- Email: [email protected]
History of antibody therapy for non-Hodgkin’s lymphoma
Vol 30, No 6, Suppl 17
December 2003
History of Antibody Therapy for Non-Hodgkin’s Lymphoma Andres Forero and Albert F. LoBuglio Monoclonal antibodies (mAbs) were the first successful targeted therapy for cancer. In contrast to the nonspecific nature of most chemotherapy, antibodies bind with high specificity to cell-surface antigens, resulting in targeted killing of malignant cells, relative sparing of normal tissues, and low toxicity. Antibody therapy has undergone substantial development since Ehrlich’s notion of a “magic bullet,” in 1890. It was not until the 1970s, however, that mAbs became viable as therapeutic tools and clinical studies showed them to be effective. The results were most impressive in hematologic malignancies, especially B-cell non-Hodgkin’s lymphoma. In 1997, rituximab (Rituxan; Genentech Inc, South San Francisco, CA, and Biogen Idec Inc, Cambridge, MA) became the first mAb approved by the US Food and Drug Administration for use in the treatment of cancer. The first approval for a radiolabeled antibody to treat cancer was in 2002 for 90Y ibritumomab tiuxetan (Zevalin; Biogen Idec). This is a conjugate of an anti-CD20 mAb (ibritumomab, the murine parent of rituximab) with the beta-emitter radionuclide 90Y. 90 Y ibritumomab tiuxetan has been shown to be safe and effective in the indicated patient population. Other radioimmunoconjugates are being investigated for the treatment of non-Hodgkin’s lymphoma, as are several immunotoxins. This article reviews important events in the development of mAb therapy and radioimmunotherapy for B-cell non-Hodgkin’s lymphoma. Semin Oncol 30 (suppl 17):1-5. © 2003 Elsevier Inc. All rights reserved.
M
ONOCLONAL antibodies (mAbs) were the first successful targeted therapy for cancer. In contrast to chemotherapy, antibodies bind with high specificity to cell-surface antigens, resulting in targeted killing of malignant cells, relative sparing of normal tissues, and low toxicity. The antiproliferative or apoptotic effects of antibodies may be because of their direct mechanisms of action or to immune antitumor mechanisms such as antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. Antibody therapy has undergone substantial development since Ehrlich’s notion of a “magic bullet,” in 1890 (Table 1). It was not until the 1970s, however, that mAbs became viable as therapeutic Seminars in Oncology, Vol 30, No 6, Suppl 17 (December), 2003: pp 1-5
tools and were subjected to clinical studies showing them to be effective. The results were most impressive in hematologic malignancies, especially B-cell non-Hodgkin’s lymphoma (NHL). In 1997 rituximab (Rituxan; Genentech Inc, South San Francisco, CA, and Biogen Idec Inc, Cambridge, MA) became the first mAb approved by the US Food and Drug Administration (FDA) for use in the treatment of cancer and the first targeted drug approved for the treatment of low-grade NHL. After the success of rituximab, other approaches have been to target radiation or toxins to tumor cells by conjugating them to mAbs. The first approval by the FDA for a radiolabeled antibody to treat cancer was in 2002 for 90Y ibritumomab tiuxetan (Zevalin; Biogen Idec Inc). This is a conjugate of an anti-CD20 mAb (ibritumomab, the murine parent of rituximab) with the betaemitter radionuclide yttrium 90.1 The radioimmunoconjugate iodine 131 tositumomab (Bexxar; Corixa Corporation, Seattle, WA) was approved by the FDA in 2003. Important advances have been made in the treatment of solid tumors with mAb therapy (eg, trastuzumab [Herceptin; Genentech, Inc, South San Francisco, CA]), but progress in this area has been slower than that in hematologic malignancies. Two immunotoxins have also been approved by the FDA. The first of these is gemtuzumab ozogamicin (Mylotarg; Wyeth Phar-
From the Department of Medicine, Division of Hematology/ Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham. Drs Forero and LoBuglio have received research grant support from Biogen Idec Inc. Address reprint requests to Andres Forero, MD, University of Alabama at Birmingham, Comprehensive Cancer Center, L.B. Wallace Tumor Institute–223, 1824 6th Ave South, Birmingham, AL 35294-3300. © 2003 Elsevier Inc. All rights reserved. 0093-7754/03/3006-1701$30.00/0 doi:10.1053/j.seminoncol.2003.10.002 1
2
FORERO AND LOBUGLIO
Table 1. Developments in Antibody Therapy for Non-Hodgkin’s Lymphoma 1890 1890
1895 1929 1968 1975 1980 1980s
1987
1994 1997 1999 2002 2003
Transferable immunity first shown in animals Idea of a “magic bullet” first proposed; hoped that therapy could be targeted to a particular site of disease First report of passive serum therapy in cancer First report of tumor-specific antiserum being made Passive serum therapy reported in humans Development of hybridoma technology for producing monoclonal antibodies First report of monoclonal antibody therapy in lymphomas Trials conducted with anti-idiotype monoclonal antibodies specific for the unique idiotype expressed on B-cell lymphomas Reduction in circulating tumor cells and regression of lymphoma tumor masses reported with 1F5 antibody to CD20; need for large doses of antibody for optimal biodistribution became apparent First published report on the chimeric monoclonal antibody to CD20 now known as rituximab Rituximab approved by FDA First published report on 90Y ibritumomab tiuxetan 90 Y ibritumomab tiuxetan approved by the FDA 131 I tositumomab approved by the FDA
maceuticals, Collegeville, PA), a combination of a humanized immunoglobulin G4 (IgG4) mAb to CD33 (hP67.6) and the toxin calicheamicin, which is used in the treatment of relapsed acute myelogenous leukemia. The other is denileukin diftitox (Ontak; Seragen, Inc, Hopkinton, MA), a recombinant fusion of interleukin 2 and truncated diphtheria toxin that is cytotoxic to interleukin 2 receptor–positive cells (CD25), which is used in the treatment of cutaneous T-cell lymphomas. In this article, we review important events in the development of mAb therapy and radioimmunotherapy for B-cell NHL. EARLY EXPERIENCE IN ANTIBODY THERAPY
Antibody-based therapy is not a new concept. In 1890, von Behring and Kitasato2 showed that sterilized cultures of diphtheria and tetanus bacilli caused the production in the blood of immunized animals of substances called antitoxins that neutralized the toxins produced by these bacilli and that toxin resistance could be transferred to an-
other animal by the administration of antisera. The term “magic bullets,” and their possible role in the treatment of infection and malignancy were first proposed by Ehrlich3 soon after. He wrote, “To find chemical substances that have special affinities for pathogenic organisms, to which they are specifically related, and would be ‘magic bullets’ which would go straight to the organisms at which they were aimed.” His strategy was “by injecting one animal with the cells of another, we can produce substances in the serum of the first, which have a specific damaging or destructive influence on these cells.”3 The first reports of passive serum therapy in the treatment of cancer were by Hericourt and Richet, in 1895,4,5 who published two reports on the use of serum that had been raised in two dogs and one donkey to treat patients with various malignancies, in whom some clinical benefits were seen. They concluded that antibodies alone were not sufficient to cure but that they might increase survival when used in combination with other therapies. Passive serum therapy was also attempted by Laszlo et al6 with serum that had been raised in humans. However, a lack of tumor-specificity resulted in disappointing clinical results and toxicity. The first report of a tumor-specific antiserum was made in 1929, on a serum developed in rabbits.7 However, the results in clinical trials in the 1960s and 1970s were again disappointing because of excessive toxicity and lack of clinical activity. DEVELOPMENT OF MONOCLONAL ANTIBODY TECHNOLOGY
It was not until the development of hybridoma technology for the production of mAbs, by Ko¨ hler and Milstein in 1975,8 that serotherapy became a clinical reality. Ko¨ hler and Milstein immortalized antibody-producing murine lymphocytes by fusing them with a murine myeloma cell line. The hybridoma cells carried the antigen specificity of the fused lymphocytes and the proliferative machinery of the malignant murine myeloma cells. This enabled the large-scale production for clinical use of mAbs with predefined specificity. The therapeutic potential of such mAb-based therapy was recognized immediately, and several studies of unconjugated mAbs to tumor-associated antigens in patients with various malignancies were conducted. Along with the advances in the production of
HISTORY OF ANTIBODY THERAPY FOR NHL
mAbs, major advances were being made in recombinant DNA technology. Knowledge of how genes for immunoglobulins are organized and expressed by B cells to form the repertoire of antibody molecules was vital to further progress.9,10 Inevitably, the methods of mAb and recombinant DNA technology were combined to resolve the problems that had been seen in using murine antibodies for human therapy. Thus, the field of antibody engineering was born. Recombinant DNA technology has been used to transform a murine antibody into a human or humanlike antibody for therapeutic uses, lessening the problems of immunogenicity and improving interactions with human effector systems of complement and Fc receptors. TRIALS OF MONOCLONAL ANTIBODIES IN NON-HODGKIN’S LYMPHOMA
Early trials of mAbs used murine antibodies that were directed to surface antigens on lymphoma and leukemia cells of B- and T-cell origin.11 The study by Nadler et al12 was an early attempt at using mAb therapy in lymphomas. This study made the early observation that circulating antigens (on cells or free antigens) could bind the administered antibody and preclude its normal circulation to tumor sites, limiting the antitumor effect of the antibodies. Miller and colleagues moved the field forward in the 1980s with a series of trials that used anti-idiotype mAbs that were specific for the idiotype expressed on B-cell lymphomas.13 Their studies showed that antibodies could induce objective responses in the majority of patients,14 with long-term control of the disease seen in some patients.15 However, producing large numbers of anti-idiotype antibodies for each patient was prohibitive. The CD20 Antigen The CD20 antigen probably functions as a calcium channel,16,17 and it is expressed on most malignant B cells, including 90% of B-cell lymphomas.18 CD20 is less densely expressed in small lymphocytic lymphoma and chronic lymphocytic leukemia.19 Investigators soon recognized CD20 as an ideal target for serotherapy of lymphoma, owing to its restricted expression on the B-cell lineage and lack of antigen modulation, with no shedding or internalization. (Some other B-cell antigens [CD19, CD22] internalize after antibody binding, making them more suitable for use with a toxin or
3
other moiety with which internalization would be needed.) Early Clinical Trials With Monoclonal Antibodies To CD20 In the 1980s the Seattle group began to explore the use of mAbs to deliver radioisotopes selectively to lymphoma tumors; they noted regressions of lymphoma in diagnostic and dosimetry studies before the radioactive therapeutic doses. In 1987, they reported the results in a small trial that used 1F5 antibody to CD20 in four patients with refractory B-cell lymphoma, in which there was clearing of circulating tumor cells and regression of lymphoma tumor masses.20 They showed that achieving substantial antibody deposition in lymph node compartments required large doses of antibodies and reported a correlation between the dose and the clinical response, even though the clinical remissions observed were of short duration. This study, and the same investigators’ early reports on 1F5 and B1 labeled with 131I, clearly showed that large doses of antibody to CD20 were necessary to saturate intravascular CD20⫹ B cells in the blood and spleen and result in optimal pharmacokinetics and biodistribution to peripheral lymph node sites of the disease.21-23 Rituximab Reff et al24 published the first report on the chimeric mAb to CD20, known initially as IDEC C2B8 and now known as rituximab. After this, results in a phase I single-dose study and a phase I dose-escalation study were published.25,26 In a subsequent phase II trial, rituximab 375 mg/kg/wk for 4 weeks was studied in patients with indolent CD20⫹ NHL that was resistant to chemotherapy.27,28 Following this, a multicenter pivotal trial of the same regimen was conducted in 166 patients with low-grade, follicular, or transformed NHL in whom at least two chemotherapy regimens had failed.29 The overall response rate was 48%, with a complete response in 6% of patients. The median duration of response in responders was 13 months. The data from this trial led to the approval of rituximab by the FDA in November 1997. RADIOIMMUNOTHERAPY FOR NONHODGKIN’S LYMPHOMA
The clinical investigation of radiolabeled mAbs was well under way before the success of rituximab.
4
Radioimmunotherapy is of interest not only because NHL is radiosensitive, but also because the radiation component of the therapy can help overcome the problem that not all tumor cells bear the antibody-targeted antigen or are physically accessible for the mAb to bind to. The early studies by Press et al30 provided insights into the need for large doses of antibody for optimal tumor localization, and investigated the use of gamma camera dosimetry to determine the radiation doses to tumors and normal tissues. Key Trials in Radioimmunotherapy The first radioimmunotherapeutic agent to be approved by the FDA was 90Y ibritumomab tiuxetan, in February 2002. One of the pivotal trials with this agent was conducted in 143 patients with chemotherapy-resistant follicular or transformed NHL who were randomized to rituximab 250 mg/m2 (to improve biodistribution) followed by 90 Y ibritumomab tiuxetan 0.4 mCi/kg or to rituximab 375 mg/m2 weekly ⫻ 4 monotherapy.31 The overall response rate with 90Y ibritumomab tiuxetan was 80% (complete response and complete response, unconfirmed, in 34%) and with rituximab monotherapy was 56% (complete response and complete response, unconfirmed, in 20%). The importance of the radiation component of 90Y ibritumomab tiuxetan has been shown in a trial in 57 patients with NHL that was refractory to rituximab, in which the overall response rate was 74% (complete response in 15%).32 Another trial has shown the efficacy and safety of a reduced dose of 90Y ibritumomab tiuxetan in patients with mild thrombocytopenia.33 A second radioimmunoconjugate, 131I tositumomab, was approved by the FDA in 2003 for the treatment of patients with CD20⫹, follicular NHL, with and without transformation, whose disease is refractory to rituximab and has relapsed following chemotherapy. It is not approved for initial treatment of patients with CD20⫹ NHL.34 A multicenter phase III trial evaluated this agent in patients with NHL that was resistant to chemotherapy.35 The response rates (65% overall, 17% complete) were compared with those with the patients’ most recent prior chemotherapy (28% and 3%, respectively). A study in similar patients with NHL that was also refractory to rituximab reported an overall response rate of
FORERO AND LOBUGLIO
58%, with a complete response in 20% of patients.36 CONCLUSION
The clinical utility of mAbs has been clearly shown, and there has been a great deal of interest in the field. Preclinical animal studies and further clinical trials are now needed to determine how radioimmunotherapy can best be combined with conventional therapies for lymphoma. Continued research will also help ensure that the antigens targeted, the radioimmunoconjugates used, and the delivery methods will be optimal. REFERENCES 1. Zevalin (ibritumomab tiuxetan) prescribing information: Cambridge, MA, Biogen Idec Inc, 2002 ¨ ber das Zustandekommen 2. von Behring E, Kitasato S: U der Diphtherie-Immunita¨ t und der Tetanus-Immunita¨ t bei Thieren. Dtsch Med Wochenschr 16:1113-1114, 1890 3. Ehrlich P: The Croonian Lecture: On immunity with special reference to cell life. Proc R Soc Lond 66:424-448, 1900 4. Hericourt J, Richet C: Physiologie pathologique– de la serotherapie dans le traitement du cancer. Comptes Rendu Hebd Seanc Acad Sci 120:948-950, 1895 5. Hericourt J, Richet C: Physiologie pathologique– de la serotherapie dans le traitement du cancer. Comptes Rendu Hebd Seanc Acad Sci 121:567-569, 1895 6. Laszlo J, Buckley CE III, Amos DB: Infusion of isologous immune plasma in chronic lymphocytic leukemia. Blood 31: 104-110, 1968 7. Lindstrom GA: An experimental study of myelotoxic sera. Therapeutic attempts in myeloid leukaemia. Acta Med Scandinavia 22:1-169, 1929 8. Ko¨ hler G, Milstein C: Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495497, 1975 9. Tonegawa S: Somatic generation of antibody diversity. Nature 302:575-581, 1983 10. Alt FW, Oltz EM, Young F, et al: VDJ recombination. Immunol Today 13:306-314, 1992 11. Ritz J, Schlossman SF: Utilization of monoclonal antibodies in the treatment of leukemia and lymphoma. Blood 59:1-11, 1982 12. Nadler LM, Stashenko P, Hardy R, et al: Serotherapy of a patient with a monoclonal antibody directed against a human lymphoma-associated antigen. Cancer Res 40:3147-3154, 1980 13. Miller RA, Maloney DG, Warnke R, et al: Treatment of B-cell lymphoma with monoclonal anti-idiotype antibody. N Engl J Med 306:517-522, 1982 14. Vuist WM, Levy R, Maloney DG: Lymphoma regression induced by monoclonal anti-idiotypic antibodies correlates with their ability to induce Ig signal transduction and is not prevented by tumor expression of high levels of bcl-2 protein. Blood 83:899-906, 1994 15. Davis TA, Maloney DG, Czerwinski D, et al: Antiidiotype antibodies can induce long-term complete remissions
HISTORY OF ANTIBODY THERAPY FOR NHL
in non-Hodgkin’s lymphoma without eradicating the malignant clone. Blood 92:1184-1190, 1998 16. Tedder TF, Boyd AW, Freedman AS, et al: The B cell surface molecule B1 is functionally linked with B cell activation and differentiation. J Immunol 135:973-979, 1985 17. Bubien JK, Zhou LJ, Bell PD, et al: Transfection of the CD20 cell surface molecule into ectopic cell types generates a Ca2⫹ conductance found constitutively in B lymphocytes. J Cell Biol 121:1121-1132, 1993 18. Anderson KC, Bates MP, Slaughenhoupt BL, et al: Expression of human B cell-associated antigens on leukemias and lymphomas: A model of human B cell differentiation. Blood 63:1424-1433, 1984 19. Almasri NM, Duque RE, Iturraspe J, et al: Reduced expression of CD20 antigen as a characteristic marker for chronic lymphocytic leukemia. Am J Hematol 40:259-263, 1992 20. Press OW, Appelbaum F, Ledbetter JA, et al: Monoclonal antibody 1F5 (anti-CD20) serotherapy of human B cell lymphomas. Blood 69:584-591, 1987 21. Kaminski MS, Zasadny KR, Francis IR, et al: Radioimmunotherapy of B-cell lymphoma with 131I-anti-B1 (antiCD20) antibody. N Engl J Med 329:459-465, 1993 22. Kaminski MS, Zasadny KR, Francis IR, et al: Iodine131-anti-B1 radioimmunotherapy for B-cell lymphoma. J Clin Oncol 14:1974-1981, 1996 23. Kaminski MS, Estes J, Zasadny KR, et al: Radioimmunotherapy with iodine 131I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: Updated results and longterm follow-up of the University of Michigan experience. Blood 96:1259-1266, 2000 24. Reff ME, Carner K, Chambers KS, et al: Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83:435-445, 1994 25. Maloney DG, Liles TM, Czerwinski D, et al: Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 84:2457-2466, 1994 26. Maloney DG, Grillo-Lo´ pez AJ, Bodkin DJ, et al: IDECC2B8: Results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin’s lymphoma. J Clin Oncol 15:32663274, 1997
5
27. Maloney DG, Grillo-Lopez AJ, White CA, et al: IDECC2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood 90:2188-2195, 1997 28. Coiffier B, Haioun C, Ketterer N, et al: Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: A multicenter phase II study. Blood 92:1927-1932, 1998 29. McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825-2833, 1998 30. Press OW, Farr AG, Borroz KI, et al: Endocytosis and degradation of monoclonal antibodies targeting human B-cell malignancies. Cancer Res 49:4906-4912, 1989 31. Witzig TE, Gordon LI, Cabanillas F, et al: Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol 20: 2453-2463, 2002 32. Witzig TE, Flinn LW, Gordon LI, et al: Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J Clin Oncol 20:3262-3269, 2002 33. Wiseman GA, Gordon LI, Multani PS, et al: Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: A phase II multicenter trial. Blood 99:4336-4342, 2002 34. Bexxar (131I tositumomab) prescribing information: Corixa Corporation, Seattle, WA, 2003 35. Kaminski MS, Zelenetz AD, Press OW, et al: 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 19:3918-3928, 2001 36. Horning SJ, Lucas JB, Younes A, et al: Iodine-131 tositumomab for non-Hodgkin’s lymphoma (NHL) patients who progressed after treatment with rituximab: Results of a multicenter phase II study. Blood 96:508a, 2000 (abstr)
December 2003
History of Antibody Therapy for Non-Hodgkin’s Lymphoma Andres Forero and Albert F. LoBuglio Monoclonal antibodies (mAbs) were the first successful targeted therapy for cancer. In contrast to the nonspecific nature of most chemotherapy, antibodies bind with high specificity to cell-surface antigens, resulting in targeted killing of malignant cells, relative sparing of normal tissues, and low toxicity. Antibody therapy has undergone substantial development since Ehrlich’s notion of a “magic bullet,” in 1890. It was not until the 1970s, however, that mAbs became viable as therapeutic tools and clinical studies showed them to be effective. The results were most impressive in hematologic malignancies, especially B-cell non-Hodgkin’s lymphoma. In 1997, rituximab (Rituxan; Genentech Inc, South San Francisco, CA, and Biogen Idec Inc, Cambridge, MA) became the first mAb approved by the US Food and Drug Administration for use in the treatment of cancer. The first approval for a radiolabeled antibody to treat cancer was in 2002 for 90Y ibritumomab tiuxetan (Zevalin; Biogen Idec). This is a conjugate of an anti-CD20 mAb (ibritumomab, the murine parent of rituximab) with the beta-emitter radionuclide 90Y. 90 Y ibritumomab tiuxetan has been shown to be safe and effective in the indicated patient population. Other radioimmunoconjugates are being investigated for the treatment of non-Hodgkin’s lymphoma, as are several immunotoxins. This article reviews important events in the development of mAb therapy and radioimmunotherapy for B-cell non-Hodgkin’s lymphoma. Semin Oncol 30 (suppl 17):1-5. © 2003 Elsevier Inc. All rights reserved.
M
ONOCLONAL antibodies (mAbs) were the first successful targeted therapy for cancer. In contrast to chemotherapy, antibodies bind with high specificity to cell-surface antigens, resulting in targeted killing of malignant cells, relative sparing of normal tissues, and low toxicity. The antiproliferative or apoptotic effects of antibodies may be because of their direct mechanisms of action or to immune antitumor mechanisms such as antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. Antibody therapy has undergone substantial development since Ehrlich’s notion of a “magic bullet,” in 1890 (Table 1). It was not until the 1970s, however, that mAbs became viable as therapeutic Seminars in Oncology, Vol 30, No 6, Suppl 17 (December), 2003: pp 1-5
tools and were subjected to clinical studies showing them to be effective. The results were most impressive in hematologic malignancies, especially B-cell non-Hodgkin’s lymphoma (NHL). In 1997 rituximab (Rituxan; Genentech Inc, South San Francisco, CA, and Biogen Idec Inc, Cambridge, MA) became the first mAb approved by the US Food and Drug Administration (FDA) for use in the treatment of cancer and the first targeted drug approved for the treatment of low-grade NHL. After the success of rituximab, other approaches have been to target radiation or toxins to tumor cells by conjugating them to mAbs. The first approval by the FDA for a radiolabeled antibody to treat cancer was in 2002 for 90Y ibritumomab tiuxetan (Zevalin; Biogen Idec Inc). This is a conjugate of an anti-CD20 mAb (ibritumomab, the murine parent of rituximab) with the betaemitter radionuclide yttrium 90.1 The radioimmunoconjugate iodine 131 tositumomab (Bexxar; Corixa Corporation, Seattle, WA) was approved by the FDA in 2003. Important advances have been made in the treatment of solid tumors with mAb therapy (eg, trastuzumab [Herceptin; Genentech, Inc, South San Francisco, CA]), but progress in this area has been slower than that in hematologic malignancies. Two immunotoxins have also been approved by the FDA. The first of these is gemtuzumab ozogamicin (Mylotarg; Wyeth Phar-
From the Department of Medicine, Division of Hematology/ Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham. Drs Forero and LoBuglio have received research grant support from Biogen Idec Inc. Address reprint requests to Andres Forero, MD, University of Alabama at Birmingham, Comprehensive Cancer Center, L.B. Wallace Tumor Institute–223, 1824 6th Ave South, Birmingham, AL 35294-3300. © 2003 Elsevier Inc. All rights reserved. 0093-7754/03/3006-1701$30.00/0 doi:10.1053/j.seminoncol.2003.10.002 1
2
FORERO AND LOBUGLIO
Table 1. Developments in Antibody Therapy for Non-Hodgkin’s Lymphoma 1890 1890
1895 1929 1968 1975 1980 1980s
1987
1994 1997 1999 2002 2003
Transferable immunity first shown in animals Idea of a “magic bullet” first proposed; hoped that therapy could be targeted to a particular site of disease First report of passive serum therapy in cancer First report of tumor-specific antiserum being made Passive serum therapy reported in humans Development of hybridoma technology for producing monoclonal antibodies First report of monoclonal antibody therapy in lymphomas Trials conducted with anti-idiotype monoclonal antibodies specific for the unique idiotype expressed on B-cell lymphomas Reduction in circulating tumor cells and regression of lymphoma tumor masses reported with 1F5 antibody to CD20; need for large doses of antibody for optimal biodistribution became apparent First published report on the chimeric monoclonal antibody to CD20 now known as rituximab Rituximab approved by FDA First published report on 90Y ibritumomab tiuxetan 90 Y ibritumomab tiuxetan approved by the FDA 131 I tositumomab approved by the FDA
maceuticals, Collegeville, PA), a combination of a humanized immunoglobulin G4 (IgG4) mAb to CD33 (hP67.6) and the toxin calicheamicin, which is used in the treatment of relapsed acute myelogenous leukemia. The other is denileukin diftitox (Ontak; Seragen, Inc, Hopkinton, MA), a recombinant fusion of interleukin 2 and truncated diphtheria toxin that is cytotoxic to interleukin 2 receptor–positive cells (CD25), which is used in the treatment of cutaneous T-cell lymphomas. In this article, we review important events in the development of mAb therapy and radioimmunotherapy for B-cell NHL. EARLY EXPERIENCE IN ANTIBODY THERAPY
Antibody-based therapy is not a new concept. In 1890, von Behring and Kitasato2 showed that sterilized cultures of diphtheria and tetanus bacilli caused the production in the blood of immunized animals of substances called antitoxins that neutralized the toxins produced by these bacilli and that toxin resistance could be transferred to an-
other animal by the administration of antisera. The term “magic bullets,” and their possible role in the treatment of infection and malignancy were first proposed by Ehrlich3 soon after. He wrote, “To find chemical substances that have special affinities for pathogenic organisms, to which they are specifically related, and would be ‘magic bullets’ which would go straight to the organisms at which they were aimed.” His strategy was “by injecting one animal with the cells of another, we can produce substances in the serum of the first, which have a specific damaging or destructive influence on these cells.”3 The first reports of passive serum therapy in the treatment of cancer were by Hericourt and Richet, in 1895,4,5 who published two reports on the use of serum that had been raised in two dogs and one donkey to treat patients with various malignancies, in whom some clinical benefits were seen. They concluded that antibodies alone were not sufficient to cure but that they might increase survival when used in combination with other therapies. Passive serum therapy was also attempted by Laszlo et al6 with serum that had been raised in humans. However, a lack of tumor-specificity resulted in disappointing clinical results and toxicity. The first report of a tumor-specific antiserum was made in 1929, on a serum developed in rabbits.7 However, the results in clinical trials in the 1960s and 1970s were again disappointing because of excessive toxicity and lack of clinical activity. DEVELOPMENT OF MONOCLONAL ANTIBODY TECHNOLOGY
It was not until the development of hybridoma technology for the production of mAbs, by Ko¨ hler and Milstein in 1975,8 that serotherapy became a clinical reality. Ko¨ hler and Milstein immortalized antibody-producing murine lymphocytes by fusing them with a murine myeloma cell line. The hybridoma cells carried the antigen specificity of the fused lymphocytes and the proliferative machinery of the malignant murine myeloma cells. This enabled the large-scale production for clinical use of mAbs with predefined specificity. The therapeutic potential of such mAb-based therapy was recognized immediately, and several studies of unconjugated mAbs to tumor-associated antigens in patients with various malignancies were conducted. Along with the advances in the production of
HISTORY OF ANTIBODY THERAPY FOR NHL
mAbs, major advances were being made in recombinant DNA technology. Knowledge of how genes for immunoglobulins are organized and expressed by B cells to form the repertoire of antibody molecules was vital to further progress.9,10 Inevitably, the methods of mAb and recombinant DNA technology were combined to resolve the problems that had been seen in using murine antibodies for human therapy. Thus, the field of antibody engineering was born. Recombinant DNA technology has been used to transform a murine antibody into a human or humanlike antibody for therapeutic uses, lessening the problems of immunogenicity and improving interactions with human effector systems of complement and Fc receptors. TRIALS OF MONOCLONAL ANTIBODIES IN NON-HODGKIN’S LYMPHOMA
Early trials of mAbs used murine antibodies that were directed to surface antigens on lymphoma and leukemia cells of B- and T-cell origin.11 The study by Nadler et al12 was an early attempt at using mAb therapy in lymphomas. This study made the early observation that circulating antigens (on cells or free antigens) could bind the administered antibody and preclude its normal circulation to tumor sites, limiting the antitumor effect of the antibodies. Miller and colleagues moved the field forward in the 1980s with a series of trials that used anti-idiotype mAbs that were specific for the idiotype expressed on B-cell lymphomas.13 Their studies showed that antibodies could induce objective responses in the majority of patients,14 with long-term control of the disease seen in some patients.15 However, producing large numbers of anti-idiotype antibodies for each patient was prohibitive. The CD20 Antigen The CD20 antigen probably functions as a calcium channel,16,17 and it is expressed on most malignant B cells, including 90% of B-cell lymphomas.18 CD20 is less densely expressed in small lymphocytic lymphoma and chronic lymphocytic leukemia.19 Investigators soon recognized CD20 as an ideal target for serotherapy of lymphoma, owing to its restricted expression on the B-cell lineage and lack of antigen modulation, with no shedding or internalization. (Some other B-cell antigens [CD19, CD22] internalize after antibody binding, making them more suitable for use with a toxin or
3
other moiety with which internalization would be needed.) Early Clinical Trials With Monoclonal Antibodies To CD20 In the 1980s the Seattle group began to explore the use of mAbs to deliver radioisotopes selectively to lymphoma tumors; they noted regressions of lymphoma in diagnostic and dosimetry studies before the radioactive therapeutic doses. In 1987, they reported the results in a small trial that used 1F5 antibody to CD20 in four patients with refractory B-cell lymphoma, in which there was clearing of circulating tumor cells and regression of lymphoma tumor masses.20 They showed that achieving substantial antibody deposition in lymph node compartments required large doses of antibodies and reported a correlation between the dose and the clinical response, even though the clinical remissions observed were of short duration. This study, and the same investigators’ early reports on 1F5 and B1 labeled with 131I, clearly showed that large doses of antibody to CD20 were necessary to saturate intravascular CD20⫹ B cells in the blood and spleen and result in optimal pharmacokinetics and biodistribution to peripheral lymph node sites of the disease.21-23 Rituximab Reff et al24 published the first report on the chimeric mAb to CD20, known initially as IDEC C2B8 and now known as rituximab. After this, results in a phase I single-dose study and a phase I dose-escalation study were published.25,26 In a subsequent phase II trial, rituximab 375 mg/kg/wk for 4 weeks was studied in patients with indolent CD20⫹ NHL that was resistant to chemotherapy.27,28 Following this, a multicenter pivotal trial of the same regimen was conducted in 166 patients with low-grade, follicular, or transformed NHL in whom at least two chemotherapy regimens had failed.29 The overall response rate was 48%, with a complete response in 6% of patients. The median duration of response in responders was 13 months. The data from this trial led to the approval of rituximab by the FDA in November 1997. RADIOIMMUNOTHERAPY FOR NONHODGKIN’S LYMPHOMA
The clinical investigation of radiolabeled mAbs was well under way before the success of rituximab.
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Radioimmunotherapy is of interest not only because NHL is radiosensitive, but also because the radiation component of the therapy can help overcome the problem that not all tumor cells bear the antibody-targeted antigen or are physically accessible for the mAb to bind to. The early studies by Press et al30 provided insights into the need for large doses of antibody for optimal tumor localization, and investigated the use of gamma camera dosimetry to determine the radiation doses to tumors and normal tissues. Key Trials in Radioimmunotherapy The first radioimmunotherapeutic agent to be approved by the FDA was 90Y ibritumomab tiuxetan, in February 2002. One of the pivotal trials with this agent was conducted in 143 patients with chemotherapy-resistant follicular or transformed NHL who were randomized to rituximab 250 mg/m2 (to improve biodistribution) followed by 90 Y ibritumomab tiuxetan 0.4 mCi/kg or to rituximab 375 mg/m2 weekly ⫻ 4 monotherapy.31 The overall response rate with 90Y ibritumomab tiuxetan was 80% (complete response and complete response, unconfirmed, in 34%) and with rituximab monotherapy was 56% (complete response and complete response, unconfirmed, in 20%). The importance of the radiation component of 90Y ibritumomab tiuxetan has been shown in a trial in 57 patients with NHL that was refractory to rituximab, in which the overall response rate was 74% (complete response in 15%).32 Another trial has shown the efficacy and safety of a reduced dose of 90Y ibritumomab tiuxetan in patients with mild thrombocytopenia.33 A second radioimmunoconjugate, 131I tositumomab, was approved by the FDA in 2003 for the treatment of patients with CD20⫹, follicular NHL, with and without transformation, whose disease is refractory to rituximab and has relapsed following chemotherapy. It is not approved for initial treatment of patients with CD20⫹ NHL.34 A multicenter phase III trial evaluated this agent in patients with NHL that was resistant to chemotherapy.35 The response rates (65% overall, 17% complete) were compared with those with the patients’ most recent prior chemotherapy (28% and 3%, respectively). A study in similar patients with NHL that was also refractory to rituximab reported an overall response rate of
FORERO AND LOBUGLIO
58%, with a complete response in 20% of patients.36 CONCLUSION
The clinical utility of mAbs has been clearly shown, and there has been a great deal of interest in the field. Preclinical animal studies and further clinical trials are now needed to determine how radioimmunotherapy can best be combined with conventional therapies for lymphoma. Continued research will also help ensure that the antigens targeted, the radioimmunoconjugates used, and the delivery methods will be optimal. REFERENCES 1. Zevalin (ibritumomab tiuxetan) prescribing information: Cambridge, MA, Biogen Idec Inc, 2002 ¨ ber das Zustandekommen 2. von Behring E, Kitasato S: U der Diphtherie-Immunita¨ t und der Tetanus-Immunita¨ t bei Thieren. Dtsch Med Wochenschr 16:1113-1114, 1890 3. Ehrlich P: The Croonian Lecture: On immunity with special reference to cell life. Proc R Soc Lond 66:424-448, 1900 4. Hericourt J, Richet C: Physiologie pathologique– de la serotherapie dans le traitement du cancer. Comptes Rendu Hebd Seanc Acad Sci 120:948-950, 1895 5. Hericourt J, Richet C: Physiologie pathologique– de la serotherapie dans le traitement du cancer. Comptes Rendu Hebd Seanc Acad Sci 121:567-569, 1895 6. Laszlo J, Buckley CE III, Amos DB: Infusion of isologous immune plasma in chronic lymphocytic leukemia. Blood 31: 104-110, 1968 7. Lindstrom GA: An experimental study of myelotoxic sera. Therapeutic attempts in myeloid leukaemia. Acta Med Scandinavia 22:1-169, 1929 8. Ko¨ hler G, Milstein C: Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495497, 1975 9. Tonegawa S: Somatic generation of antibody diversity. Nature 302:575-581, 1983 10. Alt FW, Oltz EM, Young F, et al: VDJ recombination. Immunol Today 13:306-314, 1992 11. Ritz J, Schlossman SF: Utilization of monoclonal antibodies in the treatment of leukemia and lymphoma. Blood 59:1-11, 1982 12. Nadler LM, Stashenko P, Hardy R, et al: Serotherapy of a patient with a monoclonal antibody directed against a human lymphoma-associated antigen. Cancer Res 40:3147-3154, 1980 13. Miller RA, Maloney DG, Warnke R, et al: Treatment of B-cell lymphoma with monoclonal anti-idiotype antibody. N Engl J Med 306:517-522, 1982 14. Vuist WM, Levy R, Maloney DG: Lymphoma regression induced by monoclonal anti-idiotypic antibodies correlates with their ability to induce Ig signal transduction and is not prevented by tumor expression of high levels of bcl-2 protein. Blood 83:899-906, 1994 15. Davis TA, Maloney DG, Czerwinski D, et al: Antiidiotype antibodies can induce long-term complete remissions
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in non-Hodgkin’s lymphoma without eradicating the malignant clone. Blood 92:1184-1190, 1998 16. Tedder TF, Boyd AW, Freedman AS, et al: The B cell surface molecule B1 is functionally linked with B cell activation and differentiation. J Immunol 135:973-979, 1985 17. Bubien JK, Zhou LJ, Bell PD, et al: Transfection of the CD20 cell surface molecule into ectopic cell types generates a Ca2⫹ conductance found constitutively in B lymphocytes. J Cell Biol 121:1121-1132, 1993 18. Anderson KC, Bates MP, Slaughenhoupt BL, et al: Expression of human B cell-associated antigens on leukemias and lymphomas: A model of human B cell differentiation. Blood 63:1424-1433, 1984 19. Almasri NM, Duque RE, Iturraspe J, et al: Reduced expression of CD20 antigen as a characteristic marker for chronic lymphocytic leukemia. Am J Hematol 40:259-263, 1992 20. Press OW, Appelbaum F, Ledbetter JA, et al: Monoclonal antibody 1F5 (anti-CD20) serotherapy of human B cell lymphomas. Blood 69:584-591, 1987 21. Kaminski MS, Zasadny KR, Francis IR, et al: Radioimmunotherapy of B-cell lymphoma with 131I-anti-B1 (antiCD20) antibody. N Engl J Med 329:459-465, 1993 22. Kaminski MS, Zasadny KR, Francis IR, et al: Iodine131-anti-B1 radioimmunotherapy for B-cell lymphoma. J Clin Oncol 14:1974-1981, 1996 23. Kaminski MS, Estes J, Zasadny KR, et al: Radioimmunotherapy with iodine 131I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: Updated results and longterm follow-up of the University of Michigan experience. Blood 96:1259-1266, 2000 24. Reff ME, Carner K, Chambers KS, et al: Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83:435-445, 1994 25. Maloney DG, Liles TM, Czerwinski D, et al: Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 84:2457-2466, 1994 26. Maloney DG, Grillo-Lo´ pez AJ, Bodkin DJ, et al: IDECC2B8: Results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin’s lymphoma. J Clin Oncol 15:32663274, 1997
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27. Maloney DG, Grillo-Lopez AJ, White CA, et al: IDECC2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood 90:2188-2195, 1997 28. Coiffier B, Haioun C, Ketterer N, et al: Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: A multicenter phase II study. Blood 92:1927-1932, 1998 29. McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825-2833, 1998 30. Press OW, Farr AG, Borroz KI, et al: Endocytosis and degradation of monoclonal antibodies targeting human B-cell malignancies. Cancer Res 49:4906-4912, 1989 31. Witzig TE, Gordon LI, Cabanillas F, et al: Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol 20: 2453-2463, 2002 32. Witzig TE, Flinn LW, Gordon LI, et al: Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J Clin Oncol 20:3262-3269, 2002 33. Wiseman GA, Gordon LI, Multani PS, et al: Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: A phase II multicenter trial. Blood 99:4336-4342, 2002 34. Bexxar (131I tositumomab) prescribing information: Corixa Corporation, Seattle, WA, 2003 35. Kaminski MS, Zelenetz AD, Press OW, et al: 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 19:3918-3928, 2001 36. Horning SJ, Lucas JB, Younes A, et al: Iodine-131 tositumomab for non-Hodgkin’s lymphoma (NHL) patients who progressed after treatment with rituximab: Results of a multicenter phase II study. Blood 96:508a, 2000 (abstr)