A comparative evaluation of conventional and pretargeted radioimmunotherapy of CD20-expressing lymphoma xenografts

Blood ◽  
2001 ◽  
Vol 98 (8) ◽  
pp. 2535-2543 ◽  
Author(s):  
Oliver W. Press ◽  
Melissa Corcoran ◽  
Krishnan Subbiah ◽  
Don K. Hamlin ◽  
D. Scott Wilbur ◽  
...  
Keyword(s):  
B Cell ◽  
Treatment Approach ◽  
Great Promise ◽  
B Cell Lymphomas ◽  
Marked Contrast ◽  
Hematopoietic Stem ◽  
Normal Organ ◽  
New Treatment ◽  
Anti Cd20 ◽  
Cell Support

Abstract Radioimmunotherapy with anti-CD20 monoclonal antibodies is a promising new treatment approach for patients with relapsed B-cell lymphomas. However, the majority of patients treated with conventional radiolabeled anti-CD20 antibodies eventually have a relapse because the low tumor-to-blood and tumor-to–normal organ ratios of absorbed radioactivity limit the dose that can be safely administered without hematopoietic stem cell support. This study assessed the ability of a streptavidin-biotin “pretargeting” approach to improve the biodistribution of radioactivity in mice bearing Ramos lymphoma xenografts. A pretargeted streptavidin-conjugated anti-CD20 1F5 antibody was infused, followed 24 hours later by a biotinylated N-acetylgalactosamine–containing “clearing agent” and finally 3 hours later by 111In-labeled DOTA-biotin. Tumor-to-blood ratios were 3:1 or more with pretargeting, compared with 0.5:1 or less with conventional 111In-1F5. Tumor-to–normal organ ratios of absorbed radioactivity up to 56:1 were observed with pretargeting, but were 6:1 or less with conventional 111In-1F5. Therapy experiments demonstrated that 400 μCi (14.8 MBq) or more of conventional 90Y-1F5 was required to obtain major tumor responses, but this dose was associated with lethal toxicity in 100% of mice. In marked contrast, up to 800 μCi (29.6 MBq)90Y-DOTA-biotin could be safely administered by the pretargeting approach with only minor toxicity, and 89% of the mice were cured. These data suggest that anti-CD20 pretargeting shows great promise for improving current therapeutic options for B-cell lymphomas and warrants further preclinical and clinical testing.

scholarly journals Monoclonal antibody 1F5 (anti-CD20) serotherapy of human B cell lymphomas

Blood ◽  
1987 ◽  
Vol 69 (2) ◽  
pp. 584-591 ◽  
Author(s):  
OW Press ◽  
F Appelbaum ◽  
JA Ledbetter ◽  
PJ Martin ◽  
J Zarling ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Lymph Node ◽  
B Cell ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
B Cell Lymphomas ◽  
Antigenic Modulation ◽  
Minor Response ◽  
High Doses ◽  
Anti Cd20

Abstract Four patients with refractory malignant B cell lymphomas were treated with continuous intravenous (IV) infusions of murine monoclonal antibody (MoAb) 1F5 (anti-CD20) over five to ten days. Dose-dependent levels of free serum 1F5 were detected in all patients. Two patients had circulating tumor cells and in both cases 90% of malignant cells were eliminated from the blood stream within four hours of initiation of serotherapy. Antigenic modulation did not occur, and sustained reduction of circulating tumor cells was observed throughout the duration of the infusions. Serial bone marrow aspirations and lymph node biopsies were examined by immunoperoxidase and immunofluorescence techniques to ascertain MoAb penetration into extravascular sites. High doses (100 to 800 mg/m2/d and high serum 1F5 levels (13 to 190 micrograms/mL) were required to coat tumor cells in these compartments in contrast to the low doses that were adequate for depletion of circulating cells. Clinical response appeared to correlate with dose of MoAb administered with progressive disease (52 mg), stable disease (104 mg), minor response (1,032 mg), and partial response (2,380 mg) observed in consecutive patients. The patient treated with the highest 1F5 dose achieved a 90% reduction in evaluable lymph node disease, but the duration of this remission was brief (six weeks). This study demonstrates that high doses of 1F5 can be administered to patients with negligible toxicity by continuous infusion and that clinical responses can be obtained in patients given greater than 1 g of unmodified antibody over a ten-day period.

High-Dose [131I]Tositumomab (anti-CD20) Radioimmunotherapy and Autologous Hematopoietic Stem-Cell Transplantation for Adults ≥ 60 Years Old With Relapsed or Refractory B-Cell Lymphoma

2007 ◽  
Vol 25 (11) ◽  
pp. 1396-1402 ◽  
Author(s):  
Ajay K. Gopal ◽  
Joseph G. Rajendran ◽  
Ted A. Gooley ◽  
John M. Pagel ◽  
Darrell R. Fisher ◽  
...  
Keyword(s):  
Older Adults ◽  
Stem Cell ◽  
B Cell ◽  
Therapeutic Option ◽  
B Cell Lymphoma ◽  
High Dose ◽  
High Dose Therapy ◽  
Hematopoietic Stem ◽  
Dose Therapy ◽  
Anti Cd20

Purpose The majority of patients with relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL) are older than 60 years, yet they are often denied potentially curative high-dose therapy and autologous stem-cell transplantations (ASCT) because of the risk of excessive treatment-related morbidity and mortality. Myeloablative anti-CD20 radioimmunotherapy (RIT) can deliver curative radiation doses to tumor sites while limiting exposure to normal organs and may be particularly suited for older adults requiring high-dose therapy. Patients and Methods Patients older than 60 years with relapsed B-cell NHL (B-NHL) received infusions of tositumomab anti-CD20 antibody labeled with 185 to 370 Mbq (5 to 10 mCi) [131I]-tracer for dosimetry purposes followed 10 days later by individualized therapeutic infusions of [131I]tositumomab (median, 19.4 Gbq [525 mCi]; range, 12.1 to 42.7 Gbq [328 to 1,154 mCi]) to deliver 25 to 27 Gy to the critical normal organ receiving the highest radiation dose. ASCT was performed approximately 2 weeks after therapy. Results Twenty-four patients with a median age of 64 years (range, 60 to 76 years), who had received a median of four prior regimens (range, two to 14 regimens), were treated. Thirteen patients (54%) had chemotherapy-resistant disease. The estimated 3-year overall and progression-free survival rates were 59% and 51%, respectively, with a median follow-up of 2.9 years (range, 1 to 6 years). All patients experienced expected myeloablation with engraftment of platelets (≥ 20 K/μL) and neutrophils (≥ 500/μL), occurring at a median of 9 and 15 days after ASCT, respectively. There were no treatment-related deaths, and only two patients experienced grade 4 nonhematologic toxicity. Conclusion Myeloablative RIT and ASCT is a safe and effective therapeutic option for older adults with relapsed B-NHL.

Ublituximab (TGTX-1101), a Novel, Third-Generation Anti-CD20 Antibody Demonstrates Enhanced Antitumor Activity Compared to Rituximab in Primary CNS and Intraocular Lymphoma Murine Models.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2755-2755
Author(s):  
Sabrina Donnou ◽  
Rym Ben Abdelwahed-Bagga ◽  
Jérémie Cosette ◽  
Hanane Ouakrim ◽  
Lucile Crozet ◽  
...  
Keyword(s):  
B Cell ◽  
Tumor Cells ◽  
Antitumor Effect ◽  
Intraocular Lymphoma ◽  
Third Generation ◽  
Tumor Site ◽  
Murine Models ◽  
B Cell Lymphomas ◽  
Cd20 Antibody ◽  
Anti Cd20

Abstract Abstract 2755 Background: Primary Central Nervous lymphomas (PCNSL), that comprise primary cerebral lymphoma (PCL) and primary intraocular lymphoma (PIOL), are typically CD20+ diffuse large B-cell lymphomas that have no detectable disease outside the brain or eye. Rituximab (RTX), an anti-CD20 antibody, has demonstrated encouraging clinical benefit in systemic B-cell lymphomas as well as PCL and PIOL, however, the role of RTX in treatment of PCNSL/PIOL remains controversial, and these highly aggressive malignancies are often incurable with available therapies. Therefore, additional treatment options are needed. Ublituximab (UTX) is a novel, glycoengineered chimeric anti-CD20 monoclonal antibody (mAb) that has a high affinity for FcγRIIIa (CD16) receptors, and therefore greater ADCC activity than RTX (Le Garff-Tavernier et al., 2011). Herein, we assess the antitumor effects of UTX compared to RTX in murine models of PCL and PIOL. Methods: The murine lymphoma B-cell line A20.IIA-GFP-hCD20 (H-2d) was injected into the right cerebral striatum (PCL model) or the vitreous (PIOL model) of adult BALB/c mice (H-2d); 7 days later, single doses of UTX were injected either into the tumor site intracerebrally (PCL) or intravitreously (PIOL), or at distance of the tumor site (intrathecally, PCL). RTX was used as a reference compound. Survival was monitored for injected mice for up to 100 days, and flow cytometric analyses were performed to assess tumor growth and T-cell infiltration. Results: In PCL and PIOL models, single doses of UTX had a marked antitumor effect more pronounced than that obtained with an equivalent dose of RTX. In the PCL model, there was an overall survival (OS) advantage with intracerebral injections of UTX compared to RTX (50% vs. 10%, n=10 in each group, p=0.0028). The reduction in tumor cells was correlated with an increased proportion of CD8+ T cells. Moreover, intrathecal injections of UTX increased OS compared to buffer solution. In the PIOL model, the absolute number of tumor cells analyzed 8 days after treatment had decreased more significantly (p=0.027) with UTX compared to the RTX group. This finding again confirmed the superiority of UTX in this setting. Conclusions: These results confirm that the novel, third-generation mAb, UTX has a sustained and greater antitumor effect than RTX on primary cerebral and intraocular lymphomas when assessed in vivo. Additional experiments evaluating the combination of UTX + methotrexate are ongoing. Clinical trials to evaluate UTX as an innovative therapeutic approach to treat primary cerebral and intraocular B-cell lymphomas are currently being evaluated. Disclosures: Jacquet: LFB Biotechnologies: Employment. Fridman:LFB Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Urbain:LFB Biotechnologies: Employment.

Tandem HD-chemotherapy and myeloablative radioimmunotherapy with 131I-anti-CD20 rituximab in relapsed and refractory B-cell lymphoma: Results of a phase II study of the German RAIT Study Group

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13007-13007 ◽  
Author(s):  
K. Hohloch ◽  
G. Wulf ◽  
W. Jung ◽  
E. Stitz ◽  
J. Meller ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Phase Ii Study ◽  
B Cell Lymphoma ◽  
Response Rates ◽  
Low Grade ◽  
Severe Toxicity ◽  
B Cell Lymphomas ◽  
Anti Cd20

13007 Background: Radioimmunotherapy has been shown to be effective in CD20 + B-cell lymphomas. Both non-myeloablative as well as myeloablative regimens have been employed for low grade and high grade lymphomas with impressive response rates and remission durations. Recently, the Press group and our group published data on myeloablative 131-I-anti-CD20 RAIT with high response rates and favourable long term survival especially in follicular lymphomas and transformed FL. Therefore, a phase II study is currently being done within the German Radioimmunotherapy Group, interim analysis data are presented. Methods: Patients were to receive R-Dexa-BEAM, followed by BEAM and HD-RAIT 2–6 months after BEAM. 131-I-Rituximab was administered with a maximum kidney and lung dose of 25 Gy. Sample size was calculated to be 16 to evaluate toxicity and feasibility of the tandem approach as primary endpoint. Results: 16 pts with relapsed (14) or primary refractory (2) B-cell lymphomas (FLI,II: 4pts; DLBCL: 4pts (all early relapses); transformed FL: 6 pts; MCL:1 pt, marginal zone lymphoma: 1 pt) were treated with 1 (15 pts) or 2 cycles (1 pt) of R-Dexa-BEAM. 13/16 pts achieving PR (5) or CRu (8) were treated with BEAM, 2 pts with PD and 1 with subdural hematoma were drop outs. After BEAM, 9/13 pts were in CR, 3/13 PR, 1/13 PD. Of 12 responding pts, 6 received HD-RAIT (1 pancytopenia, 1 hepatic, 2 pulmonary toxicity, 3 too early). After HD RAIT, 5/6 pts were in CR, 1 in PR. 4/6 pts (3 CR, 1 PR) are alive for 22–31 months, 2 pts died in CR, 1 of interstitial lung disease 2 months after HD-RAIT, 1 pt of pneumonia 8 months after HD-RAIT. Conclusions: Myeloablative RAIT is a feasible and effective treatment modality for relapsed poor prognosis CD20+ B-NHL not having severe toxicity due to the salvage regimen and HD-chemotherapy. HD RAIT offers the potential for long term relapse free survival. Final analysis of toxicity and outcome of this phase II study will be presented at the meeting. No significant financial relationships to disclose.

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