Phase I Trial of Recombinant Immunotoxin RFB4(dsFv)-PE38 (BL22) in Patients With B-Cell Malignancies

Kreitman, Robert J.; Squires, David; Stetler‐Stevenson, Maryalice; Noël, Pierre; FitzGerald, David J.; Wilson, Wyndham H.; Pastan, Ira

doi:10.1200/jco.2005.11.437

Cited by 249 publications

(231 citation statements)

References 44 publications

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“…Targeted toxins have also shown promise in the clinic (Kreitman et al, 2005, 2009). Limitations that have been identified include biodistribution properties and chimeric toxin neutralizing antibodies (Weldon and Pastan, 2011).…”

Section: Discussionmentioning

confidence: 99%

EGFR‐targeted Chimeras of Pseudomonas ToxA released into the extracellular milieu by attenuated Salmonella selectively kill tumor cells

Quintero

Carrafa²,

Vincent³

et al. 2016

Biotech & Bioengineering

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Tumor-targeted Salmonella VNP20009 preferentially replicate within tumor tissue and partially suppress tumor growth in murine tumor models. These Salmonella have the ability to locally induce apoptosis when they are in direct contact with cancer cells but they lack significant bystander killing, which may correlate with their overall lack of antitumor activity in human clinical studies. In order to compensate for this deficiency without enhancing overall toxicity, we engineered the bacteria to express epidermal growth factor receptor (EGFR)-targeted cytotoxic proteins that are released into the extracellular milieu. In this study, we demonstrate the ability of the Salmonella strain VNP20009 to produce three different forms of the Pseudomonas exotoxin A (ToxA) chimeric with a tumor growth factor alpha (TGFα) which results in its producing culture supernatants that are cytotoxic and induce apoptosis in EGFR positive cancer cells as measured by the tetrazolium dye reduction, and Rhodamine 123 and JC-10 mitochondrial depolarization assays. In addition, exchange of the ToxA REDLK endoplasmic reticulum retention signal for KDEL and co-expression of the ColE3 lysis protein resulted in an overall increased cytotoxicity compared to the wild type toxin. This approach has the potential to significantly enhance the antitumor activity of VNP20009 while maintaining its previously established safety profile.

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Section: Discussionmentioning

confidence: 99%

EGFR‐targeted Chimeras of Pseudomonas ToxA released into the extracellular milieu by attenuated Salmonella selectively kill tumor cells

Quintero

Carrafa²,

Vincent³

et al. 2016

Biotech & Bioengineering

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“…Recently, monoclonal antibodies and immunotoxins have emerged as a useful strategy for patients who have relapsed or refractory HCL. [21][22][23][24][25] The real need is to maximize primary responses to prolong remissions. Patients who have a complete hematological remission are frequently found to have minimal residual disease by immunohistochemical and immunophenotypic studies.…”

Section: Discussionmentioning

confidence: 99%

Hairy cell leukemia

Zinzani

Pellegrini

Stefoni

et al. 2010

Cancer

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BACKGROUND: Historically, the first treatment choices for hairy cell leukemia (HCL) were splenectomy and alphainterferon. Recently, purine analogues (pentostatin and cladribine) changed radically the treatment modality, inducing complete and durable responses in the majority of patients. METHODS: The authors analyzed the outcome of different lines of therapy in 121 HCL patients followed in their institute from 1986 to 2008, with a median follow-up of 105 months. Patients were divided into subgroups according to the number of treatments; Group A included 121 patients who underwent a front-line therapy, Group B patients (n ¼ 53) were treated with 2 lines, Group C patients (n ¼ 34) with 3 lines, Group D patients (n ¼ 17) with 4 lines, and Group E patients (n ¼ 8) with 5 lines. RESULTS: In Group A, 92 (77%) patients obtained a complete response (CR), 23 (18%) a partial response, and the remaining 6 (5%) a minor or no response; median duration of response was 2.7 years. In Group B, 53 relapsed patients achieved a second CR rate of 73.5%; median duration of response was 2.5 years. Group C contained 34 patients in a second relapse, with a CR rate after the third line of treatment of 70.5% (median duration of response, 2.2 years). In Group D, 11 (64.7%) patients obtained a CR (median duration of response, 1.6 years), and in Group E 4 (50%) of 8 patients achieved a CR (median duration of response, 1.3 years). CONCLUSIONS: This study confirms the high risk (>40% of all patients) of retreatment of HCL patients and the need to maximize primary response. Cancer 2010;116:4788-92.

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“…Tremendous efforts have been made to create a potent PE-based immunotoxin owing to its great toxicity and since it can be expressed as a single chain in E. coli. Recently, Kreitman et al (2005) conducted a phase I trial of recombinant immunotoxin: an anti-CD22 Fv fragment fused to truncated PE . This immunotoxin targets B cells in advance stages of differentiation and can be used as a target for leukemia and lymphoma.…”

Section: Immunotoxinsmentioning

confidence: 99%

Novel antibodies as anticancer agents

2007

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In recent years antibodies, whether generated by traditional hybridoma technology or by recombinant DNA strategies, have evolved from Paul Ehrlich's 'magic bullets' to a modern age 'guided missile'. In the recent years of immunologic research, we are witnessing development in the fields of antigen screening and protein engineering in order to create specific anticancer remedies. The developments in the field of recombinant DNA, protein engineering and cancer biology have let us gain insight into many cancer-related mechanisms. Moreover, novel techniques have facilitated tools allowing unique distinction between malignantly transformed cells, and regular ones. This understanding has paved the way for the rational design of a new age of pharmaceuticals: monoclonal antibodies and their fragments. Antibodies can select antigens on both a specific and a high-affinity account, and further implementation of these qualities is used to target cancer cells by specifically identifying exogenous antigens of cancer cell populations. The structure of the antibody provides plasticity resonating from its functional sites. This review will screen some of the many novel antibodies and antibody-based approaches that are being currently developed for clinical applications as the new generation of anticancer agents.

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Phase I Trial of Recombinant Immunotoxin RFB4(dsFv)-PE38 (BL22) in Patients With B-Cell Malignancies

Abstract: BL22 was well tolerated and highly effective in HCL, even after one cycle. Phase II testing is underway to define the efficacy with one cycle and to study safety when additional cycles are needed for optimal response.

Cited by 249 publications

References 44 publications

EGFR‐targeted Chimeras of Pseudomonas ToxA released into the extracellular milieu by attenuated Salmonella selectively kill tumor cells

EGFR‐targeted Chimeras of Pseudomonas ToxA released into the extracellular milieu by attenuated Salmonella selectively kill tumor cells

Hairy cell leukemia

Novel antibodies as anticancer agents

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