Bendandi, M. (Maurizio)

Cuesta, B. (Braulia)

Hernandez, M. (Milagros)

Inoges, S. (Susana)

Lopez-Diaz-de-Cerio, A. (Ascensión)

Panizo, C. (Carlos)

Perez-Calvo, J. (Javier)

Rocha, E. (Eduardo)

Rodriguez-Calvillo, M. (Mercedes)

Zabalegui, N. (Natalia)

Dadun, University of Navarra

itary hemochromatosis gene is associated with cardio-vascular death in women. Circulation 1999;100:1268-73.6. Tuomainen TK, Kontula K, Nyyssönen K, Lakka TA, Heliö T,Salonen JT. Increased risk of acute myocardial infarctionin carriers of the hemochromatosis gene Cys282Tyr muta-tion. A prospective cohort study in men in Eastern Finland.Circulation 1999;100:1274-9.7. Sullivan JL. Iron and the sex difference in heart disease risk.Lancet 1981;1:1293-4.8. Moyo VM, Mandishona E, Hasstedt SJ, Gangaidzo IT, GomoZAR, Khumalo H, et al. Evidence of genetic transmissionin African iron overload. Blood 1998;91:1076-82.Feasibility of idiotype vaccination in relapsedB-cell malignanciesFeasibility of idiotype vaccination was statistically com-pared among five different B-cell malignancies in firstrelapse. When based on hybridoma production techniques,idiotypic vaccination for relapsed B-cell malignancies wasconsistently feasible only in follicular lymphoma patients,whereas the main cause of failure in other settings was theshort survival of idiotype-producing hybridomas.haematologica 2003; 88:1438-1440(http://www.haematologica.org/2003_12/1438.htm)With two ongoing, phase-III clinical trials enrolling newly-diagnosed follicular lymphoma (FL) patients, idiotypic vaccina-tion1 is approaching the final stage of its clinical development,that of demonstrating a possible benefit to patients. However,even in the event that either or both ongoing clinical trials suc-ceed, a number of relevant questions would still remain unan-swered, in particular whether idiotype (Id) vaccines may be fea-sible for most if not all relapsed FL and for some other B-cellmalignancies.An interim analysis was performed of all Id vaccine clinicaltrials currently ongoing at our institution based on a single,major endpoint, that is actual ability to administer an Id vac-cine according to intention-to-treat. Inclusion criteria commonto all cases were that the Id vaccine production attempt wascarried out only at the time of pathologically-confirmed firstrelapse and that there was a prior, formal demonstration of thepresence of a complete, clonal and tumor-specific immunoglob-ulin on the tumor cell surface. Furthermore, all Id vaccine pro-duction attempts were carried out by the same personnel andalways using the same fusion partner (K6H6/B5, i.e. ATCC num-ber: CRL-1823), according to the standard tumor/hetero-hybridoma fusion-based method previously described.2-5 Allpatients received the chemotherapy regimen currently in use atour institution for their respective disease in first relapse (Table1). Patients with FL, mantle cell lymphoma and small lympho-cytic lymphoma were supposed to receive Id vaccine treatmentif they achieved either complete (CR) or partial (PR) response,while patients with either diffuse large cell or Burkitt’s lym-phoma were supposed to receive Id vaccine treatment only ifthey achieved a CR.Id vaccine treatment unfeasibility was evaluated as (i) relat-ed to induction treatment, if the salvage therapy did not inducea response sufficient to proceed with Id vaccination, (ii) fusion-related, if sufficient Id could not be generated to make the vac-cine, or (iii)  overall. Fusion-related feasibility was evaluated bytaking into consideration both its potential causes of failure:short hybridoma survival and loss of Id production.The feasibility of Id vaccination in relation to induction treat-ment was markedly different, being 80%-100% in indolent NHLsubtypes and 40%-50% in aggressive ones. This difference wasnot, however, due to an overall lack of efficacy of the respec-tive chemotherapy regimens, but rather to the different eligi-bility criteria for Id vaccination following chemotherapy. In fact,the overall response to induction treatment for aggressive NHLwas 75%-80% (CR+PR), but in this group only patients achiev-ing CR were considered eligible to receive Id vaccination. A farmore important factor that halted treatment was Id-secretinghybridoma production (Table 2). Fusion experiments were suc-cessful in most FL cases at the very first attempt, whereas inother NHL cases, irrespective of the ultimate Id production out-come, as many as 5 attempts had to be carried out most of thetime. Similarly, in most FL cases, the average number of suc-cessful fusion wells per 96-well plate was well above 15, where-as that of most of the other NHL cases was typically lower thanfive.Statistically significant differences in fusion-related andoverall feasibility were found between cases of FL and those ofall other NHL, indolent and aggressive lymphoma, respectively(Table 2). Both fusion-related and overall feasibility of the Idvaccine treatment for FL in first relapse were comparable withthose already described for both newly-diagnosed and relapsedpatients with the same disease.3-5 Interestingly, the Id vaccineproduction success rate was substantially low in cases of man-tle cell lymphoma (MCL), as opposed to what has been prelim-inarily described with the very same method in newly-diag-nosed MCL patients.6 This apparent discrepancy could be due,at least in theory, to MCL cells at first relapse biologicallyresembling those of aggressive NHL rather than FL clones, withobvious possible repercussions on the fusion process.Letters to the Editor1438 haematologica/journal of hematology vol. 88(12):december 2003Table 1. Induction treatment-related Id vaccine fea-sibility. Diagnosis Number Induction Number Inductionof patients treatment of  CR/PR treatment-related feasibilityFL 15 CHOP×6 9/5 14/15 (93%)MCL 5 R-HyperCVAD 2/2 4/5 ×8 (80%)SLL 5 FMC×6 4/1 5/5 (100%)DLCL 5 mini BEAM×3 2/2 2/5 + BEAM + ABMT (40%)BL 4 mini BEAM×3 2/1 2/4 + BEAM + ABMT (50%)All but FL 19 See above 10/3 + 3 13/19 (68%)MCL+SLL 10 See above 6/3 9/10 (90%)DLCL+BL 9 See above 4/3 4/9(44%)Underlined CR and PR numbers refer to the cases for which subse-quent Id vaccination was ethically acceptable according to therespective clinical trial protocols. The main cause for Id vaccine production failure was poorhybridoma survival (15/18 cases), which accounted for 100% offailures in aggressive lymphoma (9/9 cases). Loss of Id secretionby growing hybridomas accounted for only 3/18 cases of Idvaccine production failure (Table 2).All in all, our data suggest that, in the vast majority of cas-es, the feasibility of idiotypic vaccination for patients with first-relapse B-cell malignancies strictly depends on the ultimateability to produe a viable Id vaccine rather than on the proba-bility of inducing a clinical response suitable for subsequentidiotypic vaccination. In this respect, first-relapse FL clearlyappears more suitable for hybridoma-based Id vaccine produc-tion than any other first-relapse NHL subtype tested in our lab-oratory.As a major consequence of these data, clinical trials on Idvaccination for B-cell lymphomas other than FL in first relapsehave been closed. However, it is possible that alternative meth-ods to produce the Id protein, particularly those based on mol-ecular techniques,7-10 may prove far more efficient than the tra-ditional approach we used in this study.Susana Inogés, Mercedes Rodríguez-Calvillo,Ascensión López-Díaz de Cerio, Natalia Zabalegui,Javier Pérez-Calvo, Carlos Panizo, Milagros Hernandez,Braulia Cuesta, Eduardo Rocha, Maurizio BendandiCell Therapy Area, Department of Hematology, University Clin-ic of Navarra and CIMA, Pamplona, Spain, on behalf ofGEL/TAMO and PETHEMAFunding: supported in part by: FIS Ministerio de Salud - RTICCáncer C03/10 (Madrid, Spain), Departamento de Educación yCultura del Gobierno de Navarra (Pamplona, Spain), PIUNA(Pamplona, Spain), Ruzic Research Foundation (Beverly Shores,IN, USA). Maurizio Bendandi is a Leukemia andLymphoma Society Scholar in Clinical Research. Financed inpart by: FIMA Project (agreement between FIMA and UTE).Key words: idiotype vaccine, feasibility, B-cell malignancies,hybridoma.Correspondence: Maurizio Bendandi, MD, Ph.D., Department ofHematology and Cell Therapy Area, University Clinic,University of Navarra, Avda. Pio XII 36, 31008 Pamplona, Spain.Phone: international +34.948.296500. extension 2456.Fax: international  +34.948.255400. E-mail:mbendandi@unav.esManuscript processingThis manuscript was peer-reviewed by two external refereesand by an Associate Editor. The final decision to accept thispaper for publication was taken by the Editors. Manuscriptreceived July 3, 2003; accepted October 14, 2003.References1. Bendandi M. Role of anti-Id vaccines in the modern treat-ment of human follicular lymphoma. Expert Rev Anti-cancer Ther 2001;1:65-72. 2. Carroll WL, Thielemans K, Dilley J, Levy R. Mouse x humanheterohybridomas as fusion partners with human B celltumors. J Immunol Methods 1986;89:61-72.3. 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 Idexpressed by their tumors. N Engl J Med 1992;327:1209-15.4. Hsu FJ, Caspar CB, Czerwinski D, Kwak LW, Liles TM, Syren-gelas A, et al. Tumor-specific Id vaccines in the treatmentof patients with B-cell lymphoma: long-term results of aclinical trial. Blood 1997;89:3129-35.5. Bendandi M, Gocke CD, Kobrin CB, Benko FA, Sternas LA,Pennington R, et al. Complete molecular remissionsinduced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma.Nat Med 1999;5:1171-7.6. Neelapu SS, Wilson WH, Baskar S, White T, Frye R, Pen-nington R, et al. Induction of T-cell responses by tumorLetters to the Editorhaematologica/journal of hematology vol. 88(12):december 2003 1439Table 2. Fusion-related and overall Id vaccine feasibility.Diagnosis No. of Fusion attempts 96-well plates Successful fusion wells Fusion-related Cause of Overallpatients median (range) median (range) median (range) feasibility fusion failure feasibility(SHS/LIP)FL 15 1 (1-5) 10 ( 8-12) 186 (63-238) 13/15 (87%)* 1/1 13/15 (87%)*MCL 5 5 (3-5) 15 (12-15) 65 (38-102) 2/5 (40%) 2/1 1/5 (20%)SLL 5 5 (2-5) 15 (10-15) 66 (27-71) 1/5 (20%) 3/1 1/5 (20%)DLCL 5 5 15 (10-15) 51 (29-62) 0/5 (0%) 5/0 0/5 (0%)BL 4 5 15 (11-15) 53 (38-80) 0/4 (0 %) 4/0 0/4 (0%)All but FL 19 5 (2-5) 15 (10-15) 57 ( 27-102) 3/19 (16%)* 14/2 2/19(11%)*MCL+SLL 10 5 (2-5) 15 (10-15) 65 (27-102) 3/10 (30%)* 5/2 2/10 (20%)*DLCL+BL 9 5 15 (10-15) 51 (29-80) 0/9 (0%)* 9/0 0/9 (0%)*Fisher’s exact test with Bonferroni’s correction was used to compare both the likelihood of a successful fusion and the overall feasibility of thetreatment among patients with either FL or the remaining subtypes of both indolent and aggressive lymphoma. The level of significancerequired after this post-hoc correction was 0.025 (exact 2-tailed P). SHS: Short hybridoma survival. LIP: Loss of Id production. *p < 0.01.antigen vaccination in mantle cell lymphoma followingrituximab-based treatment. J Clin Oncol 2003; 22 Suppl1:663a[abstract].7. McCormick AA, Kumagai MH, Hanley K, Turpen TH, HakimI, Grill LK, et al. Rapid production of specific vaccines forlymphoma by expression of the tumor-derived single-chain Fv epitopes in tobacco plants. Proc Natl Acad SciUSA 1999;96:703-8.8. Timmerman JM, Singh G, Hermanson G, Hobart P, Czer-winski DK, Taidi B, et al. Immunogenicity of a plasmid DNAvaccine encoding chimeric Id in patients with B-cell lym-phoma. Cancer Res 2002;62:5845-52.9. Osterroth F, Alkan O, Mackensen A, Lindemann A, Fisch P,Skerra A, et al. Rapid expression cloning of humanimmunoglobulin Fab fragments for the analysis of antigenspecificity of B cell lymphomas and anti-idiotype lym-phoma vaccination. J Immunol Methods 1999; 229:141-53.10. Osterroth F, Garbe A, Fisch P, Veelken H. Stimulation ofcytotoxic T cells against idiotype immunoglobulin ofmalignant lymphoma with protein-pulsed or idiotype-transduced dendritic cells. Blood 2000; 95:1342-9.Letters to the Editor1440 haematologica/journal of hematology vol. 88(12):december 2003 

Feasibility of idiotype vaccination in relapsed B-cell malignancies

Universidad de Navarra

Feasibility of idiotype vaccination in relapsed B-cell malignancies

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