Non-myeloablative Radioimmunotherapy for Non-Hodgkin’s Lymphoma

Schaefer-Cutillo, Julia; Friedberg, Jonathan W.

doi:10.1053/j.seminhematol.2008.02.009

Seminars in Hematology

2008

DOI: 10.1053/j.seminhematol.2008.02.009

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Non-myeloablative Radioimmunotherapy for Non-Hodgkin’s Lymphoma

Julia Schaefer-Cutillo

Jonathan W. Friedberg

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Cited by 13 publications

(11 citation statements)

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“…Two anti-CD20 IgGradioconjugates, 90 Y-ibritumomab tiuxetan (Zevalin) and 131 I-tositumomab (Bexxar), have been approved by the U.S. Food and Drug Administration for the treatment of relapsed/ refractory, indolent, or transformed B-cell NHL. Several studies have shown that radio-immunotherapy is well-tolerated, has the highest single-agent activity observed in lymphoma therapy, and can provide durable responses even in patients who had failed previous treatments, including rituximab therapy (9).…”

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confidence: 99%

Superior Antitumor Activity of SAR3419 to Rituximab in Xenograft Models for Non-Hodgkin's Lymphoma

Al‐Katib

Aboukameel

Mohammad³

et al. 2009

Clinical Cancer Research

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Purpose: To investigate the activity of SAR3419, a novel humanized anti-CD19 antibody (huB4), conjugated to a cytotoxic maytansine derivative N 2 '-deacetyl-N 2 '-(4-mercapto-4-methyl-1-oxopentyl) maytansine, in preclinical xenograft models for non-Hodgkin's lymphoma. Experimental Design: Antitumor activity of SAR3419 was assessed as a single agent and in comparison with conventional therapies using a subcutaneous model for diffuse large B-cell lymphoma (WSU-DLCL2) and a systemic model for follicular small cleaved cell lymphoma (WSU-FSCCL) in mice with severe combined immune deficiency. Results: Our results showed that in these chemotherapy-resistant models, SAR3419 was more effective than CHOP (cyclophosphamide-Adriamycin-vincristine-prednisone) regimen or rituximab. Only treatment with SAR3419 led to survival of the whole group of animals to the end of the experiment (150-155 days) in both models. Higher doses of SAR3419 (15 and 30 mg/kg) were more effective than lower dose of 7.5 mg/kg. The immunoconjugation was necessary because neither huB4 nor DM4 alone had significant activity. Treatment with rituximab resulted in antitumor activity in both models comparable with the low dose of SAR3419. Cyclophosphamide-Adriamycin-vincristineprednisone alone showed modest activity in both models. Necropsy and tissue staining in the WSU-FSCCL systemic model revealed that all deaths featured leptomeningeal lymphoma in the control and treated groups. Interestingly, some of the animals that survived to the end of the experiment and seemed healthy at time of euthanasia did show microscopic evidence of lymphoma. Conclusions: Overall, SAR3419 is a very active immunotoxin in preclinical models for human B-cell lymphoma and holds promise as a novel and well-tolerated therapy in B-cell non-Hodgkin's lymphoma.

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confidence: 99%

Superior Antitumor Activity of SAR3419 to Rituximab in Xenograft Models for Non-Hodgkin's Lymphoma

Al‐Katib

Aboukameel

Mohammad³

et al. 2009

Clinical Cancer Research

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“…Ant i-CD20 antibodies are exceptionally good therapeutics for non-Hodgkin lymphoma (NHL), with both unlabeled and radiolabeled antibodies approved or being evaluated for frontline use (1)(2)(3)(4)(5). We and others have focused on pretargeted methods for delivery of radionuclides, because these treatments are less toxic and more effective than is direct radioimmunotherapy in animal models (6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

Pretargeted Versus Directly Targeted Radioimmunotherapy Combined with Anti-CD20 Antibody Consolidation Therapy of Non-Hodgkin Lymphoma

Sharkey¹,

Karacay²,

Johnson³

et al. 2009

J Nucl Med

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We determined whether therapeutic responses using a bispecific antibody that pretargeted 90 Y-hapten-peptide radioimmunotherapy or a directly radiolabeled, humanized, 90 Y-anti-CD20 IgG (veltuzumab) could be improved by combining these treatments with unlabeled humanized antibodies against CD22 (epratuzumab), CD74 (milatuzumab), or veltuzumab. Methods: Nude mice bearing established subcutaneous Ramos human Burkitt lymphoma were treated with antibodies alone or in combination with pretargeted radioimmunotherapy (PT-RAIT) or radioimmunotherapy, and tumor growth was monitored. Biodistribution studies examined the effect that predosing with unlabeled veltuzumab had on radioimmunotherapy and PT-RAIT targeting. Results: None of the unconjugated antibodies was effective against established and rapidly growing xenografts, but PT-RAIT, at approximately 30% of its maximum tolerated dose, and radioimmunotherapy alone, at its maximum tolerated dose, were able to arrest growth and even entirely ablate tumors in some animals. Only combinations with veltuzumab improved therapeutic responses, most significantly when a veltuzumab regimen (weekly, 1.0 mg followed by 3 · 0.5 mg) was initiated 1 wk after PT-RAIT or 90 Y-veltuzumab. Biodistribution data indicated that when unlabeled veltuzumab (1.0 or 0.25 mg) was administered in advance of the radiolabeled veltuzumab or bispecific antibody injection, tumor uptake was significantly reduced ( 111 In-veltuzumab, 47% and 25%, respectively; 111 In-hapten-peptide, 74% and 49%, respectively). Despite an approximately 50% decrease in radioactivity uptake in the tumor, antitumor responses were not diminished significantly for 90 Y-veltuzumab, and in the case of PT-RAIT responses were improved. However, higher amounts of predosed veltuzumab reduced the effects of PT-RAIT. Conclusion: These studies suggest that administering unlabeled anti-CD20 IgG therapy after the radioactivity dose provides the best efficacy and that the amount of unlabeled anti-CD20 IgG administered as a predose to anti-CD20-targeted radionuclide therapy should be minimized.

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“…Rituximab resistance is due to depletion of complement and effector cells, alteration in complement regulatory protein expression, polymorphisms in FcγRIIIa, selection of neoplastic cells expressing mutated or not expressing CD20 antigen [8]. In order to overtake these limitations different strategies have been exploited.The first strategy consists in the augment of Rituximab potency and efficacy by the conjugation to a radionuclide [9] A different strategy to improve the results obtained with Rituximab is based on the selection of new engineered anti-CD20 antibodies characterized by reduced immunogenicity and/or enhanced binding affinity for CD20 antigen and for the FcγRIIIa receptor on effector NK cells. A first group of engineered antibodies (also named second generation anti-CD20 mAbs) has been developed with the intent to reduce immunogenicity; it consists of humanised molecules, with murine portion restricted to only hypervariable regions, or fully human molecules (OFA, veltuzumab, and ocrelizumab).…”

mentioning

confidence: 99%

“…The first strategy consists in the augment of Rituximab potency and efficacy by the conjugation to a radionuclide [9] or a toxic compound, namely drug [10] or toxin [11]. Immunoconjugates can trigger neoplastic cell death through several pathways and their efficacy only minimally depends on CDC and ADCC.…”

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confidence: 99%

Novel Strategies to Improve Rituximab Efficacy in Non-Hodgkin's Lymphomas

Polito¹

2015

Glob J Cancer Ther

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005eertechz thrombocytopenia, hypotension, anemia, bronchospasm, urticaria, headache, abdominal pain, and arrhythmia. These adverse reactions were usually reversible with appropriate treatment. Only rare cases of death were reported [7].Despite the great therapeutic value of Rituximab, many treated patients relapse or become resistant after treatment. Rituximab resistance is due to depletion of complement and effector cells, alteration in complement regulatory protein expression, polymorphisms in FcγRIIIa, selection of neoplastic cells expressing mutated or not expressing CD20 antigen [8]. In order to overtake these limitations different strategies have been exploited.The first strategy consists in the augment of Rituximab potency and efficacy by the conjugation to a radionuclide [9] A different strategy to improve the results obtained with Rituximab is based on the selection of new engineered anti-CD20 antibodies characterized by reduced immunogenicity and/or enhanced binding affinity for CD20 antigen and for the FcγRIIIa receptor on effector NK cells. A first group of engineered antibodies (also named second generation anti-CD20 mAbs) has been developed with the intent to reduce immunogenicity; it consists of humanised molecules, with murine portion restricted to only hypervariable regions, or fully human molecules (OFA, veltuzumab, and ocrelizumab). A second group (also named third generation anti-CD20 mAbs) consists of engineered antibodies with humanised CDR and modified Fc regions, to augment binding affinity for the FcRIIIa receptor and consequently ADCC (rhumAb v114, ocaratuzumab, obinutuzumab, TRU-015, EMAB-6) [2,4]. Most of these new mAbs are still in clinical trials and several positive results have been reported, despite their complete clinical potential has not been yet exploited.Certainly, the availability of a panel of human anti-CD20 mAbs EditorialNon-Hodgkin's lymphomas (NHLs) are the second fastest growing cancer in terms of incidence and deaths in the United States and Europe. NHLs are a heterogeneous cancer group including several haematological neoplasias with different degree of aggressiveness. In spite of the progresses, conventional therapies do not ensure long-term survival [1]. The NHL patients, who have a poor life expectation, could take advantage from innovative therapeutic strategies, such as immunotherapy. Specific antibodies can preferentially bind tumour cells over normal tissues. This specificity is based upon characteristics (surface antigens) that are completely independent from the parameters that allow for differential toxicity of chemo-and radiotherapy. The vascular nature of most lymphomas and their antigen expression make these tumours a favourable setting for treatment with monoclonal antibodies. In fact, the first successful use of antibodies as treatments for cancer was demonstrated in NHLs [2,3]. CD20 has been largely exploited as target antigen for immunotherapy with antibodies because it is expressed at high levels on B-lymphoma cells and is not expressed on stem c...

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Non-myeloablative Radioimmunotherapy for Non-Hodgkin’s Lymphoma

Cited by 13 publications

References 41 publications

Superior Antitumor Activity of SAR3419 to Rituximab in Xenograft Models for Non-Hodgkin's Lymphoma

Superior Antitumor Activity of SAR3419 to Rituximab in Xenograft Models for Non-Hodgkin's Lymphoma

Pretargeted Versus Directly Targeted Radioimmunotherapy Combined with Anti-CD20 Antibody Consolidation Therapy of Non-Hodgkin Lymphoma

Novel Strategies to Improve Rituximab Efficacy in Non-Hodgkin's Lymphomas

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