The tumour-targeting human L19-IL2 immunocytokine: Preclinical safety studies, phase I clinical trial in patients with solid tumours and expansion into patients with advanced renal cell carcinoma

Johannsen, Manfred; Spitaleri, Gianluca; Curigliano, Giuseppe; Roigas, Jan; Weikert, Steffen; Kempkensteffen, Carsten; Roemer, Andreas; Kloeters, Christian; Rogalla, Patrik; Pecher, Gabriele; Miller, Kurt; Berndt, Alexander; Kosmehl, Hartwig; Trachsel, Eveline; Kaspar, Manuela; Lovato, Valeria; González-Iglesias, Reinerio; Giovannoni, Leonardo; Menssen, Hans D.; Neri, Dario; Braud, Filippo de

doi:10.1016/j.ejca.2010.07.033

Cited by 162 publications

(147 citation statements)

References 22 publications

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“…In contrast with MDSCs, no prognostic role of Tregs was observed in what is thus far the largest study of patients with advanced melanoma published recently (38). Moreover, a sustained increase in the frequency and absolute count of lymphocytes (mainly of the CD4 þ T cells) and the temporary increase of NK cell count was observed here, as previously reported for IL2-based treatments (20). The analysis of NY-ESO-1-and Melan-A-specific T cells, for which a strong prognostic impact was previously demonstrated by our group in stage IV patients (31), was inconclusive in this trial.…”

Section: Discussionsupporting

confidence: 59%

“…The effect could be obtained only in immunocompetent mice (but not in nude mice), indicating the requirement of T cells for the complete eradication of tumors. Both of these therapeutic agents have been extensively studied individually in clinical trials (20,21,47,48), and the antigen recognized by the L19 antibody has an identical sequence in mice and humans. These findings provided a rationale for a combination trial in melanoma, which is currently ongoing.…”

Section: Discussionmentioning

confidence: 99%

“…L19-IL2 has already been studied in many preclinical models, and in patients, in phase I monotherapy studies of renal cell carcinoma (20) or in combination with dacarbazine in metastatic melanoma (21), with encouraging results.…”

Section: Introductionmentioning

confidence: 99%

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Intralesional Treatment of Stage III Metastatic Melanoma Patients with L19–IL2 Results in Sustained Clinical and Systemic Immunologic Responses

Weide¹,

Eigentler²,

Pflugfelder³

et al. 2014

Cancer Immunology Research

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L19-IL2 is a recombinant protein comprising the cytokine IL2 fused to the single-chain monoclonal antibody L19. In previous studies, intralesional injection with IL2 has shown efficacy for the locoregional treatment of cutaneous/subcutaneous metastases in patients with advanced melanoma. The objectives of this study were to investigate whether (i) intralesional delivery of a targeted form of IL2 would yield similar results, with reduction of injection frequency and treatment duration; and (ii) systemic immune responses were induced by the local treatment. Patients with stage IIIB/IIIC melanoma and cutaneous/subcutaneous injectable metastases received weekly intratumoral injections of L19-IL2 at a maximum dose of 10 MIU/week for 4 consecutive weeks. Tumor response was evaluated 12 weeks after the first treatment. Twenty-four of 25 patients were evaluable for therapyinduced responses. A complete response (CR) by modified immune-related response criteria (irRC) of all treated metastases was achieved in 6 patients (25%), with long-lasting responses in most cases (5 patients for !24 months). Objective responses were documented in 53.9% of all index lesions [44.4% CR and 9.5% partial responses (by irRC)], and 36.5% of these remained stable, while 9.5% progressed. Toxicity was comparable with that of free IL2, and no serious adverse events were recorded. A significant temporary increase of peripheral regulatory T cells and natural killer cells, sustained increase of absolute CD4 þ lymphocytes, and decrease of myeloid-derived suppressor cells were observed upon treatment. Finally, we recorded encouraging data about the progression time to distant metastases and overall survival. Cancer Immunol Res; 2(7); 668-78. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

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Intralesional Treatment of Stage III Metastatic Melanoma Patients with L19–IL2 Results in Sustained Clinical and Systemic Immunologic Responses

Weide¹,

Eigentler²,

Pflugfelder³

et al. 2014

Cancer Immunology Research

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“…Other L19-based immunotherapeutics are currently being developed clinically (L19-IL2 and L19-TNF) and have shown good tolerability and promising first signs of activity in cancer patients with metastases (47,48). In the future, PET scans with 124 I-L19SIP described here may be useful to preselect patients who are ideally suited to receive treatment with L19-based immunocytokines, based on the observation of preferential antibody uptake in tumor lesions.…”

Section: Discussionmentioning

confidence: 99%

Radretumab Radioimmunotherapy in Patients with Brain Metastasis: A 124I-L19SIP Dosimetric PET Study

Poli

Bianchi

Virotta

et al. 2013

Cancer Immunology Research

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Radioimmunotherapy (RIT) with 131 I-labeled L19SIP (radretumab; a small immunoprotein format antibody directed against the ED-B domain of fibronectin; $80 kDa molecular weight) has been investigated in several clinical trials. Here, we describe the use of immuno-PET imaging with iodine-124 ( 124 I)-labeled L19SIP to predict doses delivered to tumor lesions and healthy organs by a subsequent radretumab RIT in patients with brain metastases from solid cancer. Bone marrow doses were evaluated both during the diagnostic phase and posttherapy, measuring activities in blood (germanium detector) and whole body (lanthanum bromide detector). Expected doses for radretumab administration (4,107 MBq/m 2 ) were calculated from data obtained after administration of an average of 167 MBq 124 I-L19SIP to 6 patients. To assess lesion average doses, the positron emission tomography (PET) scanner was calibrated for the use of 124 I with an International Electrotechnical Commission (IEC) Body Phantom and recovery coefficients were calculated. The average dose to bone red marrow was 0.21 Gy/GBq, with high correlation between provisional and actual posttherapy doses. Although the fraction of injected activity in normal organs was similar in different patients, the antibody uptake in the neoplastic lesions varied by as much as a factor of 60. Immuno-PET with 124 I-labeled L19SIP offers significant advantages over conventional 131 I imaging, in particular accuracy of dosimetric results. Furthermore, the study indicates that antibody uptake can be highly variable even in different lesions of the same patient and that immuno-PET procedures may guide product development with armed antibodies. Cancer Immunol Res; 1(2); 134-43. Ó2013 AACR.

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“…In the absence of RT, tumors ultimately progressed. 22 In addition, the combination of RT and L19 (a small-immunoprotein with immunostimulatory effects 23,24 targeting extradomain-B [a marker of neoangiogenesis expressed on fibronectin with variable expression in different tumor types 25 ) linked with interleukin 2 (IL-2) has demonstrated the potential for synergy. In preclinical models, the coadministration of L19-IL2 with RT in C51 colon carcinoma cells (with high extradomain-B expression) was synergistic, with lesser effects in tumor types that had lower extradomain-B expression.…”

Section: Immunologic Effects Of Rtmentioning

confidence: 99%

Irradiation and immunotherapy: From concept to the clinic

Salama

Postow

Salama

2016

Cancer

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In recent years, an increased understanding of T‐cell–regulatory mechanisms has led to the development of a novel class of immune‐checkpoint inhibitors that have robust clinical activity against a broad array of malignancies—even those that historically were not believed to be sensitive to immune therapy. With this, there has been renewed interest in the potential for synergy with more traditional forms of anticancer therapy like radiation therapy (RT). The role of RT in palliation or as definitive treatment for certain malignancies has been well established. Yet, in recent years, the concept has come to light that RT could be an attractive partner for use in combination with other immunotherapies. The effects of RT include not only control of an irradiated tumor but also multiple immunomodulatory effects on both the tumor and the microenvironment, priming tumors for an immune‐mediated response. Herein, the authors summarize relevant preclinical data and rationale supporting the synergy of combined RT and immunotherapy and highlight recent clinical work on promising combination strategies. Cancer 2016;122:1659‐71. © 2016 American Cancer Society.

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The tumour-targeting human L19-IL2 immunocytokine: Preclinical safety studies, phase I clinical trial in patients with solid tumours and expansion into patients with advanced renal cell carcinoma

Cited by 162 publications

References 22 publications

Intralesional Treatment of Stage III Metastatic Melanoma Patients with L19–IL2 Results in Sustained Clinical and Systemic Immunologic Responses

Intralesional Treatment of Stage III Metastatic Melanoma Patients with L19–IL2 Results in Sustained Clinical and Systemic Immunologic Responses

Radretumab Radioimmunotherapy in Patients with Brain Metastasis: A 124I-L19SIP Dosimetric PET Study

Irradiation and immunotherapy: From concept to the clinic

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