Immunotherapy of metastatic melanoma by intratumoral injections of Vero cells producing human IL-2: Phase II randomized study comparing two dose levels

Rochlitz, Christoph; Dréno, Brigitte; Jantscheff, Peter; Cavalli, F.; Squiban, Patrick; Acres, Bruce; Baudin, Martine; Escudier, Bernard; Heinzerling, Lucie; Morant, Rudolf; Herrmann, Richard; Dietrich, Pierre‐Yves; Dummer, Reinhard

doi:10.1038/sj.cgt.7700441

Cited by 29 publications

(13 citation statements)

References 37 publications

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“…In addition, the coadministration of hIL-2 and hGM-CSF -producing xenogeneic cell, could convert the primary tumor destroyed by the SG into a tumor vaccine, 14,[17][18][19] as verified by the pronounced increase of immune cell infiltration after CT with respect to pretreatment biopsies (Figure 2).…”

Section: Local Combined Treatment Induced Immune Cell Infiltrationmentioning

confidence: 94%

Suicide gene and cytokines combined nonviral gene therapy for spontaneous canine melanoma

et al. 2008

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Canine spontaneous melanoma is a highly aggressive tumor resistant to current therapies. We evaluated the safety, efficacy and antitumor effects of direct intratumor injections of lipoplexes encoding herpes simplex thymidine kinase coadministrated with ganciclovir, and irradiated transgenic xenogeneic cells secreting 20-30 mg day À1 of human granulocyte-macrophage colonystimulating factor and interleukin-2. Toxicity was minimal or absent in all patients. This combined treatment (CT) induced tumor regression and a pronounced immune cell infiltration. The objective responses (47%: 21/45) averaged 80% of tumor mass loss. Local CT also induced systemic antitumor response evidenced by complete remission of one pulmonary metastasis and by the significantly higher percentage of metastasis-free patients (76: 34/45)) until the study ending compared to untreated (UC: 29%, 5/17), surgery-treated (CX: 48%, 11/23) or suicide gene-treated controls (SG: 56%, 9/16) (Fisher's exact test). CT significantly improved median survival time: 160 (57-509) days compared to UC (69 (10-169)), or ). CT also increased (Po0.00001, Kaplan-Meier analysis) metastasis-free survival: 4509 (57-509) days with respect to UC: 41 (10-169), CX: 133 (43-216) and SG: 4159 (41-159). Therefore, CT controlled tumor growth by delaying or preventing distant metastasis, thereby significantly extending survival and recovering the quality of life.

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Section: Local Combined Treatment Induced Immune Cell Infiltrationmentioning

confidence: 94%

Suicide gene and cytokines combined nonviral gene therapy for spontaneous canine melanoma

et al. 2008

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“…25 In addition, xenogeneic cells, release of the powerful IL-2 and GM-CSF synergy could promote a strong systemic immune response. [22][23][24][25][26] Evidence of SV efficacy was the remarkable increase in median overall survival of patients free of local disease (41312 days, n ¼ 49, Table 7) whose main difference from the SC group (78 days, n ¼ 51, Table 6) was the SV. In addition, SV succeeded in controlling the systemic disease by suppressing distant metastases in 78% of CT patients (Table 4) and delaying their appearance twofold in the remaining 22% (Table 5).…”

Section: Discussionmentioning

confidence: 99%

“…[22][23][24][25][26] In previous experiments, we demonstrated that subcutaneous injection of 3 million hIL-2-secreting CHO cells to healthy Balb/c mice weighing 30 g produced measurable seric hIL-2 for 72 h, with a peak of about 150 pg hIL-2 ml À1 at 48 h. Then, subcutaneously injected xenogeneic cells could easily last 3 days in dog patients. In addition, neither symptoms of acute xenograft rejection nor delayed-type hypersensitivity were observed during treatment.…”

Section: Discussionmentioning

confidence: 99%

Cytokine-enhanced vaccine and suicide gene therapy as surgery adjuvant treatments for spontaneous canine melanoma

Finocchiaro

Glikin

2007

Gene Ther

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We evaluated the safety, efficacy and anti-tumor effects of a surgery adjuvant treatment on canine patients with malignant melanoma. This approach combined suicide gene therapy with a subcutaneous vaccine composed by formolized tumor cells and irradiated xenogeneic cells producing human interleukin-2 and granulocyte-macrophage colony-stimulating factor. The post-surgical margin of the cavity was infiltrated with lipid-complexed thymidine kinase suicide gene coadministrated with ganciclovir. Toxicity was minimal or absent in all patients. With respect to surgery-treated controls (SC), this combined treatment (CT) significantly increased the fraction of patients local disease-free from 6 to 58% and distant metastases-free from 43 to 78% (Fisher's Exact test).In addition, CT significantly improved both SC overall 78 (23-540) and metastasis-free survival 112 (0-467) days to more than 1312 days (respective ranges: 43-1312 and 0-1312) (Kaplan-Meier analysis). In those patients subjected to partial surgery or presenting local recurrence, the efficacy of CT was verified by a 49% of objective responses that averaged 85% of tumor mass loss, while 22% displayed tumor progression as 94% of SC did. Therefore, surgery adjuvant CT controlled tumor growth, delaying or preventing post-surgical recurrence and distant metastasis, significantly extending survival and recovering the quality of life.

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“…28,29) and hGM-CSF [30][31][32] was administered. 16,[18][19][20] These whole tumor cell vaccines have the advantage of immunizing the patient with a broader array of tumor-associated antigens, increasing the likelihood of effective immunostimulation.…”

Section: Discussionmentioning

confidence: 99%

Cytokine-enhanced vaccine and suicide gene therapy as surgery adjuvant treatments for spontaneous canine melanoma: 9 years of follow-up

Finocchiaro

Glikin

2012

Cancer Gene Ther

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We present here the updated results after 9 years of the beginning of a trial on canine patients with malignant melanoma. This surgery adjuvant approach combined local suicide gene therapy with a subcutaneous vaccine composed by tumor cells extracts and xenogeneic cells producing human interleukin-2 and granulocyte-macrophage colony-stimulating factor. Toxicity was absent or minimal in all patients (0pVCOG-CTCAE gradep1). With respect to surgery-treated controls (ST), the complete surgery (CS) arm of this combined treatment (CT) significantly increased the fraction of local disease-free patients from 13 to 81% and distant metastases free from 32 to 84%. Even though less effective than the CS arm, the partial surgery (PS) arm of this CT was significantly better controlling the disease than only surgery (14% while PS-ST: 0%, Po0.01 and CS-ST: 5%, Po0.05). In addition, CT produced a significant sevenfold (CS) and threefold (PS) increase in overall survival. The CS-CT arm significantly improved both CS-ST metastasis-free-and melanoma overall survival from 99 days (respective ranges: 11-563 and 10-568) to 42848 days (81-2848 and 35-2848). Thus, more of 50% of our CT patients died of melanoma unrelated causes, transforming a lethal disease into a chronic one. Finally, surgery adjuvant CT delayed or prevented post-surgical recurrence and distant metastasis, significantly improved disease-free and overall survival maintaining the quality of life. Long-term safety and efficacy of this treatment are supported by the high number of CT patients (283) and extensive follow-up (49 years). The successful clinical outcome encourages the further translation of similar approaches to human gene therapy trials.

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Immunotherapy of metastatic melanoma by intratumoral injections of Vero cells producing human IL-2: Phase II randomized study comparing two dose levels

Cited by 29 publications

References 37 publications

Suicide gene and cytokines combined nonviral gene therapy for spontaneous canine melanoma

Suicide gene and cytokines combined nonviral gene therapy for spontaneous canine melanoma

Cytokine-enhanced vaccine and suicide gene therapy as surgery adjuvant treatments for spontaneous canine melanoma

Cytokine-enhanced vaccine and suicide gene therapy as surgery adjuvant treatments for spontaneous canine melanoma: 9 years of follow-up

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