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CD20 monoclonal antibody therapy for B-cell lymphona van der Kolk, L.E.

Publication date 2001

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Citation for published version (APA): van der Kolk, L. E. (2001). CD20 monoclonal antibody therapy for B-cell lymphona.

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Introductionn and outline of the thesis

Introductionn and outline of the thesis

Introduction n

Low-gradee non-Hodgkin's lymphoma (NHL) Non-Hodgkin'ss lymphomas are a heterogeneous group of malignancies of mature lymphoid cells.. Over 90% of the non-Hodgkin's lymphomas is of B-cell origin. The clinical course variess from indolent to highly aggressive. Over the past decades, several lymphoma classificationss have been developed and used in different parts of the world.1 The Kiel classification2,, introduced in 1974, relates the different lymphomas to the differentiation stagess of normal T- and B-cells, i.e. to their 'normal counterpart'. It is based on morphology andd immunophenotypical analysis of lymphoma cells. In the 'Working Formulation'3, lymphomass have been subdivided into low-, intermediate-, and high-risk lymphomas, dependentt on their clinical behavior. This classification was based on the analysis of the clinicall data of a large group of lymphoma patients treated in the 1970's. The Working

Tablee 1. Comparison of Working Formulation and REAL classification with respect to B-lineage lymphomas s

Workingg formulation REALL classifcation

A** Small lymphocytic lymphoma consistent with CLL B-celll chronic lymphocytic leukemia Lymphoplasmacytoidlymphoma/immunocytoma a Smalll lymphocytic lymphoma B-celll prolymphocyte leukemia Smalll lymphocytic, plasmacytoid lymphoma Lymphoplasmacytoidd lymphoma Smalll lymphocytic lymphoma Extranodall marginal zone B-cel! lymphoma Smalll lymphocytic lymphoma Nodall marginal zone B-cell lymphoma Smalll lymphocytic lymphoma Splenicc marginal zone B-cell lymphoma Hairyy cell leukemia Plasmacytoma a Plasmacytoma/Myeloma a BB Follicular, predominantly small cleaved cell Folliclee center lymphoma, follicular grade I

CC Follicular, mixed small cleaved and large cell Folliclee center lymphoma, follicular grade II

DD Follicular, predominantly large cell Folliclee center lymphoma, follicular grade III EE Diffuse lymphoma, small cleaved cell Folliclee center lymphoma, diffuse small cell Mantlee cell lymphoma FF Diffuse, mixed small and large cell Folliclee center lymphoma, diffuse small cell GG Diffuse, large cell lymphoma Diffusee large B-cell lymphoma

HH Diffuse large cell immunoblastic lymphoma Diffusee large B-cell lymphoma II Lymphoblastic lymphoma B-precursorr lymphoblastic lymphoma JJ Small non-cleaved, Burkitt's lymphoma Burkitt'ss lymphoma Smalll non-cleaved, non-Burkitt's lymphoma Highh grade B-cell lymphoma, Burkitt-like

Workingg Formulation A-C: low-grade non-Hodgkin's lymphomas; D-G: intermediate-grade NHL; H-J: high-gradee NHL

9 9 Chapterr 1

formulationn and Kiel classification have been used predominantly in the United States and Europee respectively. However, in order to be able to compare scientific data (e.g. on treatment results),, one lymphoma classification is definitely required. Therefore, the Revised European- Americann lymphoma classification (REAL) was presented by hematologists and pathologists fromm Europe, the Unites States and Asia in 1994 (table 1).4 This classification not only uses morphologyy and immunophenotyping, but also incorporates cytogenetic, molecular and clinicall data in order to categorize the different lymphomas. Recently, the 'World Health Organizationn Classification of hematologic malignancies' was introduced.5 This classification closelyy resembles the REAL classification with respect to the non-Hodgkin's lymphomas. Low-gradee lymphomas are characterized by an indolent clinical course, with a median survival off 8-10 years after diagnosis. Management of low-grade NHL varies from wait-and-see to single-agentt or aggressive combination chemotherapy. Although 60-90% of patients achievess a remission after initial treatment, all patients eventually relapse. Both response ratee and response duration to subsequent therapies decline, indicating an increasing chemoresistancee of the lymphoma.6 Unfortunately, over the past decades overall survival hass not significantly been altered by therapy, and curation has not been described.67

Antibodyy based immunotherapy Althoughh there are many different forms of immunotherapy (table 2), at present only monoclonall antibody(mAb)-based therapies have reached the stage of extensive clinical

Tablee 2. Treatment modalities in immunotherapy

Passive e tumorr specific monoclonall antibodies (mAbs) unconjugatedd mAbs radiolabeledd mAbs toxin-conjugatedd mAbs cytokine/chemokine-conjugatedd mAbs drug/enzyme-conjugatedd mAbs bispeciff ic mAbs tumorspecificc T-cells nonn specific LAKK cells cytokines s anti-cytokinemAbs s

Active e tumorspecific c vaccinationn using tumorr cells proteins// peptides ( DC) DNA A nonn specific Bacilluss Calmette-Guerin (BCG) Corynee bacterium Parvum

Abbreviation:: LAK cells: lymphokine-activated killer cells; DC= dendritic cells

10 0 Introductionn and outline of the thesis

testing.. Theoretically, mAb-based therapy offers an attractive approach for the treatment off malignancies. By targeting tumor-specific antigens, antibody-based therapy is expected too confer less non-specific toxicity than chemotherapy. Moreover, since mAbs might use distinctt cytotoxic mechanisms, chemoresistance of tumor cells may be overcome.8 Thee clinical efficacy of unconjugated mAbs is dependent on certain critical characteristics off both the target antigen and the mAb itself. First, the target antigen should be tumor- specific,, present on all tumor cells in sufficient density and it should not be expressed on otherr tissues. For optimal interaction between antigen and antibody, the affinity of the antibodyy for the antigen is also of importance. Furthermore, upon ligation, the target antigen shouldd not internalize or be shed, resulting in antigen-negative tumor cells. In case of shedding,, soluble antigen may hamper interaction of the mAbs with the target cells.9;10 Withh respect to the mAb itself, certain problems may limit its efficacy (table 3). First, since mAbss are large proteins, kinetics of tissue distribution of mAbs are slow when compared to smalll molecules and penetration into large tumors, which are often poorly vasculated, might

bee suboptimal. Furthermore, tissue distribution may not be uniform. F(ab')2 fragments, F(ab') fragmentss or single-chain Fv constructs are smaller proteins and therefore may have a better tissuee penetration. However, shorter half-life and lower in vivo stability are limitations that maymay impede clinical efficacy of these smaller constructs.1113 Second, antibodies may be immunogenic,, leading to the formation of antibodies resulting in neutralization and/or

Tablee 3. Potential obstacles to monoclonal antibodybased therapies

11 non-specific binding of the mAb to normal tissues 22 low antigen density on tumor cells/induction/presence of antigen-negative tumor cells 33 low affinity of mAb for antigen 44 antigen modulation (shedding/internalization) 55 poor penetration of mAbs into (bulky) tumors 66 induction of anti-mAb antibodies 77 inability of the mAb to activate host effector mechanisms/resistance of tumor cells to cytotoxic mechanismss of the mAb

clearancee of the therapeutic antibody. This problem was first identified in initial clinical trials withh murine antibodies, in which human anti-mouse antibodies were formed rapidly in a considerablee proportion of patients (~ 25%).1415 Finally, the efficacy of the murine antibodies mayy be limited due to the variable ability of different murine Fc-tails to interact with human effectorr mechanisms. These latter two problems can be overcome by using chimeric antibodies,, in which the variable region of the murine antibody is coupled to a human Fc- tail.. Chimeric antibodies are less immunogenic, have a longer half-life and are more efficient; inn mediating Fc-dependent functions.16"18

11 1 Chapterr 1

Anti-tumorr mechanisms of unconjugated mAbs include direct mechanisms like the induction off apoptosis or a growth arrest, and indirect mechanisms, i.e. complement-dependent cytotoxicityy (CDC) and antibody-dependent cellular cytotoxicity (ADCC).18;19 Inn addition to unconjugated antibodies, conjugated antibodies are already used clinically. Antibodiess may be conjugated to radioactive isotopes, such as 131 iodine <1311) or 90 yttrium ("Y),, or to toxic conjugates from plant or bacterial origin, such as ricin, diphtheria toxin or pseudomonass exotoxin. The characteristics of target antigen and antibody which are requiredd for the potential efficacy of unconjugated mAbs also apply for conjugated antibodies.. However, certain differences exist. 13111 and ^Y exert their cytotoxicity through the emission of p-partides that induce DNA damage too cells residing within a rather wide range from the target cell (0.8 mm for1311 to 5.3 mm for 90Y).. Therefore, the density of the target antigen is of less importance when radio- immunoconjugatess are used than in case of unconjugated mAbs. Even antigen-negative cells cann be killed, and radio-isotopes may be more efficient in patients with large tumors.9 Immunotoxinss exert their cytotoxicity through inhibition of protein synthesis. Hence upon ligation,, internalization of the target antigen and antibody is a requirement for the efficacy off immunotoxins, whereas for unconjugated mAbs internalization is a major disadvantage. Sincee immunotoxins are large molecules, the problem of tumor penetration is even more importantt than for unconjugated mAbs. Furthermore, in addition to the antibody, the toxin iss immunogenic as well and this leads to the formation of anti-toxin antibodies in over 30% off patients.2071 Toxicity of immunotoxins includes hepatotoxicity, capillary leakage and myalgia.. These side effects may limit the clinical applicability of immunotoxins.^2123

Antibody-basedd immunotherapy for low-grade NHL Non-Hodgkin'ss lymphomas express a number of B-cell specific antigens including CD19, CD20, CD21,, CD22 and CD37, all of which have been tried as a target for immunotherapy, either withh unconjugated mAbs or with mAbs conjugated to radio-isotopes or toxins.24-31 Almost all malignanciess of B-cell origin express a surface immunoglobulin. The antigenic determinants off the variable regions of the heavy and light chains of the immunoglobulin (the idiotype) are aa true tumor-specific antigen. Significant clinical responses have been observed after treatment withh anti-idiotype (Id) antibodies.'4 However, anti-Id antibodies are patient specific and are thuss very laborious and expensive to produce. Moreover, after treatment of patients with anti-Idd mAbs, the emergence of Id-negative cells was reported, allowing the tumor to escape fromm this therapy.32 By far the best clinical results have been achieved with CD20 mAbs, either unconjugatedd or conjugated to radio-isotopes (table 4).3"6 Thee CD20 antigen is a nonglycosylated 33 to 37 kD phosphoprotein, expressed on more thann 95 % of normal and malignant B-cells. It consists of four transmembrane spanning

12 2 Introductionn and outline of the thesis

Tablee 4. Clinical results with various CD20 mAbs antibody y patients s numberr of ORR(CR) RD ref patients s unconjugatedd rituximab; low-gradee or follicular 166 48%% (6%) 13 17 CD200 mAbs chimeric, hlgG1; lymphoma a rituximab/ / Mabthera a

13111 labeled 1311 tositumomab; low-gradee or transformed 59 71%% (34%) 8.9 3< CD200 mAbs murine, mlgG2a; NHL,, de novo Bexxar r intermediatee or high-gradee NHL

low-gradee or 47 57%% (32%) 9.9 63 transformedd NHL

indolent,, transformed 38 ordee novo follicular largee cell NHL, relapsed 58%% (21%) 15 64 afterr rituximab

«VV labeled ^Y ibritumomab relapsedd or refractory 70* CD200 mAbs tiuxetan; murine, low-gradee lymphoma, mlgG1;Zevalin n orr transformed B-NHL 80%% (30%) 10.9+ 36

follicularr lymphoma, refractoryy after rituximab 54

74%% (15%) 7.7+ 35 13111 labeled 13111 tositumomab; relapsedd low- intermediate- 299 86% (79%) 37* CD200 mAbs murine,, mlgG2a; orr high-grade NHL highh dose + Bexxar r AuSCT T

Abbreviations:: ORR - overall response rate; CR = complete remission; RD = median duration of response (inn months), defined as date that the response is first noted until the last date at which the measurement satisfiess the requirements for this response; AuSCT = autologous stem cell transplantation. ** 143 patients were randomized to receive either ¥ ibritumomab tiuxetan or rituximab. ORR to rituximab wass 56% (4% CR). ** TTF = time to treatment failure, defined as date of first study treatment to the firstt date at which progressive disease is documented.

regions,, with both the N- and C-terminal ends located on the cytoplasmatic side of the membranee and only a minor portion of the molecule exposed to the cell-surface. The CD20 antigenn is present from the pre-B cell stage until the plasma cell stage and is not expressed onn other hematologic cells or nonlymphoid cells. Thee exact function of the CD20 molecule has not yet been elucidated. In vitro studies have shownn that ligation of CD20 with murine CD20 monoclonal antibodies induces a calcium

13 3 Chapterr 1

influx,, activation of protein tyrosine kinases and serine/threonine and tyrosine phosphorylation off intracellular proteins. Furthermore, CD20 was found to play a role in B-cell differentiation andd proliferation.37 However, the natural ligand of CD20 is not known. Furthermore, mice carryingg a CD20 gene disruption were found to have a normal phenotype, and no disturbances inn B-cell development and function were described.38 Chimericc CD20 mAbs (IDEC-C2B8, rituximab) consist of human lgG1 and kappa constant regionss and variable antigen recognition sites from the murine CD20 mAb IDEC-2B8. It has beenn demonstrated in vitro that chimeric CD20 mAbs can induce complement-dependent cytotoxicityy (CDC)39;4 and antibody-dependent cellular cytotoxicity (ADCC) in B-cell lines, thee latter with mononuclear cells as effector cells.18 Furthermore, ligation of CD20 inhibits B- celll proliferation and CD20 mAbs can induce apoptosis in B-cell-lines, which is enhanced afterr crosslinking.41-43 Chimericc CD20 mAbs have been shown to have clinical activity in patients with relapsed low-gradee lymphoma. In a clinical trial in which 166 patients were treated with 375 mg/m2 rituximabb weekly x4, the overall response rate was 50% with a median time to progression off > 13 months. Moreover, the chimeric antibody was very well tolerated and only few patientss developed human anti-mouse antibodies (HAMA).17 Ensuing these favorable results, safetyy and efficacy of rituximab is currently being studied in other CD20-positive B-cell malignancies,, for example aggressive lymphoma4*46, post-transplant lymphoma4750, or chronicc lymphocytic leukemia (CLL).515S Furthermore, the use of rituximab in combination withh chemotherapeutic regimens or its feasibility as maintenance therapy are currently being investigated.56"58 8

AimAim and outline of this thesis

AA possibility to improve the efficacy of unconjugated mAbs might be to enhance the efficacy off the effector cells involved in ADCC, one of the possible anti-tumor mechanisms of monoclonall antibodies. Freshly isolated neutrophils are capable of functioning as effector cellss in ADCC. However, after exposure to granulocyte colony-stimulating factor (G-CSF), thee cytotoxic capacity of neutrophils in ADCC is greatly enhanced.19159 It has been demonstratedd in vitro as well as in vivo in healthy volunteers, that G-CSF induces the expression off Fcy-receptor type I (FcyRI) on neutrophils via an effect on myeloid precursor cells.60:61 This FcyRR appears to be the main FcyR involved in neutrophil-mediated ADCC.19;59;61;62 Furthermore, G-CSFF administration leads to a large increase in the number of circulating (FcyRI-positive) neutrophils.. Thus, adding G-CSF to rituximab therapy could theoretically augment the efficacy

14 4 Introductionn and outline of the thesis off rituximab by exploiting the mechanism of ADCC. Therefore, we developed a phase l/lI clinicall trial to evaluate the safety (phase I) and efficacy (phase II) of the combination of rituximabb and G-CSF in relapsed low-grade lymphoma patients. Inn chapter 2, we describe the results of the clinical trial evaluating the safety and efficacy of thee combination of rituximab and G-CSF. Data are compared to (historical) data obtained withh rituximab monotherapy. Althoughh treatment with rituximab is generally well tolerated, side effects can be severe andd life threatening, notably in patients with high numbers of circulating B-cells.51 We investigatedd the mechanism underlying these side effects and provide new strategies to preventt them. Results are described in chapter 3. Althoughh the cytotoxic capacity of neutrophils in ADCC with various antibodies and target cellss is greatly enhanced after stimulation with G-CSF, the capacity of neutrophils to induce CD20-dependentt ADCC has previously been questioned.59 HLA class II mAbs were found to bee the only mAbs capable of inducing B-cell lysis with G-CSF-stimulated PMN as effector cells.. Therefore, we investigated the ability of G-CSF stimulated PMN in CD20-dependent ADCC,, and compared this with HLA class ll-dependent ADCC. Results of these in vitro experimentss are described in chapter 4. Treatmentt with rituximab leads to a rapid depletion of B cells from the peripheral blood. B cellss disappear already after the first infusion, and levels return to normal only 9-12 months afterr 'completion of treatment. Clinically, this sustained B-cell depletion neither leads to a decreasee in immunoglobulin levels, nor to an increase in the number of infections. However, thee exact influence of rituximab on the humoral immune response has not been studied in detail,, and this knowledge may be of specific importance for studies investigating the feasibilityy of rituximab as maintenance therapy, in which rituximab may be administered for upp to two years. Therefore, we investigated the effect of rituximab treatment on the primary andd secondary humoral immune response, by immunizing patients both before and after rituximabb treatment with two primary antigens (keyhole limpet hemocyanin and hepatitis A)) and two recall antigens (tetanus toxoid and poliomyelitis vaccine). Results of this study aree described in chapter 5. Inn addition to mediating CDC and ADCC, chimeric CD20 antibodies were found to induce apoptosis.. We investigated the intracellular pathways of CD20-induced apoptosis, and comparedd them with pathways activated by triggering CD95 (Fas) or the B-cell receptor (BCR).. Results of this study are described in chapter 6. AA summary and discussion of future perspectives are presented in chapter 7.

15 5 Chapterr 1

Referencee List

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16 6 Introductionn and outline of the thesis

22.. Grossbard ML, Gribben JG, Freedman AS, et al. Adjuvant immunotoxin therapy with anti-B4- blockedd ricin after autologous bone marrow transplantation for patients with B-cell non-Hodgkin's lymphoma.. Blood. 1993;81:2263-2271. 23.. Grossbard ML, Lambert JM, Goldmacher VS, et al. Anti-B4-blocked ricin: a phase I trial of 7-day continuouss infusion in patients with B-cell neoplasms. J.Clin.Oncol. 1993; 11:726-737. 24.. Brown SL, Miller RA, Horning SJ, et al. Treatment of B-cell lymphomas with anti-idiotype antibodies alonee and in combination with alpha interferon. Blood. 1989;73:651-661. 25.. Multani PS, O'Day S, Nadler LM, Grossbard ML. Phase II clinical trial of bolus infusion anti-B4 blockedd ricin immunoconjugate in patients with relapsed B

17 7 Chapterr 1

43.. Hofmeister JK, Cooney D, Coggeshall KM. Clustered CD20 Induced Apoptosis: Src-Family Kinase, thee Proximal Regulator of Tyrosine Phosphorylation, Calcium Influx, and Caspase 3-Dependent Apoptosis.. Blood Cells Mol.Dis. 2000;26:133-143. 44.. Coiffier B, Haioun C, Ketterer N, et al. Rituximab (anti-CD20 monoclonal antibody) for the treatment off patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood. 1998;92:1927-1932. . 45.. Foran JM, Rohatiner AZ, Cunningham D, et al. European phase II study of rituximab (chimeric anti-CD200 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previouslyy treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma. J.Clin.Oncol.. 2000;18:317-324. 46.. Winkler U, Schulz H, Klein T, et al. Treatment of patients with mantle

18 8 Introductionn and outline of the thesis

60.. Kerst J, van de Winket J, Evans A, et al. Granulocyte colony-stimulating factor induces hFc gamma Rll (CD64 antigen)-positive neutrophils via an effect on myeloid precursor cells. Blood. 1993;81:1457-1464. . 61.. Kerst J, de Haas M, van der Schoot C, et al. Recombinant granulocyte colony-stimulating factor administrationn to healthy volunteers: induction of immunophenotypically and functionally altered neutrophilss via an effect on myeloid progenitor cells. Blood. 1993;82:3265-3272. 62.. Valerius T, Repp R, de Wit T, et al. Involvement of the high-affinity receptor for IgG (Fc gamma Rl;; CD64) in enhanced tumor cell cytotoxicity of neutrophils during granulocyte colony-stimulating factorr therapy. Blood. 1993;82:931-939. 63.. Vose JM, Wahl RL, Saleh M, et al. Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractoryy low-grade and transformed low-grade B-cell non-Hodgkin's lymphomas.. J.CIin.Oncol. 2000;18:1316-1323. 64.. Homing SJ, Lucas J, Younes A, et al. Iodine-131 tositumomab for non-Hodgkin's lymphoma (NHL)) patients who progressed after treatment with rituximab: results of a multi-center phase II studyy [abstract]. Blood. 2000;96:2184a 65.. Liu SY, Eary JF, Petersdorf SH, et al. Follow-up of relapsed B-cell lymphoma patients treated with iodine-131-- labeled anti-CD20 antibody and autologous stem-cell rescue. J.CIin.Oncol. 1998;16:3270-3278. .

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