Macrophages contribute to the antitumor activity of the anti-CD30 antibody SGN-30

Blood ◽  
2007 ◽  
Vol 110 (13) ◽  
pp. 4370-4372 ◽  
Author(s):  
Ezogelin Oflazoglu ◽  
Ivan J. Stone ◽  
Kristine A. Gordon ◽  
Iqbal S. Grewal ◽  
Nico van Rooijen ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Effector Cell ◽  
Treatment Strategies ◽  
Large Cell ◽  
Hematologic Malignancies ◽  
Effector Cells ◽  
Cell Functions ◽  
Cell Ablation

Increased expression of CD30 is associated with a variety of hematologic malignancies, including Hodgkin disease (HD) and anaplastic large cell lymphoma (ALCL). The anti-CD30 monoclonal antibody SGN-30 induces direct antitumor activity by promoting growth arrest and DNA fragmentation of CD30+ tumor cells. In this study, we investigated the contributions of Fc-mediated effector cell functions to SGN-30 activity. We determined that antibody-dependent cellular phagocytosis, mediated by macrophages, to contribute significantly to antitumor activity in vitro. To delineate the identity of the host effector cells involved in mediating antitumor activity in vivo, we studied the effects of effector cell ablation in a disseminated model of HD (L540cy). Depletion of macrophages markedly reduced efficacy of SGN-30, demonstrating that macrophages contribute significantly to SGN-30 efficacy in this model. These findings may have implications for patient stratification or combination treatment strategies in clinical trials conducted with SGN-30 in HD and ALCL.

Loss of CD20 Expression and Exhaustion of Effector Cells Limit ADCC in CLL Patients Treated with Rituximab.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1610-1610 ◽  
Author(s):  
Berengere Vire ◽  
Justin SA Perry ◽  
Elinor Lee ◽  
Lawrence S Stennett ◽  
Leigh Samsel ◽  
...  
Keyword(s):  
Nk Cells ◽  
Effector Cell ◽  
Cell Function ◽  
Nk Cell ◽  
Cell Surface Expression ◽  
Target Cells ◽  
Effector Cells ◽  
Cell Functions ◽  
Anti Cd20

Abstract Abstract 1610 Poster Board I-636 A major mechanism how the chimeric anti-CD20 monoclonal antibody rituximab (RTX) depletes B-cells is antibody-dependent cellular cytotoxicity (ADCC). ADCC has been modeled in-vitro and in mouse models. However, investigations on ADCC directly in patients treated with RTX are scarce. Recent efforts have focused on improving ADCC through modifications in the Fc binding portion of novel antibodies or through stimulation of effector cell functions with GM-CSF. A more detailed understanding of ADCC as a therapeutic process is needed to optimize such strategies and to identify biomarkers of improved efficacy. Here we report a comprehensive analysis of ADCC in previously untreated CLL patients during the first two RTX infusions (375mg/m2) given in combination with fludarabine every 4 weeks. Following the initial infusion of RTX the absolute lymphocyte count (ALC) decreased by a median of 74% at 2h, followed by a partial recrudescence of cells so that by 24h the median decrease in ALC reached 39% (n=11). ADCC is mediated by effector cells that include NK cells, monocytes/macrophages, and granulocytes. First, we investigated changes in NK cell function: consistent with NK cell activation we found an increase in CD69 at 2, 6 and up to 24h (median 4.2-fold, p=0.005, n=10) after RTX administration and increased expression of the degranulation marker CD107a/b (median 1.9-fold, p<0.001, n=5) and down-regulation of perforin expression (median decrease 63%, p<0.001, n=5) at 4h from treatment start. Activation of NK cells is triggered by the engagement of CD16/FcγRIIIa by RTX coated CLL cells. Interestingly, CD16 expression on NK cells was rapidly lost, already apparent at 2h and maximal at 6h from the start of the RTX infusion (median decrease 82%, p=0.02, n=10) and was not completely recovered by 24h. We also found a significant decrease in expression of CD16 on granulocytes (78%, p<0.001, n=5) but an increase in monocytes (3.9-fold, p<0.001, n=5). In addition to loss of CD16, we found that the cytotoxic capacity of the effector cells was rapidly exhausted: in an oxidative-burst assay, monocytes showed a significant decrease in the production of reactive oxygen species 4h after initiation of RTX infusion (median 60% decrease, p=0.043) and at 6h from the start of the RTX infusion NK cell-mediated killing of K562 target cells was reduced by half (p<0.001, n=3). Interestingly, both the acute reaction to RTX infusions that manifest as a cytokine release syndrome and changes in effector cell function peaked during the first hours of the RTX infusion. We hypothesized that this might be due to the process of CD20 shaving, a rapid and pronounced decrease of CD20 cell surface expression modeled in-vitro and in mice as the result of a mechanism called trogocytosis that relies on the direct and rapid exchange of cell membrane fragments and associated molecules between effectors and target cells (Beum, J Immunol, 2008). First, we used western blot analysis of total CD20 protein in CLL cells and found a rapid loss of CD20 that was apparent already at 2h resulting in virtually complete loss of expression at 24h. Next, we used ImageStream technology to directly visualize ADCC interactions in-vivo. We indeed detected transfer of CD20 from CLL cells to NK cells and monocytes, resulting in complete CD20 loss in circulating CLL cells. While we detected transfer of CD20 into both cell types, monocytes were much more engaged in trogocytosis than NK cells. Consistently, 4h post RTX infusion we found a significant increase in intracellular RTX in granulocytes and monocytes using intracellular staining for human IgG. CD20 shaving appears to be of particular importance given that immunohistochemical analyses revealed that persistent disease in the bone marrow aspirates after 4 cycles of RTX treatment was mostly CD20 negative. Collectively, our results identify loss of CD20 from CLL cells by trogocytosis and exhaustion of immune effector mechanisms as limitations for anti-CD20 immunotherapy. These data identify possible avenues for improving CD20 mediated immunotherapy and characterize endpoints on which different anti-CD20 antibodies can be compared. Given that trogocytosis appears to be a common occurrence our findings likely have general importance to immunotherapy of hematologic malignancies. Disclosures No relevant conflicts of interest to declare.

scholarly journals In Vitro and In Vivo Characterization of CD19/CD3 Tandab AFM11 and CD19/CD16A Tandab AFM12 Targeting NHL

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2763-2763
Author(s):  
Xing Zhao ◽  
Narendiran Rajasekaran ◽  
Uwe Reusch ◽  
Michael Weichel ◽  
Kristina Ellwanger ◽  
...  
Keyword(s):  
T Cell ◽  
Target Cell ◽  
Binding Sites ◽  
Effector Cell ◽  
Nk Cell ◽  
Target Cells ◽  
Tumor Target ◽  
Effector Cells

Abstract Introduction: CD19 is expressed by B cells from early development through differentiation into plasma cells, and represents a validated target for the development of therapeutic antibodies to treat B cell malignancies such as Non Hodgkin Lymphoma (NHL) and acute lymphoblastic leukemia (ALL). Different CD19-targeting T-cell engagers are investigated in clinical studies for the treatment of NHL or ALL, including Affimed's AFM11, a bispecific CD19/CD3 TandAb antibody, which is currently investigated in a phase 1 dose escalation study. Indeed, Affimed's bispecific tetravalent platform comprises not only T-cell engaging TandAbs with two binding sites for CD3, but also NK-cell recruiting TandAbs with two binding sites for CD16A. In the present study, Affimed's AFM11, was characterized and compared in in vitro and in vivo studies with the CD19/CD16A TandAb AFM12. Methods: Analogous to the CD19/CD3 TandAb AFM11, a bispecific tetravalent TandAb AFM12 was constructed with two binding sites for CD19 and two sites for CD16A. Both TandAbs were characterized side by side for their biophysical properties, binding affinities to CD19+ tumor target cells and to their respective effector cells by flow cytometry. Kinetics and dose-response characteristics were evaluated in in vitro cytotoxicity assays. Potency and efficacy of both TandAbs were compared on different CD19+ tumor target cell lines using primary human effector cells. To compare the efficacy of AFM11 and AFM12 a patient-derived tumor xenograft model was developed. Results: AFM12 mediated efficacious target cell lysis with a very fast on-set in vitro. Lysis induced by AFM11 was less efficacious (lower specific lysis than AFM12) but reproducibly more potent (lower EC50 value). In addition to the potency and efficacy of AFM11 and AFM12, different aspects of safety, such as effector cell activation in the presence and absence of target cells were investigated and will be described. Conclusions: Affimed's CD19/CD3 and CD19/CD16A TandAbs with identical anti-CD19 tumor-targeting domains but different effector cell-recruiting domains represent interesting molecules to study T-cell- or NK-cell-based immunotherapeutic approaches. The comparison of AFM11 and AFM12 demonstrated that AFM12-mediated lysis was fast and efficacious, whereas AFM11 showed a higher potency. In summary, the NK-cell recruiting TandAb AFM12 represents an alternative to T-cell recruiting molecules, as it may offer a different side effect profile, comparable to that of AFM13, the first NK-cell TandAb clinically investigated. Disclosures No relevant conflicts of interest to declare.

Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies

Blood ◽  
2005 ◽  
Vol 105 (8) ◽  
pp. 3058-3065 ◽  
Author(s):  
Robert Z. Orlowski ◽  
Peter M. Voorhees ◽  
Reynaldo A. Garcia ◽  
Melissa D. Hall ◽  
Fred J. Kudrik ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Liposomal Doxorubicin ◽  
Phase 1 ◽  
Pegylated Liposomal Doxorubicin ◽  
Complete Response ◽  
Hematologic Malignancies ◽  
Maximum Tolerated Dose ◽  
Chemotherapeutic Agents

Abstract Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.

Engineered anti-CD70 antibody with multiple effector functions exhibits in vitro and in vivo antitumor activities

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 1185-1192 ◽  
Author(s):  
Julie A. McEarchern ◽  
Ezogelin Oflazoglu ◽  
Leigh Francisco ◽  
Charlotte F. McDonagh ◽  
Kristine A. Gordon ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Hematologic Malignancies ◽  
Effector Cells ◽  
Effector Functions ◽  
Normal Tissues ◽  
Non Hodgkin Lymphoma ◽  
Human Igg1 ◽  
Constant Domains

Abstract Antigens expressed on malignant cells in the absence of significant expression on normal tissues are highly desirable targets for therapeutic antibodies. CD70 is a TNF superfamily member whose normal expression is highly restricted but is aberrantly expressed in hematologic malignancies including non-Hodgkin lymphoma (NHL), Hodgkin disease, and multiple myeloma. In addition, solid tumors such as renal cell carcinoma, nasopharyngeal carcinoma, thymic carcinoma, meduloblastoma, and glioblastoma express high levels of this antigen. To functionally target CD70-expressing cancers, a murine anti-CD70 monoclonal antibody was engineered to contain human IgG1 constant domains. The engineered antibody retained the binding specificity of the murine parent monoclonal antibody and was shown to induce Fc-mediated effector functions including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis in vitro. Further, administration of this antibody significantly prolonged survival of severe combined immunodeficient (SCID) mice bearing CD70+ disseminated human NHL xenografts. Survival of these mice was dependent upon the activity of resident effector cells including neutrophils, macrophages, and natural killer (NK) cells. These data suggest that an anti-CD70 antibody, when engineered to contain human IgG1 constant domains, possesses effector cell–mediated antitumor activity and has potential utility for anticancer therapy.

scholarly journals Characterization of a humanized IgG4 anti-HLA-DR monoclonal antibody that lacks effector cell functions but retains direct antilymphoma activity and increases the potency of rituximab

Blood ◽  
2006 ◽  
Vol 108 (8) ◽  
pp. 2736-2744 ◽  
Author(s):  
Rhona Stein ◽  
Zhengxing Qu ◽  
Susan Chen ◽  
David Solis ◽  
Hans J. Hansen ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Effector Cell ◽  
Cell Functions ◽  
Hla Dr ◽  
Complement Dependent Cytotoxicity ◽  
Survival Pathway ◽  
Anti Cd20

AbstractHLA-DR is under investigation as a target for monoclonal antibody (mAb) therapy of malignancies. Here we describe a humanized IgG4 form of the anti-HLA-DR mAb L243, hL243γ4P (IMMU-114), generated to provide an agent with selectivity toward neoplastic cells that can kill without complement-dependent cytotoxicity (CDC) or antibody-dependent cellular-cytotoxicity (ADCC), so as to reduce reliance on intact immunologic systems in the patient and effector mechanism-related toxicity. In vitro studies show that replacing the Fc region of hL243γ1, a humanized IgG1 anti-HLA-DR mAb, with the IgG4 isotype abrogates the effector cell functions of the antibody (ADCC and CDC) while retaining its antigen-binding properties, antiproliferative capacity (in vitro and in vivo), and the ability to induce apoptosis concurrent with activation of the AKT survival pathway. Growth inhibition was evaluated compared with and in combination with the anti-CD20 mAb rituximab, with the combination being more effective than rituximab alone in inhibiting proliferation. Thus, hL243γ4P is indistinguishable from hL243γ1 and the parental murine mAb in assays dependent on antigen recognition. The abrogation of ADCC and CDC, which are believed to play a major role in side effects of mAb therapy, may make this antibody an attractive clinical agent. In addition, combination of hL243γ4P with rituximab offers the prospect for improved patient outcome.

scholarly journals BMS-936564/MDX-1338: A Fully Human Anti-CXCR4 Antibody Induces Apoptosis In Vitro and Shows Antitumor Activity In Vivo in Hematologic Malignancies

2012 ◽  
Vol 19 (2) ◽  
pp. 357-366 ◽  
Author(s):  
Michelle R. Kuhne ◽  
Tanya Mulvey ◽  
Blake Belanger ◽  
Sharline Chen ◽  
Chin Pan ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Hematologic Malignancies

scholarly journals Enavatuzumab, a Humanized Anti-TWEAK Receptor Monoclonal Antibody, Exerts Antitumor Activity through Attracting and Activating Innate Immune Effector Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Shiming Ye ◽  
Melvin I. Fox ◽  
Nicole A. Belmar ◽  
Mien Sho ◽  
Debra T. Chao ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Antitumor Activity ◽  
Tumor Cells ◽  
Tumor Xenograft ◽  
Immune Effector ◽  
Effector Cells ◽  
Innate Immune Effector ◽  
Receptor Monoclonal Antibody

Enavatuzumab is a humanized IgG1 anti-TWEAK receptor monoclonal antibody that was evaluated in a phase I clinical study for the treatment of solid malignancies. The current study was to determine whether and how myeloid effector cells were involved in postulated mechanisms for its potent antitumor activity in xenograft models. The initial evidence for a role of effector cells was obtained in a subset of tumor xenograft mouse models whose response to enavatuzumab relied on the binding of Fc of the antibody to Fcγ receptor. The involvement of effector cells was further confirmed by immunohistochemistry, which revealed strong infiltration of CD45+ effector cells into tumor xenografts in responding models, but minimal infiltration in nonresponders. Consistent with the xenograft studies, human effector cells preferentially migrated toward in vivo-responsive tumor cells treated by enavatuzumab in vitro, with the majority of migratory cells being monocytes. Conditioned media from enavatuzumab-treated tumor cells contained elevated levels of chemokines, which might be responsible for enavatuzumab-triggered effector cell migration. These preclinical studies demonstrate that enavatuzumab can exert its potent antitumor activity by actively recruiting and activating myeloid effectors to kill tumor cells. Enavatuzumab-induced chemokines warrant further evaluation in clinical studies as potential biomarkers for such activity.

scholarly journals Functional Characterization of Gamma Delta T Cells and Allogeneic Activated NK Cells As Effector Cells for Tafasitamab (MOR208)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3801-3801
Author(s):  
Jung Hyun Her ◽  
Dominik Pretscher ◽  
Sungyoo Cho ◽  
Yu-Kyeong Hwang ◽  
Timm Hoeres ◽  
...  
Keyword(s):  
T Cells ◽  
Combination Therapy ◽  
B Cell ◽  
Nk Cells ◽  
Effector Cell ◽  
Γδ T Cells ◽  
Target Cells ◽  
Effector Cells

Introduction Tafasitamab (MOR208) is an Fc-enhanced, humanized, monoclonal antibody that binds to the human B cell surface antigen CD19. CD19 is broadly and homogeneously expressed across different B cell malignancies, including diffuse large B cell lymphoma (DLBCL), and amplifies B cell receptor signaling and induces tumor cell proliferation. Tafasitamab is currently in clinical development in patients with relapsed or refractory DLBCL in combination with the immunomodulatory drug lenalidomide (L-MIND study) and the chemotherapeutic agent bendamustine (B-MIND study). The modes of action of tafasitamab comprise antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and direct cytotoxicity (apoptosis). Tafasitamab carries two amino acid exchanges in the Fc region to increase its affinity to Fcγ receptors, including FcγRIIIa. FcγRIIIa plays a key role in mediating ADCC and is expressed on the surface of natural killer (NK) cells, as well as the majority of γδ T cells. MG4101 (a novel therapeutic agent consisting of cryopreserved, ex vivo-expanded, highly activated NK cells) has demonstrated potent anticancer activity in preclinical in vitro and in vivo studies. Currently, MG4101 is in clinical development in patients with malignant lymphoma and advanced solid tumors. Here, we have characterized two FcγRIIIa receptor-expressing cell types, γδ T cells and NK cells (MG4101), as effector cells for tafasitamab in vitro and explored the concept of supplementing MG4101 during tafasitamab therapy using disseminated in vivo models of non-Hodgkin's lymphoma. Methods γδ T cells (CD3+/γδ T cell receptor+) were derived from different donors by stimulation of peripheral blood mononuclear cells with zoledronate/IL-2 for 9-10 days. These were applied as effector cells in in vitro ADCC assays with tafasitamab in Mino and Jeko-1 mantle cell lymphoma (MCL) cell lines, as well as primary patient-derived chronic lymphocytic lymphoma (CLL) and MCL cells. Further, effector cell activity of MG4101 was assessed using tafasitamab-mediated ADCC assays in Raji and Ramos Burkitt's lymphoma cells. The concept of combining tafasitamab with allogeneic effector cell therapy in vivo was studied in two therapeutic survival models of disseminated lymphoma in SCID mice. In the Raji model, tafasitamab (0.05 µg/mouse) was given on Day 1 after intravenous (IV) tumor inoculation, while MG4101 (2x107 cells/mouse) was given on Days 1, 3, 6, 8 and 10. In the Ramos model, tafasitamab (10 mg/kg) and MG4101 (2x107 cells/mouse) were applied twice weekly for 3 weeks starting on Days 3 and 4, respectively, after IV tumor inoculation. Results Tafasitamab in combination with γδ T cells showed distinctly increased ADCC in Mino and Jeko-1 target cells in vitro, compared with a negative control IgG1 antibody. ADCC assays with patient-derived CLL and MCL target cells confirmed tafasitamab-mediated cytotoxic activity and demonstrated a clear enhancement in activity compared with the non-Fc-enhanced version of tafasitamab that was unable to induce substantial cytotoxicity. In vitro ADCC assays with tafasitamab and MG4101 on Raji and Ramos cell lines confirmed potent effector cell activity of the ex vivo-expanded, cryopreserved, allogeneic NK cells. In the disseminated Raji survival model, combination therapy with a single low dose of tafasitamab (0.05 µg) and MG4101 resulted in a distinct increase in survival of the mice with an increased life span (ILS) of 100% compared with monotherapy (ILS of 57% for tafasitamab and 50% for MG4101). Of note, the combination demonstrated a substantial and more than additive enhancement in survival in the more therapeutic Ramos survival model (Figure 1). Combination therapy with tafasitamab (10 mg/kg) and MG4101 NK cells resulted in superior antitumor activity (ILS of 103%) compared with either tafasitamab monotherapy (ILS of 49%) or MG4101 alone (ILS of 25%). Conclusions FcγRIIIa-expressing immune cell types, including NK cells and γδ T cells, are potent effector cells for tafasitamab-mediated ADCC. Combination therapy with tafasitamab and allogeneic MG4101 NK cells in vivo demonstrated a more than additive survival benefit compared with tafasitamab or MG4101 monotherapy in a disseminated therapeutic lymphoma model. Combination of tafasitamab supplemented with immune effector cells could represent a promising new approach for lymphoma therapy. Disclosures Her: GC LabCell: Employment, Patents & Royalties. Cho:GC LabCell: Employment, Patents & Royalties. Hwang:GC LabCell: Employment, Equity Ownership, Patents & Royalties. Boxhammer:MorphoSys AG: Employment, Patents & Royalties. Steidl:MorphoSys AG: Employment. Patra:MorphoSys AG: Employment. Schanzer:MorphoSys AG: Employment. Endell:MorphoSys AG: Employment, Patents & Royalties.

scholarly journals Antitumor activity of anti-CD30 immunotoxin (Ber-H2/saporin) in vitro and in severe combined immunodeficiency disease mice xenografted with human CD30+ anaplastic large-cell lymphoma

Blood ◽  
1995 ◽  
Vol 85 (8) ◽  
pp. 2139-2146 ◽  
Author(s):  
L Pasqualucci ◽  
M Wasik ◽  
BA Teicher ◽  
L Flenghi ◽  
A Bolognesi ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cell Lymphoma ◽  
Severe Combined Immunodeficiency ◽  
Large Cell ◽  
Combined Immunodeficiency ◽  
Large Cell Lymphoma ◽  
Immunodeficiency Disease ◽  
Severe Combined Immunodeficiency Disease

To develop a novel adjunctive therapy for CD30 (Ki-1)+ anaplastic large-cell lymphoma (ALCL), we investigated in preclinical studies the antitumor activity of an immunotoxin (IT) constructed by coupling the plant ribosome-inactivating protein saporin (SO6) to the monoclonal antibody (MoAb) Ber-H2 that is directed against the CD30 molecule, a new member of the tumor necrosis factor receptor (TNFR) super-family. The activity of Ber-H2/SO6 IT was tested both in vitro against the CD30+ ALCL-derived cell line JB6 and in vivo using our severe combined immunodeficiency disease (SCID) mouse model of human xenografted CD30+ ALCL. In vitro, the Ber-H2/SO6 IT was selectively and highly toxic to the JB6 cell line [50% inhibiting concentration (IC50), 3.23 x 10(-12) mol/L as SO6]. In vivo, a 3-day treatment with nontoxic doses of Ber-H2/SO6 (50% of LD50) induced lasting complete remissions (CR) in 80% of mice when started 24 hours after tumor transplantation. In contrast, injection of the IT at later stages of tumor growth (mice bearing subcutaneous tumors of 40- to 60-mm3 volume), induced CR in only 6 of 21 (approximately 30%) mice and significantly delayed tumor growth rate (P < .01). This finding suggests that maximum effect of the anti-CD30 IT is observed when tumor cell burden is small. Persistent tumors from IT-treated mice consisted of CD30+ cells, thus excluding the possibility that selection of CD30-negative mutant clones during IT therapy was responsible for resistance to treatment. We conclude that Ber-H2/SO6 IT is an effective agent against CD30+ ALCL growing in SCID mice, suggesting its possible role as adjuvant therapy in patients with CD30+ ALCL refractory to standard treatments.

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