A Dose-Escalation and Signal-Generating Study of the Immunocytokine L19-IL2 in Combination with Dacarbazine for the Therapy of Patients with Metastatic Melanoma

Eigentler, Thomas; Weide, Benjamin; Braud, Filippo de; Spitaleri, Gianluca; Romanini, Antonella; Pflugfelder, Annette; González-Iglesias, Reinerio; Tasciotti, Annaelisa; Giovannoni, Leonardo; Schwager, Kathrin; Lovato, Valeria; Kaspar, Manuela; Trachsel, Eveline; Menssen, Hans D.; Neri, Dario; Garbe, Claus

doi:10.1158/1078-0432.ccr-11-1203

Cited by 137 publications

(121 citation statements)

References 41 publications

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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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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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“…[10][11][12] In particular, we have used the F8, L19 and F16 antibodies 10,13,14 for the development of armed antibodies, some of which have begun clinical testing in oncology and in rheumatology. 15,16 The tumor targeting properties of these antibodies have been documented in mouse models of cancer and in patients. The F8 and L19 antibodies (specific to the alternativelyspliced EDA and EDB domain of fibronectin, respectively) are particularly suitable for in vivo pharmacodelivery applications, as they recognize their cognate antigen in mouse and man with identical affinity.…”

mentioning

confidence: 99%

The antibody‐based targeted delivery of interleukin‐4 and 12 to the tumor neovasculature eradicates tumors in three mouse models of cancer

Hemmerle

Neri

2013

Intl Journal of Cancer

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Preclinical studies with recombinant murine interleukin 4 (IL4) in models of cancer have shown potent tumor growth inhibition. However, systemic administration of human IL4 to cancer patients exhibited modest antitumor activity and considerable toxicities. To improve the therapeutic index and reduce side effects of this cytokine, we developed of a novel "immunocytokine" based on sequential fusion of murine IL4 with the antibody fragment F8 (specific to the alternatively spliced extra-domain A of fibronectin, a marker for tumor-angiogenesis) in diabody format. The resulting fusion protein, termed F8-IL4, retained full antigen-binding activity and cytokine bioactivity and was able to selectively localize on solid tumors in vivo. When used as single agent, F8-IL4 inhibited tumor growth in three different immunocompetent murine cancer models (F9 teratocarcinoma, CT26 colon carcinoma and A20 lymphoma). Furthermore, F8-IL4 showed synergistic effects when coadministered with immunocytokines based on IL2 and IL12. Indeed, combination therapy with an IL12-based immunocytokine yielded complete tumor eradication, in spite of the fact that IL4 and IL12 display opposite immunological mechanisms of action in terms of their polarization of T-cell based responses. No weight loss or any signs of toxicity were observed in treated mice, both in monotherapy and in combination, indicating a good tolerability of the immunocytokine treatment. Interestingly, mice cured from CT26 tumors acquired a durable protective antitumor immunity. Depletion experiments indicated that the antitumor activity was mediated by CD81 T cells and by NK cells.Cytokines are potent modulators of the activity of the immune system, which can be used for therapeutic purposes. A number of cytokines (e.g., IL2, interferon-alpha and TNF) are frequently used for the treatment of cancer patients, but these agents can be toxic even at low doses (i.e., few milligrams), preventing the escalation to therapeutically active regimens.1 The antibody-based targeted delivery of cytokines ("immunocytokines") to the site of disease represents a promising avenue for increasing the therapeutic index of cytokine products, increasing activity and sparing normal organs.2 Proinflammatory immunocytokines (e.g., those based on IL2, IL12, IL15 and TNF) often display a potent antitumoral effect in mouse models of cancer.3-7 By contrast, antiinflammatory immunocytokines (e.g., those based on IL10) confer a therapeutic benefit in mouse models of chronic inflammatory conditions (rheumatoid arthritis and endometriosis 8,9 ) but have no impact on tumor growth (Trachsel and Neri, unpublished results).We have mainly used antibodies specific to splice-isoforms of fibronectin and of tenascin-C as vehicles for pharmacodelivery applications, as these antigens are virtually undetectable in the normal healthy adult (exception made for placenta, endometrium and some vessels in the ovaries) while being strongly expressed in the majority of solid tumors and lymphomas, with a prominent vascular staining p...

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“…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%

“…The median patient age was 68.4 years (range, 36.5-90.5 years). Most patients were treated in stage IIIC (21), and 4 patients were treated in stage IIIB. All metastases were accessible and injected in all patients.…”

Section: Patients and Treatmentsmentioning

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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A Dose-Escalation and Signal-Generating Study of the Immunocytokine L19-IL2 in Combination with Dacarbazine for the Therapy of Patients with Metastatic Melanoma

Cited by 137 publications

References 41 publications

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

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

The antibody‐based targeted delivery of interleukin‐4 and 12 to the tumor neovasculature eradicates tumors in three mouse models of cancer

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

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