Cancer Immunology, Immunotherapy

, Volume 55, Issue 12, pp 1451–1458 | Cite as

Survival benefit associated with human anti-mouse antibody (HAMA) in patients with B-cell malignancies

  • Ignacio Azinovic
  • Gerald L. DeNardo
  • Kathleen R. Lamborn
  • Gary Mirick
  • Desiree Goldstein
  • Bonnie M. Bradt
  • Sally J. DeNardo
Original Article


Background: About one-third of patients with relapsed B-cell malignancies develop human anti-mouse antibody (HAMA) following mouse antibody treatment. The purpose of this study was to assess the relationship between HAMA and survival in patients given a mouse anti-lymphoma monoclonal antibody (mAb), Lym-1, directed against a unique epitope of HLA-DR antigen that is up-regulated on malignant B-cells. Methods: ELISA was used to quantify HAMA in 51 patients with B-cell malignancies treated with iodine-131 (131I) labeled Lym-1. Sera were collected prior to and following radioimmunotherapy (RIT) with 131I-Lym-1 until documented to be HAMA negative or throughout lifetime. Univariate, then multivariate analyses including other risk factors, were used to analyze the relationship of HAMA to survival. The relationships of HAMA to prior chemotherapies and to absolute lymphocyte counts prior to RIT were also assessed. Results: Eighteen of 51 patients (35%) developed HAMA following RIT (range of ultimate maximum titers, 6.6–1,802 μg/ml). Using the time dependent Cox proportional hazards model, maximum HAMA titers were associated with survival (P=0.02). HAMA continued to be significant for survival in multivariate analyses that included known risk factors. In Landmark analysis of 39 patients that survived at least 16 weeks, median survival of patients with HAMA less than 5 μg/ml was 61 versus 103 weeks for patients with HAMA equal or greater than 5 μg/ml at 16 weeks (P=0.02). The median survival of the five patients with highest maximum HAMA titers was 244 weeks. At 16 weeks, there was an inverse correlation between the maximum HAMA titer and the number of previous chemotherapies (P<0.003). Absolute lymphocyte counts prior to 131I-Lym-1 treatment for patients that seroconverted were higher than those for patients that did not seroconvert (P=0.01). Conclusions: Patients with B-cell malignancies that developed high HAMA titers had longer survival that was not explained by risk factors or histologic grade, suggesting the importance of the immune system.


Non-Hodgkin’s lymphoma Radioimmunotherapy Survival Human anti-mouse antibody Monoclonal antibody HLA-DR 



This research was supported by grants from the National Cancer Institute (PHS CA 47829) and the Department of Energy (DE FG03-84ER60233). I.A. was supported by a grant from the Hospital San Jaime, Torrevieja, Alicante (Spain).


  1. 1.
    DeNardo GL, DeNardo SJ, Goldstein DS, Kroger LA, Lamborn KR, Levy NB, McGahan JP, Salako QA, Shen S, Lewis JP (1998) Maximum tolerated dose, toxicity, and efficacy of 131I-Lym-1 antibody for fractionated radioimmunotherapy of non-Hodgkin’s lymphoma. J Clin Oncol 16:3246–3256PubMedGoogle Scholar
  2. 2.
    DeNardo GL, DeNardo SJ, Lamborn KR, Goldstein DS, Levy NB, Lewis JP, O’Grady LF, Raventos A, Kroger LA, Macey DJ, McGahan JP, Mills SL, Shen S (1998) Low-dose fractionated radioimmunotherapy for B-cell malignancies using 131I-Lym-1 antibody. Cancer Biother Radiopharm 13:239–254PubMedGoogle Scholar
  3. 3.
    Kaminski MS, Zelenetz AD, Press OW, Saleh M, Leonard J, Fehrenbacher L, Lister TA, Stagg RJ, Tidmarsh GF, Kroll S, Wahl RL, Knox SJ, Vose JM (2001) Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin’s lymphomas. J Clin Oncol 19:3918–3928PubMedGoogle Scholar
  4. 4.
    McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK (1998) Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825–2833PubMedGoogle Scholar
  5. 5.
    Witzig TE, Gordon LI, Cabanillas F, Czuczman MS, Emmanouilides C, Joyce R, Pohlman BL, Bartlett NL, Wiseman GA, Padre N, Grillo-Lopez AJ, Multani P, White CA (2002) Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol 20:2453–2463CrossRefPubMedGoogle Scholar
  6. 6.
    Reff ME, Heard C (2001) A review of modifications to recombinant antibodies: attempt to increase efficacy in oncology applications. Crit Rev Oncol Hematol 40:25–35PubMedCrossRefGoogle Scholar
  7. 7.
    Abramowicz D, Crusiaux A, Goldman M (1992) Anaphilactic shock after retreatment with OKT3 monoclonal antibody. N Engl J Med 327:736PubMedCrossRefGoogle Scholar
  8. 8.
    Dillman RO, Beauregard JC, Halpern SE, Clutter M (1986) Toxicities and side effects associated with intravenous infusions of murine monoclonal antibodies. J Biol Response Mod 5:73–84PubMedGoogle Scholar
  9. 9.
    van der Linden EF, van Kroonenburgh MJ, Pauwels EK (1988) Side effects of monoclonal antibody infusions for the diagnosis and treatment of cancer. Int J Biol Markers 3:147–153PubMedGoogle Scholar
  10. 10.
    Khazaeli MB, Conry M, LoBuglio AF (1994) Human immune response to monoclonal antibodies. J Immunother 15:42–52PubMedCrossRefGoogle Scholar
  11. 11.
    DeNardo GL, Kroger LA, Mirick GR, Lamborn KR, DeNardo SJ (1995) Analysis of antiglobulin (HAMA) response in a group of patients with B-lymphocyte malignancies treated with 131I-Lym-1. Int J Biol Markers 10:67–74PubMedGoogle Scholar
  12. 12.
    Kaminski MS, Estes J, Zasadny KR, Francis IR, Ross CW, Tuck M, Regan D, Fisher S, Gutierrez J, Kroll S, Stagg R, Tidmarsh G, Wahl RL (2000) Radioimmunotherapy with iodine (131)I tositumomab for relapsed refractory B-cell non-Hodgkin lymphoma: update results and long-term follow-up of the University of Michigan experience. Blood 96:1259–1266PubMedGoogle Scholar
  13. 13.
    Miotti S, Negri DR, Valota O, Calabrese M, Bolhuis RL, Gratama JW, Colnaghi MI, Canevari S (1999) Level of anti-mouse-antibody response induced by bi-specific monoclonal antibody OC/TR in ovarian-carcinoma patients is associated with longer survival. Int J Cancer 84:62–68CrossRefPubMedGoogle Scholar
  14. 14.
    Riethmuller G, Schneider-Gadicke E, Schlimok G, Schmiegel W, Raab R, Hoffken K, Gruber R, Pichlmaier H, Hirche H, Pichlmayr R (1994) Randomised trial of monoclonal antibody for adjuvant therapy of resected Dukes’ C colorectal carcinoma. German Cancer Aid 17-1A Study Group. Lancet 343:1177–1183CrossRefPubMedGoogle Scholar
  15. 15.
    Witzig TE, White CA, Wiseman GA, Gordon LI, Emmanouilides C, Raubitschek A et al (1999) Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20+ B-cell non-Hodgkin’s lymphoma. J Clin Oncol 17:3793–3803PubMedGoogle Scholar
  16. 16.
    Bradt BM, DeNardo GL, Mirick G, DeNardo SJ (2003) Documentation of idiotypic cascade in patient after Lym-1 RIT: basis for extended survival? Clin Cancer Res 9:4007s–4012sPubMedGoogle Scholar
  17. 17.
    Cheung NK, Guo HF, Cheung IY (2000) Correlation of anti-idiotype network with survival following anti-G(D2) monoclonal antibody 3F8 therapy of stage 4 neuroblastoma. Med Pediatr Oncol 35:635–637CrossRefPubMedGoogle Scholar
  18. 18.
    Fagerberg J, Frodin JE, Wigzell H, Mellstedt H (1993) Induction of an immune network cascade in cancer patients treated with monoclonal antibodies (ab1). I May induction of ab1-reactive T cells and anti-anti-idiotypic antibodies (ab1) lead to tumor regression after mAb therapy? Cancer Immunol Immunother 37:264–270CrossRefPubMedGoogle Scholar
  19. 19.
    Rose LM, Deng CT, Scott S, Xiong CY, Lamborn KR, Gumerlock PH, DeNardo GL, Meares CF (1999) Critical Lym-1 binding residues on polymorphic HLA-DR molecules. Mol Immunol 36:789–797CrossRefPubMedGoogle Scholar
  20. 20.
    Lamborn KR, DeNardo GL, DeNardo SJ, Goldstein DS, Shen S, Larkin EC, Kroger LA (1997) Treatment-related parameters predicting efficacy of Lym-1 radioimmunotherapy in patients with B-lymphocytic malignancies. Clin Cancer Res 3:1253–1260PubMedGoogle Scholar
  21. 21.
    DeNardo GL, Mirick GR, Kroger LA, Bradt BM, Lamborn KR, DeNardo SJ (2003) Characterization of human IgG anti-mouse antibody (HAMA) in patients with B-cell malignancies. Clin Cancer Res 9:4013s–4021sPubMedGoogle Scholar
  22. 22.
    DeNardo GL, Lamborn KR, DeNardo SJ, Goldstein DS, Dolber-Smith EG, Kroger LA, Larkin EC, Shen S (1995) Prognostic factors for radioimmunotherapy in patients with B-lymphocytic malignancies. Cancer Res 55(Suppl):5893–5898Google Scholar
  23. 23.
    Shipp MA, Harrington DP, Anderson JR, Armitage JO, Bonadonna G, Brittinger G, Cabanillas F, Canellos GP, Coiffier B, Connors JM, Cowan D, Crowther D, Dahlberg S, Engelhard M, Fisher RI, Gisselbrecht C, Horning SJ, Lepage E, Lister A, Meerwaldt JH, Montserrat E, Nissen NI, Oken MM, Peterson BA, Tondini C, Velasquez WS, Yeap BY (1993) A predictive model for aggressive NHL: the international non-Hodgkin’s lymphoma prognostic factors project. N Engl J Med 329:987–994CrossRefPubMedGoogle Scholar
  24. 24.
    Epstein AL, Marder RJ, Winter JN, Stathopoulos E, Chen FM, Parker JW, Taylor CR (1987) Two new monoclonal antibodies, Lym-1 and Lym-2, reactive with human-B-lymphocytes and derived tumors, with immunodiagnostic and immunotherapeutic potential. Cancer Res 47:830–840PubMedGoogle Scholar
  25. 25.
    Hu E, Epstein AL, Naeve GS, Gill I, Martin S, Sherrod A, Nichols P, Chen D, Mazumder A, Levine AM (1989) A phase 1a clinical trial of Lym-1 monoclonal antibody serotherapy in patients with refractory B cell malignancies. Hematol Oncol 7:155–166PubMedCrossRefGoogle Scholar
  26. 26.
    Beyer WH (2000) Non-parametric statistics. In: Beyer WH (ed) Handbook of tables for probability and statistics. CRC Press, Boca Raton, pp 445–448Google Scholar
  27. 27.
    Anderson JR, Cain KC, Gelber RD (1983) Analysis of survival by tumor response. J Clin Oncol 1:710–719PubMedGoogle Scholar
  28. 28.
    Buyse ME, Staquet MJ, Sylvester RJ (1984) Cancer clinical trials: methods and practice. Oxford University Press, New YorkGoogle Scholar
  29. 29.
    Gupta S (1981) Immunodeficiencies in Hodgkin’s Disease. Part I: T-cell mediated immunity, Part II: B cell immunity, complement systems and phagocytic cell systems. Clin Bull 11:58–119PubMedGoogle Scholar
  30. 30.
    Fisher RI, Kaminski MS, Wahl RL, Knox SJ, Zelenetz AD, Vose JM, Leonard JP, Kroll S, Goldsmith SJ, Coleman M (2006) Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin’s lymphomas. J Clin Oncol 23:7565–7573CrossRefGoogle Scholar
  31. 31.
    Gordon LI, Molina A, Witzig T, Emmanouilides C, Raubitschek A, Darif M, Schilder RJ, Wiseman G, White CA (2004) Durable responses after ibritumomab tiuxetan radioimmunotherapy for CD20+ B-cell lymphoma: long term followup of a phase 1/2 study. Blood 103:4429–4431CrossRefPubMedGoogle Scholar
  32. 32.
    Wiseman GA, Witzig TE (2006) Yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin) induces long-term durable responses in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma. Cancer Biother Radiopharm 20:181–184Google Scholar
  33. 33.
    Kaminski MS, Tuck M, Estes J, Kolstad A, Ross CW, Zasadny K, Regan D, Kison P, Fisher S, Kroll S, Wahl R (2005) 131I-Tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 352:441–449CrossRefPubMedGoogle Scholar
  34. 34.
    Baum RP, Neisen A, Hertel A, Hess H, Donnerstag B, Sykes T, Sykes C, Suresh M, Noujaim A, Hor G (1994) Activating anti-idiotypic human anti-mouse antibodies for immunotherapy of ovarian carcinoma. Cancer 73(Suppl 3):1121–1125PubMedCrossRefGoogle Scholar
  35. 35.
    Cheung NK, Cheung IY, Canete A, Yeh SJ, Kushner B, Bonilla MA, Heller G, Larson SM (1994) Antibody response to murine anti-GD2 monoclonal antibodies: correlation to patient survival. Cancer Res 54:2228–2233PubMedGoogle Scholar
  36. 36.
    Cheung NK, Guo HF, Heller G, Cheung IY (2000) Induction of Ab3 and Ab3’ antibody associated with long-term survival after anti-G(D2) antibody therapy of stage 4 neuroblastoma. Clin Cancer Res 6:2653–2660PubMedGoogle Scholar
  37. 37.
    Frodin JE, Lefvert AK, Mellstedt H (1992) The clinical significance of HAMA in patients treated with mouse monoclonal antibodies. Cell Biophys 21:153–165PubMedGoogle Scholar
  38. 38.
    Losman MJ, Hansen HJ, Sharkey RM, Goldenberg DM, Monestier M (1991) Human response against NP-4, a mouse antibody to carcinoembryonic antigen: human anti-idiotype antibodies mimic an epitope on the tumor antigen. Proc Natl Acad Sci USA 88:3421–3425PubMedCrossRefGoogle Scholar
  39. 39.
    Gruber R, van Haarlem LJM, Warnaar SO, Holz E, Riethmuller G (2000) The human antimouse immunoglobulin response and the anti-idiotypic network have no influence on clinical outcome in patients with minimal residual colorectal cancer treated with monoclonal antibody CO17-1A. Cancer Res 60:1921–1926PubMedGoogle Scholar
  40. 40.
    DeNardo GL, O’Donnell RT, Rose LM, Mirick GR, Kroger LA, DeNardo SJ (1999) Milestones in the development of Lym-1 therapy. Hybridoma 18:1–11PubMedCrossRefGoogle Scholar
  41. 41.
    Frodin JE, Faxas ME, Hagstrom B, Lefvert AK, Masucci G, Nilsson B, Steinitz M, Unger P, Mellstedt H (1991) Induction of anti-idiotypic (ab2) and anti-anti-idiotypic (ab3) antibodies in patients treated with mouse monoclonal antibody 17-1A (ab1). Relation to the clinical outcome—an important antitumoral effector function? Hybridoma 10:421–421PubMedGoogle Scholar
  42. 42.
    DeNardo SJ, Kroger LA, MacKenzie MR, Mirick GR, Shen S, DeNardo GL (1998) Prolonged survival associated with immune response in a patient treated with Lym-1 mouse monoclonal antibody. Cancer Biother Radiopharm 13:1–12PubMedCrossRefGoogle Scholar
  43. 43.
    Timmerman JM (2002) Vaccine therapies for non-Hodgkin’s lymphoma. Curr Treat Opt Oncol 3:307–315CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Ignacio Azinovic
    • 1
  • Gerald L. DeNardo
    • 2
    • 4
  • Kathleen R. Lamborn
    • 3
  • Gary Mirick
    • 2
  • Desiree Goldstein
    • 2
  • Bonnie M. Bradt
    • 2
  • Sally J. DeNardo
    • 2
  1. 1.Department of RadiotherapyHospital San JaimeAlicanteSpain
  2. 2.Davis Medical Center, Department of Internal MedicineUniversity of CaliforniaSacramentoUSA
  3. 3.Department of Neurological SurgeryUniversity of California at San FranciscoSan FranciscoUSA
  4. 4.Molecular Cancer Institute, Davis Medical CenterUniversity of CaliforniaSacramentoUSA

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