P38 Radioimmunotherapy (RIT) of refractory or relapsed Hodgkin's lymphoma (HL) with 90Yttrium-labelled antiferritin antibody

Decaudin, Didier; Levy, Ronald; Lokiec, François; Madar, Olivier; Brossel, R.; Morschhauser, Franck; Songeur, Valentine; Djeridane, Malika; Kadouche, Jean; Pecking, A

doi:10.1016/s1359-6349(08)70053-3

Cited by 3 publications

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“…An alternative strategy has been to arm mAbs with radionuclides. Radioimmunotherapy using 90 Y-anti-ferritin and 131 I-anti-CD30 antibodies has resulted in partial (PRs) and CRs in HL (12)(13)(14)(15). Deficiencies with these approaches reflect the lack of tumor specificity of ferritin-targeted antibodies and the small number of CD30-expressing Reed-Sternberg cells in the tumor.…”

mentioning

confidence: 99%

⁹⁰Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma

Janik

Morris

O’Mahony

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Despite significant advances in the treatment of Hodgkin's lymphoma (HL), a significant proportion of patients will not respond or will subsequently relapse. We identified CD25, the IL-2 receptor alpha subunit, as a favorable target for systemic radioimmunotherapy of HL. The scientific basis for the clinical trial was that, although most normal cells with exception of Treg cells do not express CD25, it is expressed by a minority of Reed-Sternberg cells and by most polyclonal T cells rosetting around Reed-Sternberg cells. Forty-six patients with refractory and relapsed HL were evaluated with up to seven i.v. infusions of the radiolabeled anti-CD25 antibody 90 Y-daclizumab. 90 Y provides strong β emissions that kill tumor cells at a distance by a crossfire effect. In 46 evaluable HL patients treated with 90 Y-daclizumab there were 14 complete responses and nine partial responses; 14 patients had stable disease, and nine progressed. Responses were observed both in patients whose Reed-Sternberg cells expressed CD25 and in those whose neoplastic cells were CD25 − provided that associated rosetting T cells expressed CD25. As assessed using phosphorylated H2AX (γ-H2AX) as a bioindicator of the effects of radiation exposure, predominantly nonmalignant cells in the tumor microenvironment manifested DNA damage, as reflected by increased expression of γ-H2AX. Toxicities were transient bone-marrow suppression and myelodysplastic syndrome in six patients who had not been evaluated with bone-marrow karyotype analyses before therapy. In conclusion, repeated 90 Y-daclizumab infusions directed predominantly toward nonmalignant T cells rosetting around Reed-Sternberg cells provided meaningful therapy for select HL patients.T reatment with combination chemotherapy, radiation, and hematopoietic stem cell transplantation has increased the disease-free survival in Hodgkin's lymphoma (HL) from less than 5% in 1963 to more than 80% at present (1-6). Recently the US Food and Drug Administration approved brentuximab vedotin for the treatment of relapsed HL (7). Furthermore the anti-PD1 agent pembrolizumab has shown promising results in classic HL (8). Nevertheless, a significant fraction of patients do not respond to treatment or subsequently relapse. To date more than 30 different mAb preparations directed toward antigens expressed by malignant Reed-Sternberg cells have been studied (6). These include mAbs linked to drugs or toxins targeting CD25 or CD30 expressed on Reed-Sternberg cells (6-11). Brentuximab vedotin, an anti-CD30 antibody drug conjugate, has induced a significant number of responses in refractory HL (7, 11). Although other antibody immunotoxins have demonstrated some clinical efficacy, they have yielded few complete responses (CRs) (6, 9, 10). An alternative strategy has been to arm mAbs with radionuclides. Radioimmunotherapy using 90 Y-anti-ferritin and 131 I-anti-CD30 antibodies has resulted in partial (PRs) and CRs in HL (12-15). Deficiencies with these approaches reflect the lack of tumor specificity of ferritin-targ...

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confidence: 99%

⁹⁰Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma

Janik

Morris

O’Mahony

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The arming of monoclonal antibodies by linking them to cellular toxins or radionuclides is to target these agents specifically to tumors. 3,9,10,[12][13][14][15][16][17][18]23,[40][41][42][43][44][45][46][47][48][49][50] One advantage of the use of a radiolabeled monoclonal antibody conjugate for therapy over unmodified monoclonal antibodies or monoclonal antibodies linked to toxins is that with the appropriate choice of radionuclide radiolabeled antibodies can kill cells at a distance of several cell diameters and thereby make targets of the antigen-negative tumor cells adjacent to antigenexpressing normal cells.…”

Section: Discussionmentioning

confidence: 99%

“…Various monoclonal antibodies with different antigenic targets have been employed to deliver targeted RIT. 3,[14][15][16][17][18]23,[40][41][42][43][44][45][46][47][48][49][50] In an effort to evaluate RIT as part of the salvage regimen pre-ASCT, there have been a number of trials of 90 Y ibritumomab tiuxetan (Zevalin anti-CD20), followed by BEAM-conditioning regimen and autologous hematopoietic stem cell transplantation (ASCT) in relapsed and refractory high-risk B cell non-HL. In each of the studies, the combined use of RIT with BEAM plus autologous stem hematopoietic cell transplant was feasible with acceptable toxicity even in elderly and heavily pretreated patients.…”

Section: Discussionmentioning

confidence: 99%

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⁹⁰Y-Daclizumab (Anti-CD25), High-Dose Carmustine, Etoposide, Cytarabine, and Melphalan Chemotherapy and Autologous Hematopoietic Stem Cell Transplant Yielded Sustained Complete Remissions in 4 Patients with Recurrent Hodgkin's Lymphoma

Conlon

Sportès

Brechbiel

et al. 2020

Cancer Biotherapy and Radiopharmaceuticals

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Background: Despite advances in therapy of Hodgkin's lymphoma (HL), a proportion of patients will not respond or relapse. The authors had previously identified CD25, IL-2Ra, as a target for systemic radioimmunotherapy of HL since most normal cells do not express CD25, but it is expressed by a minority of Hodgkin/Reed-Sternberg (HRS) cells and most Tregs rosetting around HRS cells. Study Design and Treatment: This was a single institution, nonrandomized, open-label phase I/II trial of radiolabeled 90 Y-daclizumab, an anti-CD25 monoclonal antibody, BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning treatment followed by autologous hematopoietic stem cell transplant (ASCT). Four patients with refractory and relapsed HL were treated in this trial with 3 patients receiving a single dose of 564.6-574.6 MBq 90 Y-daclizumab and the fourth patient receiving two doses of 580.9-566.1 MBq 90 Y-daclizumab followed by high-dose chemotherapy and ASCT. Results: All 4 evaluable patients treated with 90 Y-daclizumab obtained complete responses (CRs) that are ongoing 4.5-7 years following their stem cell transplant. The spectrum and severity of adverse events were mild and more importantly none of the patients, including several with multiple therapies before this treatment, developed the myelodysplastic syndrome. Discussion: Targeting by daclizumab was not directed primarily at tumor cells, but rather the nonmalignant CD25-expressing T cells adjacent to the HRS cells and 90 Y-daclizumab provided strong enough b emissions to kill CD25-negative tumor cells at a distance by a crossfire effect. Furthermore, the strong b irradiation killed normal cells in the tumor microenvironment. Conclusions: 90 Y-daclizumab (anti-CD25), high-dose BEAM chemotherapy and ASCT was well tolerated and yielded sustained complete remissions in all 4 patients with recurrent HL patients who completed their treatment. Significance: Despite advances, a proportion of patients with HL will not have a CR to their initial treatment, and some with CRs will relapse. They demonstrated that the addition of 90 Y-daclizumab into the preconditioning

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“…This study suggests that the use of rituximab to deplete reactive B cells may potentially increase the host immune response against cHL, This observation has not been validated in patients receiving rituximab, however. Present in the interstitium of HRS cells Immunolabeled antiferritin antibodies [24][25][26] cHL classic Hodgkin lymphoma, HRS Hodgkin and Reed-Sternberg, NLPHL nodular lymphocyte-predominant Hodgkin lymphoma …”

Section: Introductionmentioning

confidence: 99%

Does Rituximab Have a Place in Treating Classic Hodgkin Lymphoma?

Oki

Younes

2010

Curr Hematol Malig Rep

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Monoclonal antibodies targeting surface proteins on the malignant Hodgkin and Reed-Sternberg (HRS) cells are currently under intensive investigation with promising early results. Of particular interest is the CD20 antigen, because it is expressed not only on a small fraction of HRS cells but also on the benign reactive B cells in the microenvironment. The rationale of using rituximab in classic Hodgkin lymphoma (cHL) comprises several points: 1) HRS cells infrequently express CD20; 2) elimination of CD20-positive reactive B cells supporting HRS cells would deprive the malignant cells of survival signals; 3) elimination of reactive B cells may also potentially increase host immune response against HRS cells; 4) HRS stem cells express CD20. Although this rationale has not generally been confirmed in patients, promising results in managing cHL have occurred in early-phase clinical trials of rituximab, including trials of rituximab as a single agent in refractory or recurrent cHL, rituximab plus gemcitabine in refractory or recurrent cHL, and rituximab plus ABVD in newly diagnosed cHL. Based on the results of these trials, several prospective clinical trials using rituximab in the management of advanced-stage cHL and early-stage cHL are ongoing. These trials further clarify the role of rituximab in cHL. Enrollment of patients with this "classic" disease in clinical trials is encouraged.

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P38 Radioimmunotherapy (RIT) of refractory or relapsed Hodgkin's lymphoma (HL) with 90Yttrium-labelled antiferritin antibody

Cited by 3 publications

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⁹⁰Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma

⁹⁰Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma

⁹⁰Y-Daclizumab (Anti-CD25), High-Dose Carmustine, Etoposide, Cytarabine, and Melphalan Chemotherapy and Autologous Hematopoietic Stem Cell Transplant Yielded Sustained Complete Remissions in 4 Patients with Recurrent Hodgkin's Lymphoma

Does Rituximab Have a Place in Treating Classic Hodgkin Lymphoma?

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P38 Radioimmunotherapy (RIT) of refractory or relapsed Hodgkin's lymphoma (HL) with 90Yttrium-labelled antiferritin antibody

Cited by 3 publications

References 0 publications

90Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma

90Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma

90Y-Daclizumab (Anti-CD25), High-Dose Carmustine, Etoposide, Cytarabine, and Melphalan Chemotherapy and Autologous Hematopoietic Stem Cell Transplant Yielded Sustained Complete Remissions in 4 Patients with Recurrent Hodgkin's Lymphoma

Does Rituximab Have a Place in Treating Classic Hodgkin Lymphoma?

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⁹⁰Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma

⁹⁰Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma

⁹⁰Y-Daclizumab (Anti-CD25), High-Dose Carmustine, Etoposide, Cytarabine, and Melphalan Chemotherapy and Autologous Hematopoietic Stem Cell Transplant Yielded Sustained Complete Remissions in 4 Patients with Recurrent Hodgkin's Lymphoma