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Treatment of Patients with Malignant Lymphomas with Monoclonal Antibodies

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Treatment of Patients with Malignant Lymphomas with Monoclonal Antibodies Bone Marrow Transplantation (2000) 25, Suppl. 2, S50–S53 2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Treatment of patients with malignant lymphomas with monoclonal antibodies H Tesch, A Engert, O Manzke, V Diehl and H Bohlen Klinik I fuer Innere Medizin, Universitaet zu Koeln, Koeln, Germany Summary: Results and discussion Malignant lymphomas represent a heterogenous group of B and T cell-derived malignancies. Most lymphomas Native monoclonal antibodies are sensitive to chemo- and radiotherapy, however many patients will eventually relapse. Immunothera- Since the first description of therapy using monoclonal anti- peutic approaches including monoclonal antibodies, bodies in 1979, several phase I and II trials have been cytokines or vaccination approaches may offer an alter- initiated to evaluate both safety and antitumoral activity of native treatment of chemotherapy-resistant residual this approach. Native MoAbs can kill a tumor cell through cells especially in cases with low tumor burden or various mechanisms including complement activation, anti- residual disease following chemo- or radiotherapy. body-dependent cellular cytotoxicity (ADCC), phago- Monoclonal antibodies have been successfully applied in cytosis of antibody-coated tumor cells, inhibition of cell their native form, or coupled with radioisotopes or tox- cycle progression, and induction of apoptosis.2,3 Alterna- ins to selectively destroy lymphoma cells and promising tively, MoAbs can eliminate a tumor cell by inhibiting results in early clinical trials have been obtained. Alter- growth factor receptors or molecules involved in signal natively, bispecific antibodies and idiotypic vaccination transduction and cell proliferation. strategies are used to target autologous T cells to elimin- The group of R Levy at Stanford reported on promising ate lymphoma cells. A humanized anti-CD20 antibody results in B-lymphocytic malignancies using anti-idiotypic showed excellent results in chemotherapy refractory monoclonal antibodies (anti-Id MoAbs).4,5 Side-effects lymphomas and has recently been approved for clinical were moderate and included chills, fever, dyspnea, nausea, application in CD20 positive B cell lymphomas. Bone diarrhea, myalgia, and the development of human anti- Marrow Transplantation (2000) 25, Suppl. 2, S50–S53. mouse antibodies (HAMA). Complete and partial Keywords: malignant lymphoma; monoclonal anti- remissions had been observed together with a strong corre- bodies; immunotherapy lation of anti-Id MoAb-mediated signal transduction and tumor regression as measured by the induction of cellular protein tyrosine phosphorylation.6 Several trials evaluated Malignant lymphomas represent a heterogeneous group of the effect of the Campath-1H MoAb directed against the B and T cell-derived tumors. Most entities respond to CDw52 antigen, expressed on B and T cell lymphomas. In chemo- and/or radiotherapy and, depending on the histo- addition to common side-effects such as fever, rigor and logical subtype, up to 80% complete remissions (CR) can neutrocytopenia, severe opportunistic infections due to the be achieved. The main reason for tumor recurrence is the depletion of CD4- and CD8-positive T lymphocytes were development of lymphoma cell clones resistant to the initial reported.7 High response rates up to 70% were reported therapy. The use of monoclonal antibodies (MoAbs) or when Campath-1H was administered in CLL patients.8 other immunotherapeutic strategies may be useful to eradi- Exciting results have been demonstrated in clinical phase cate such chemotherapy-resistant tumor cells. Clinical trials I/II trials with the chimeric mouse/human anti-CD20 MoAb in lymphoma patients showed a strong correlation between IDEC-C2B8 (IgG1), which binds complement and induces poor outcome and the presence of minimal residual disease, ADCC as well as programmed cell death (apoptosis).2 A which can be detected by polymerase chain reaction (PCR)1 large phase II trial revealed a response rate of 50% in low at very high sensitivity. Also, autologous stem cell prep- and intermediate grade lymphomas with significantly better arations from patients with lymphomas frequently contain responses in patients with low tumor masses. At our depart- residual lymphoma cells. Since residual lymphoma cells ment more than 80 patients with relapsed or refractory lym- may contribute to an overt clinical relapse, the elimination phomas including mantle cell lymphomas were treated with of these residual cells may have a great clinical impact and IDEC-C2B8 so far and toxicities were generally low. How- is followed in purging strategies. ever, patients with a higher tumor load in the peripheral blood developed signs of severe cytokine release.9 Current trials investigate the role of anti-CD20 antibody treatment Correspondence: Dr V Diehl, Klinik I fuer Innere Medizin, Universitaet in high grade lymphomas and in combination with chemo- zu Koeln, Joseph-Stelzmann-Str 9, 50924 Koeln, Germany therapy. Antibody treatment of lymphomas H Tesch et al S51 Radioimmunoconjugates Grossbard and colleagues39 performed similar phase I stud- ies in patients with B-NHL using the anti-CD19 MoAb B4 Radioimmunoconjugates may offer a number of advan- coupled to blocked ricin (bR). In this study nine out of 25 tages: (1) endocytosis is not required for cytotoxicity; (2) patients developed HAMA and HARA, and one CR and the use of an isotope enables the eradication of antigen- two PR were reported. In a phase II trial, 50 patients were negative ‘bystander’ tumor cells; (3) radioimmunoconju- treated with ITs after high-dose chemotherapy and stem cell gates allow biodistribution experiments to detect the local- transplantation at a reduced dose of 30 ␮g/kg/day over 7 ization of the conjugate at the tumor site. Antibodies can days. In 34 evaluable patients no relapse occurred between either be labeled directly using 131iodine, 99mtechnetium or 99m 90 111 1 and 3 years after transplantation. The Cancer and Acute indirectly ( Tc, Y, In) using bifunctional chelating Leukemia Group B (CALGB) initiated a randomized multi- agents. center phase III study in which patients in CR after high- Several clinical trials using non-myeloablative and mye- dose chemotherapy receive anti-B4-bR over a 7-day loablative doses of radiolabeled MoAbs (R-MoAbs) were period).18 conducted in lymphoma patients. Excellent response rates were achieved with the 131I-labeled B1 MoAb against the CD20 antigen using a single non-myeloablative dose of 30– Bispecific monoclonal antibodies 10 160 mCi in patients with refractory lymphomas. Of 28 Bispecific monoclonal antibodies (BiMAbs) recognize two treated patients, 14 achieved a CR and eight PR. Non- different antigens via their two binding sites.19 BiMAbs can hematologic toxicities were generally mild but hematologic be used to crosslink lymphoma cells with immunological toxicities proved dose-limiting. effector cells like macrophages, T cells or NK cells which High-dose radioimmunotherapy seems to be even more can lyse tumor cells. An alternative approach is the design superior compared to low-dose therapy. Out of 43 patients of BiMAbs directed against a tumor cell antigen and a pro- with relapsed NHL, which were initially trace-labeled, 24 11 drug-converting enzyme such as alkaline phosphatase to demonstrated satisfactory tumor imaging. Subsequently, convert relatively non-toxic cytostatic prodrugs like mito- these patients received a single infusion of the R-MoAb up mycin phosphate or etoposide phosphate into the active to 777 mCi. The dose limiting myelosuppression required cytostatic drugs mitomycin and etoposide, respectively. In reinfusion of autologous bone marrow in 15/19 patients. addition, toxins like saporin or radioisotopes conjugated to Two PR and 16 CR were observed among 24 patients, and haptens can be targeted to tumor cells via BiMAbs. nine patients remained in CR over a period of 3 to 53 BiMAbs can be generated by chemical crosslinking of months. In a recently published phase II trial, 21 patients two monoclonal antibodies or F(abЈ) fragments,20 by were treated with therapeutic doses (345–785 mCi) of 131I- 12 somatic fusion of two distinct hybridoma cell lines (hybrid- B1, with subsequent autologous stem cell transplantation. hybridomas or tetradoma),19 or by recombinant antibody A summary of these phase I/II studies showed an overall technology.21 Most BiMAbs aim to activate T cells by survival of 93% with a median follow-up of 2 years. 22 ␥ ␤ crosslinking of the TCR/CD3 complex. After binding of In contrast to -emitters, -emitters deliver sufficient the BiMAb to the TCR/CD3 complex, the T-lymphocytes doses over a distance of 100 to 1000 cell diameters without 13 become pre-activated requiring further stimulation to fully the need for hospitalization. In a recently published trial, 23 90 exert their cytotoxic activity. The additional costimulating Y-labeled anti-Id MoAbs were used for the treatment of molecule can be provided by cytokines such as IL-2, IL- nine patients with refractory NHL. Toxicities were mild and 12, and TNF-␣, or by CD28-mediated costimulation. two patients achieved a CR and one patient a PR. Haagen et al24 tested several CD3xCD19 BiMAbs against B cell lines and primary lymphoma cells. These Immunotoxins BiMAbs induced remarkable cytotoxic activity in the pres- ence of activated T cells, as well as proliferation and cyto- Immunotoxins (ITs) can selectively bind and destroy their toxicity in resting T cells. We used bispecific
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