, Wellesley, MA. Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA; the 95th Annual Meeting of the American Association of Cancer Research, March 27-31, 2004, Orlando, FL; and the 31st Annual Meeting of the Arbeitsgemeinschaft Dermatologische Forschung, February 26-28, 2004, Dresden, Germany. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Akira S, Uematsu S, Takeuchi O: Pathogen recognition and innate immunity. Cell 124:783-801, 2006[CrossRef][Medline] 2. Kadowaki N, Ho S, Antonenko S, et al: Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 194:863-869, 2001 3. Bauer S, Kirschning CJ, Hacker H, et al: Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc Natl Acad Sci U S A 98:9237-9242, 2001 4. Hornung V, Rothenfusser S, Britsch S, et al: Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 168:4531-4537, 2002 5. Krieg AM: Therapeutic potential of toll-like receptor 9 activation. Nat Rev Drug Discov 5:471-484, 2006[CrossRef][Medline] 6. West MA, Wallin RP, Matthews SP, et al: Enhanced dendritic cell antigen capture via toll-like receptor-induced actin remodeling. Science 305:1153-1157, 2004 7. Sparwasser T, Vabulas RM, Villmow B, et al: Bacterial CpG-DNA activates dendritic cells in vivo: T helper cell-independent cytotoxic T cell responses to soluble proteins. Eur J Immunol 30:3591-3597, 2000[CrossRef][Medline] 8. Balch CM, Buzaid AC, Soong SJ, et al: Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635-3648, 2001 9. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 10. Krieg AM, Efler SM, Wittpoth M, et al: Induction of systemic TH1-like innate immunity in normal volunteers following subcutaneous but not intravenous administration of CPG 7909, a synthetic B-class CpG oligodeoxynucleotide TLR9 agonist. J Immunother 27:460-471, 2004[Medline] 11. Uhlmann E, Vollmer J: Recent advances in the development of immunostimulatory oligonucleotides. Curr Opin Drug Discov Devel 6:204-217, 2003[Medline] 12. Britten CM, Meyer RG, Frankenberg N, et al: The use of clonal mRNA as an antigenic format for the detection of antigen-specific T lymphocytes in IFN-gamma ELISPOT assays. J Immunol Methods 287:125-136, 2004[CrossRef][Medline] 13. Dieckmann D, Bruett CH, Ploettner H, et al: Human CD4(+)CD25(+) regulatory, contact-dependent T cells induce interleukin 10-producing, contact-independent type 1-like regulatory T cells. J Exp Med 196:247-253, 2002 14. Harada Y, Kawano MM, Huang N, et al: Identification of early plasma cells in peripheral blood and their clinical significance. Br J Haematol 92:184-191, 1996[CrossRef][Medline] 15. Kerkmann M, Rothenfusser S, Hornung V, et al: Activation with CpG-A and CpG-B oligonucleotides reveals two distinct regulatory pathways of type I IFN synthesis in human plasmacytoid dendritic cells. J Immunol 170:4465-4474, 2003 16. Sturzebecher S, Maibauer R, Heuner A, et al: Pharmacodynamic comparison of single doses of IFN-beta1a and IFN-beta1b in healthy volunteers. J Interferon Cytokine Res 19:1257-1264, 1999[CrossRef][Medline] 17. Hartmann G, Weiner GJ, Krieg AM: CpG DNA: A potent signal for growth, activation, and maturation of human dendritic cells. Proc Natl Acad Sci U S A 96:9305-9310, 1999 18. Krug A, Towarowski A, Britsch S, et al: Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12. Eur J Immunol 31:3026-3037, 2001[CrossRef][Medline] 19. Biron CA, Nguyen KB, Pien GC, et al: Natural killer cells in antiviral defense: Function and regulation by innate cytokines. Annu Rev Immunol 17:189-220, 1999[CrossRef][Medline] 20. Link BK, Ballas ZK, Weisdorf D, et al: Oligodeoxynucleotide CPG 7909 delivered as intravenous infusion demonstrates immunologic modulation in patients with previously treated non-Hodgkin's lymphoma. J Immunother 29:558-568, 2006[Medline] 21. Rothenfusser S, Hornung V, Ayyoub M, et al: CpG-A and CpG-B oligonucleotides differentially enhance human peptide-specific primary and memory CD8+ T-cell responses in vitro. Blood 103:2162-2169, 2004 22. Speiser DE, Lienard D, Rufer N, et al: Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J Clin Invest 115:739-746, 2005[CrossRef][Medline] 23. Baines J, Celis E: Immune-mediated tumor regression induced by CpG-containing oligodeoxynucleotides. Clin Cancer Res 9:2693-2700, 2003 24. Zou W: Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6:295-307, 2006[CrossRef][Medline] 25. Bernasconi NL, Traggiai E, Lanzavecchia A: Maintenance of serological memory by polyclonal activation of human memory B cells. Science 298:2199-2202, 2002 26. Thompson JA, Kuxel T, Bukowski F, et al: Phase Ib trial of a targeted TLR9 CpG immunomodulator (CPG 7909) in advanced renal cell carcinoma (RCC). J Clin Oncol 22:417s, 2004 (suppl; abstr 4644) 27. Kim Y, Girardi M, McAuley S, et al: Cutaneous T-cell lymphoma (CTCL) responses to a TLR9 agonist CPG immunomodulator (CPG 7909), a phase I study. J Clin Oncol 22:582s, 2004 (suppl; abstr 6600) 28. Leichman G, Gravenor D, Woytowitz D, et al: CPG-7909, a TLR9 agonist, added to first-line taxane/platinum for advanced non-small cell lung cancer, a randomzed, controlled phase II study. J Clin Oncol 23:630s, 2005 (suppl; abstr 7039) Submitted June 17, 2006; accepted October 5, 2006.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
) target lesion.
) week 54/week 0 NKC ratio of patient 14 (sustained responder during therapy, sampling failure at week 8; *P = .034 or P = .019, if patient 14 is excluded or included, respectively). PR, partial response; SD, stable disease; PD, progressive disease.
