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Blood, 1 February 2007, Vol. 109, No. 3, pp. 951-953. Prepublished online as a Blood First Edition Paper on October 10, 2006; DOI 10.1182/blood-2006-03-013136. This Article Abstract Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2006-03-013136v1 109/3/951    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Weng, W.-K. Articles by Levy, R. Search for Related Content PubMed PubMed Citation Articles by Weng, W.-K. Articles by Levy, R. Related Collections Neoplasia Immunotherapy Brief Reports Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS Brief Report Humoral immune response and immunoglobulin G Fc receptor genotype are associated with better clinical outcome following idiotype vaccination in follicular lymphoma patients regardless of their response to induction chemotherapy Wen-Kai Weng1, Debra Czerwinski1, and Ronald Levy1 1 Division of Medical Oncology, Department of Internal Medicine, Stanford University School of Medicine, Stanford, CA    Abstract Top Abstract Introduction Patients, materials, and methods Results and discussion Authorship References   We have reported that anti-idiotype antibody response and FcRIIIa 158 valine/valine (V/V) genotype both correlate with better outcome in a group of 136 follicular lymphoma patients receiving idiotype vaccination after induction chemotherapy. Here, we examined whether this correlation is related in any way to the chemotherapy response. In patients with complete response (CR), the 5-year progression-free survival (PFS) was 69% for patients with antibody response and/or V/V genotype, while the PFS was only 40% for patients with neither; the median time to progression (TTP) was 10.47 versus 3.46 years (P = .012). In patients with partial response (PR), the 5-year PFS was 57% for patients with antibody response and/or V/V genotype, and 17% for patients with neither; the median TTP was not reached versus 1.31 years (P = .001). This study further confirms the strong association of clinical outcome with antibody response and with the functionally more active form of the Fc receptor in patients receiving idiotype vaccination regardless of their response to induction chemotherapy.    Introduction Top Abstract Introduction Patients, materials, and methods Results and discussion Authorship References   Active immunotherapies that generate long-lasting immune responses against tumor antigen(s) by the patient may be an appealing strategy to treat non-Hodgkin lymphoma. One approach being tested is vaccination against the unique sequences of immunoglobulin (idiotype, Id) expressed by each patient's tumor.1 The goal of vaccination is to generate anti-Id immune responses, which may actively eliminate tumor cells and lead to better outcome.2 Lymphoma patients vaccinated with Id protein make humoral and cellular anti-Id immune responses to a variable degree, depending upon the vaccine regimen.3–5 In one study, anti-Id cellular immune responses are believed to induce molecular remission in vaccinated patients.6 In contrast, we have recently shown that anti-Id humoral immune responses and FcRIIIa 158 V/V genotype are associated with better clinical outcome in a larger group of lymphoma patients.7 In these studies, patients received Id vaccines when they were in remission after induction chemotherapy. Therefore, the response to induction chemotherapy could have had an impact on their outcome. In this report, we determined the influence of chemotherapy response on the clinical outcome and whether the predictive value for better outcome of antibody response and V/V genotype applied to patients who had different chemotherapy responses.    Patients, materials, and methods Top Abstract Introduction Patients, materials, and methods Results and discussion Authorship References   Idiotype vaccination studies This retrospective study included 136 patients who received idiotype vaccination using different study protocols between 1988 and 2000. The patient characteristics are summarized in Table S1, which is available on the Blood website (see the Supplemental Materials link at the top of the online article). To be included in vaccine trials, all patients were required to receive induction chemotherapy to achieve at least a partial response before vaccination. The responses were scored according to the criteria of Cheson et al.8 The follicular lymphoma international prognostic index (FLIPI) score at the time of induction chemotherapy was available on 127 patients to determine their risk group as described.9 Vaccinations were initiated at least 2 months after completion of chemotherapy. During the vaccination, 86 patients received chemical adjuvant, 18 patients received GM-CSF, and 32 patients had Id protein-pulsed dendritic cells.1,5,10,11 The vaccination was usually composed of 4 to 5 monthly injections according to individual protocols. Postvaccination follow-up was conducted every 3 to 4 months for the first 2 to 3 years, and then semiannually or annually. The median follow-up after induction chemotherapy was 8.26 years for the entire group. All vaccination studies were conducted according to institutional review board–approved protocols, and informed consent was obtained from all patients. Immune response assessments A specific humoral anti-Id immune response was determined by prespecified criteria when a 4-fold increase in anti-Id antibody titer was found after vaccination compared with before vaccination and with the irrelevant Id proteins using enzyme-linked immunosorbent assay.5,11 Anti-Id cellular immune response was determined by T-cell proliferation assays by culturing peripheral blood mononuclear cells (PBMCs) in media alone or with tumor Id, or irrelevant Id proteins.1,11,12 Prespecified criteria required that incorporation of [3H]-thymidine more than twice the background (media alone) was observed on 2 or more occasions to be considered positive. Immune responses were measured before vaccination, 2 weeks following each vaccination, and 3 and 6 months after last injection. In general, anti-Id immune responses were detected after 3 to 4 vaccinations and peaked after 4 to 5 vaccinations. The anti-Id antibodies were sustained for several months. The cellular immune responses declined quickly after last vaccine and were undetected after 3 months in most of the cases. Analysis of FcRIIIa and FcRIIa polymorphisms Genomic DNA was prepared from tumor cells or PBMCs using a QIAGEN DNA extraction kit (QIAGEN, Valencia, CA) or from the serum as described.12 The FcRIIIa 158 V/F and FcRIIa 131 H/R genotypes were determined using TaqMan technology on an ABI Prism 7900HT Sequence Detector System (Applied Biosystems, Foster City, CA) with FcRIIIa- and FcRIIa-specific primer pairs and allele-specific probes.7 Statistical analysis The median time to progression (TTP) and difference in the progression-free survival (PFS) were determined using the Kaplan-Meier estimation and log-rank statistic (PRISM for Macintosh; GraphPad Software, San Diego, CA). A multivariate analysis using Cox proportional hazard model was performed to identify independent prognostic variables influencing the PFS (StatView 5.0.1; SAS, Cary, NC).    Results and discussion Top Abstract Introduction Patients, materials, and methods Results and discussion Authorship References   Responses to induction chemotherapy and clinical outcome The anti-Id immune response has been shown to correlate with better clinical outcome in follicular lymphoma patients who received a custom Id vaccine.5,10 However, these patients all received induction chemotherapy of different regimens to reduce tumor burdens and all were in remission at the time of vaccination (Table S2). We first analyzed the influence of chemotherapy response on clinical outcome of a group of 136 consecutive vaccinated patients from our previous report, for whom even longer follow-up is now available. Overall, 93 (68%) patients achieved complete response (CR) and 43 (32%) patients achieved PR after chemotherapy. The development of anti-Id humoral or cellular immune response and the FcRIIIa and IIa genotype distribution did not differ between CR and PR patients (Table S1). As expected, the CR patients had longer TTP after the last chemotherapy. The estimated 5-year PFS was 54% for CR and 34% for PR patients, with median TTP estimate at 5.87 and 1.62 years, respectively (P = .012) (Figure 1A). Certain chemotherapy reagents such as fludarabine have been to shown to suppress T-cell function13 and might have a negative effect on idiotype vaccination. However, in our study, use of fludarabine or adriamycin had no effect on the clinical outcome (Table 1). View larger version (12K): [in this window] [in a new window]   Figure 1. Kaplan-Meier estimates of progression-free survival by response to induction chemotherapy, and humoral immune response and V/V genotype. Progression-free survival curves were plotted by response to induction chemotherapy (A), or by humoral anti-Id immune responses and/or FcRIIIa 158 V/V genotype in CR (B), PR (C), and all (D) patients. CR represents patients with complete response or complete response unconfirmed. PR represents patients with partial response. Other represents patients without either anti-Id antibodies or FcRIIIa 158 V/V genotype. TTP indicates median time to progression.   View this table: [in this window] [in a new window]   Table 1. Prognostic factors for freedom from progression: Cox proportional hazard model   The clinical impact of anti-Id Abs and V/V genotype in different chemotherapy response groups We have previously shown that anti-Id antibody response and/or V/V genotype correlated with longer TTP.7 This result suggested the importance of vaccine-induced antitumor antibodies and that these antibodies mediate tumor killing more efficiently with effector cells bearing the FcRIIIa of V/V genotype. Here, we analyzed the correlation of anti-Id Abs and V/V genotype together with clinical outcome in different chemotherapy response subgroups. The TTP of CR patients with anti-Id Abs and/or V/V genotype (total of 45 patients) was longer than CR patients with neither (10.47 vs 3.46 years, P = .012), with estimated 5-year PFS of 69% and 40%, respectively (Figure 1B). Similarly, PR patients with anti-Id Abs and/or V/V genotype (total of 19 patients) also had a longer TTP than patients with neither (not reached vs 1.31 years, P < .001), with 5-year PFS of 57% and 17%, respectively (Figure 1C). The observations in both animal models and early clinical studies suggest that vaccines may be more effective in the setting of minimal residual disease.14 Therefore, it was predicted that clinical impact of Id vaccination would have been more pronounced in CR patients.6 In contrast to the prediction, prolonged TTP associated with anti-Id Abs and/or V/V genotype was clearly shown in both CR and PR patients (Figure 1B, 1C). In fact, the prolonged TTP was even more profound in PR patients. The PR patients who had anti-Id Abs and/or V/V genotype had an identical survival curve compared with CR patients with anti-Id Abs and/or V/V genotype (TTP: not reached vs 10.47 years, P = .899). In contrast, for those who had neither, PR did significantly worse than CR patients (TTP: 1.31 vs 3.46 years, P = .004) (Figure 1D). This suggested that antibody response may be able to control the gross residual disease and delay tumor progression in PR patients. It is the first time that a potential benefit of idiotype vaccination has been implicated in a large number of patients with gross disease. In contrast, the anti-Id cellular immune response had no impact on TTP in either CR or PR patients (data not shown). In fact, patients with cellular immune response showed a trend toward a worse outcome (Table 1). The biologic explanation for this observation is not clear. One possibility is that our assay measured CD4+ T-cell response but did not measure the potentially antitumor cytotoxic CD8+ T cells. The FLIPI scores were available on 127 patients. Patients of different risk groups did not differ in their chemotherapy response or in their anti-Id immune responses (Table S3). However, low-risk patients had longer TTP than intermediate/high-risk patients (Figure S1A). Additionally, in the intermediate/high-risk patients, anti-Id Abs and/or V/V genotype was associated with a longer TTP (10.47 vs 2.18 years, P < .001), while no difference was found within the low-risk patients (Figure S1B-C). This result further confirmed the association of better outcome with anti-Id Abs and/or V/V genotype in patients with unfavorable clinical features. In a multivariate analysis, CR along with anti-Id Abs and FcRIIIa 158 V/V genotype emerged as 3 independent positive predictors for longer PFS, whereas none of the others had an impact (Table 1). Our data support a model in which antitumor antibody-dependent cell-mediated cytotoxicity (ADCC) plays an important role in the antitumor effect of Id vaccination in both CR and PR patients. Therefore, in contrast to previous assumptions, idiotype vaccination should not be limited to patients with minimal residual disease. While some patients may have gross diseases after induction, the vaccine-induced antibody response may be able to control the disease and delay tumor progression and the need for subsequent treatment. None of the patients in this report received rituximab during their prevaccination cytoreduction. The clinical effect of Id vaccination may differ in rituximab-treated patients.15    Authorship Top Abstract Introduction Patients, materials, and methods Results and discussion Authorship References   Conflict-of-interest disclosure: The authors declare no competing financial interests. Correspondence: Wen-Kai Weng, Division of Oncology CCSR 1105, 269 Campus Dr, Stanford University School of Medicine, Stanford, CA 94305-5306; e-mail: wkweng{at}stanford.edu.    Acknowledgments   This work was supported by grants CA34233 and CA33399 from the US Public Health Service–National Institutes of Health (NIH). W.K.W. is recipient of an NIH-NCI K08 Award CA111827. R.L. is an American Cancer Society Clinical Research Professor.    Footnotes   Submitted March 28, 2006; accepted August 27, 2006. Prepublished online as Blood First Edition Paper, October 10, 2006 DOI: 10.1182/blood-2006-03-013136 The online version of this article contains a data supplement. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.    References Top Abstract Introduction Patients, materials, and methods Results and discussion Authorship References   Kwak LW, Campbell MJ, Czerwinski DK, Hart S, Miller RA, Levy R. Induction of immune responses in patients with B-cell lymphoma against the surface-immunoglobulin idiotype expressed by their tumors. N Engl J Med 1992; 327:1209–1215.[Abstract] Ruffini PA, Neelapu SS, Kwak LW, Biragyn A. Idiotype vaccination for B-cell malignancies as a model for therapeutic cancer vaccines. Haematologica 2002; 87:989–1001.[Abstract/Free Full Text] Osterroth F, Garbe A, Fisch P, Veelken H. Stimulation of cytotoxic T cells against idiotype immunoglobulin of malignant lymphoma with protein-pulsed or idiotype-transduced dendritic cells. Blood 2000; 95:1342–1349.[Abstract/Free Full Text] McCarthy H, Ottensmeier CH, Hamblin TJ, Stevenson FK. Anti-idiotype vaccines. Brit J Haematol 2003; 123:770–781.[CrossRef][Medline] [Order article via Infotrieve] Hsu FJ, Caspar CB, Czerwinski D, et al. Tumor-specific idiotype vaccines in the treatment of patients with B-cell lymphoma: long-term results of a clinical trial. Blood 1997; 89:3129–3135.[Abstract/Free Full Text] Bendandi M, Gocke CD, Kobrin CB, et al. Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma. 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This article has been cited by other articles: W. Z. Ai, R. Tibshirani, B. Taidi, D. Czerwinski, and R. Levy Anti-idiotype antibody response after vaccination correlates with better overall survival in follicular lymphoma Blood, June 4, 2009; 113(23): 5743 - 5746. [Abstract] [Full Text] [PDF] B. Friedrichs, S. Siegel, M. Kloess, A. Barsoum, J. Coggin Jr., J. Rohrer, I. Jakob, M. Tiemann, K. Heidorn, C. Schulte, et al. Humoral Immune Responses against the Immature Laminin Receptor Protein Show Prognostic Significance in Patients with Chronic Lymphocytic Leukemia J. Immunol., May 1, 2008; 180(9): 6374 - 6384. [Abstract] [Full Text] [PDF] L. Binyamin, R. K. Alpaugh, T. L. Hughes, C. T. Lutz, K. S. Campbell, and L. M. Weiner Blocking NK Cell Inhibitory Self-Recognition Promotes Antibody-Dependent Cellular Cytotoxicity in a Model of Anti-Lymphoma Therapy J. Immunol., May 1, 2008; 180(9): 6392 - 6401. [Abstract] [Full Text] [PDF] E. Carlotti, G. A. Palumbo, E. Oldani, D. Tibullo, S. Salmoiraghi, A. Rossi, J. Golay, A. Pulsoni, R. Foa, and A. Rambaldi Fc{gamma}RIIIA and Fc{gamma}RIIA polymorphisms do not predict clinical outcome of follicular non-Hodgkin's lymphoma patients treated with sequential CHOP and rituximab Haematologica, August 1, 2007; 92(8): 1127 - 1130. [Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2006-03-013136v1 109/3/951    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Weng, W.-K. Articles by Levy, R. Search for Related Content PubMed PubMed Citation Articles by Weng, W.-K. Articles by Levy, R. Related Collections Neoplasia Immunotherapy Brief Reports Clinical Trials and Observations Social Bookmarking                   What's this?

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