Phase I/II Trial of Tremelimumab in Patients With Metastatic Melanoma

Camacho, Luis H.; Antonia, Scott; Sosman, Jeffrey A.; Kirkwood, John M.; Gajewski, Thomas F.; Redman, Bruce G.; Pavlov, Dmitri; Bulanhagui, C. A.; Bozón, Viviana; Gómez-Navarro, Jesús; Ribas, Antoni

doi:10.1200/jco.2008.19.2435

Cited by 287 publications

(207 citation statements)

References 23 publications

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“…Interestingly, 10mg/kg was the MTD identified in the first-in-human study of tremelimumab 9 and ultimately this dose was found to be more tolerable when dosed at a frequency of every 3 months. 10 We found no evidence that CP-870,893 aggravated tremelimumab-associated toxicity or vice versa, nor did a new spectrum of autoimmunity emerge.…”

Section: Discussionmentioning

confidence: 59%

“…Although each mAb has been tested separately and shown single-agent activity in patients with advanced melanoma, 7,8 the combination has not. Tremelimumab is a fully human IgG2 anti-CTLA-4 mAb that produced clinical activity 8-10 similar to ipilimumab, although it did not improve OS when compared to chemotherapy in a randomized phase III study. 8 CP-870,893 is a fully human IgG2 agonist mAb evaluated in a single-dose study, a weekly infusion study, and studies combining CP-870,893 with chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

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Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

et al. 2018

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We report long-term clinical outcomes and immune responses observed from a phase 1 trial of agonist CD40 monoclonal antibody (mAb) and blocking CTLA-4 mAb in patients with metastatic melanoma. Twenty-four patients previously untreated with checkpoint blockade were enrolled. The agonistic CD40 mAb CP-870,893 and the CTLA-4 blocking mAb tremelimumab were dosed concomitantly every 3 weeks and 12 weeks, respectively, across four dose combinations. Two patients developed dose-limiting grade 3 immune-mediated colitis that led to the definition of the maximum tolerated dose (MTD). Other immune-mediated toxicity included uveitis (n = 1), hypophysitis (n = 1), hypothyroidism (n = 2), and grade 3 cytokine release syndrome (CRS) (n = 1). The estimated MTD was 0.2 mg/kg of CP-870,893 and 10 mg/kg of tremelimumab. In 22 evaluable patients, the objective response rate (ORR) was 27.3%: two patients (9.1%) had complete responses (CR) and four (18.2%) patients had partial responses (PR). With a median follow-up of 45 months, the median progression-free survival (PFS) was 3.2 months (95% CI, 1.3–5.1 months) and median overall survival (OS) was 23.6 months (95% CI, 11.7–35.5 months). Nine patients are long-term survivors (> 3 years), 8 of whom subsequently received other therapy including PD-1 mAb, surgery, or radiation therapy. Elevated baseline soluble CD25 was associated with shorter OS. Immunologically, treatment was associated with evidence of T cell activation and increased tumor T cell infiltration that was accomplished without therapeutic PD-1/PD-L1 blockade. These results suggest opportunities for immune activation and cancer immunotherapy beyond PD-1.

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Section: Discussionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

et al. 2018

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“…Similarly, comparisons of growth rates of PAN02 tumors in different strains of mice were affected by the presence of lymphocytes and the amount of host Ido1 expression: tumor doubling is fastest in immunodeficient mice and slowest in Ido1 −/− mice. 2 These data also suggest that a lack of host Ido1 activity can, to some extent, impede tumor growth. Finally, we have shown that TILs are more prevalent and more active after treatment with an IDO1 inhibitor.…”

Section: Discussionmentioning

confidence: 81%

“…Suppressive mechanisms in place to rein in normal immune responses may be usurped by tumor cells to limit the effectiveness of antitumor responses (8). Interference with two of these, CTLA4 and the PD1/PDL1 axis, is currently being tested clinically and providing a similar low-frequency but durable benefit to patients (2,3,9). Another such mechanism under investigation is tryptophan depletion through enhanced indoleamine-2,3-dioxygenase (IDO) activity.…”

Section: Introductionmentioning

confidence: 99%

Hydroxyamidine Inhibitors of Indoleamine-2,3-dioxygenase Potently Suppress Systemic Tryptophan Catabolism and the Growth of IDO-Expressing Tumors

Koblish

Hansbury

Bowman

et al. 2010

Molecular Cancer Therapeutics

238

191

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Malignant tumors arise, in part, because the immune system does not adequately recognize and destroy them. Expression of indoleamine-2,3-dioxygenase (IDO; IDO1), a rate-limiting enzyme in the catabolism of tryptophan into kynurenine, contributes to this immune evasion. Here we describe the effects of systemic IDO inhibition using orally active hydroxyamidine small molecule inhibitors. A single dose of INCB023843 or INCB024360 results in efficient and durable suppression of Ido1 activity in the plasma of treated mice and dogs, the former to levels seen in Ido1-deficient mice. Hydroxyamidines potently suppress tryptophan metabolism in vitro in CT26 colon carcinoma and PAN02 pancreatic carcinoma cells and in vivo in tumors and their draining lymph nodes. Repeated administration of these IDO1 inhibitors impedes tumor growth in a dose-and lymphocyte-dependent fashion and is well tolerated in efficacy and preclinical toxicology studies. Substantiating the fundamental role of tumor cell-derived IDO expression, hydroxyamidines control the growth of IDO-expressing tumors in Ido1-deficient mice. These activities can be attributed, at least partially, to the increased immunoreactivity of lymphocytes found in tumors and their draining lymph nodes and to the reduction in tumor-associated regulatory T cells. INCB024360, a potent IDO1 inhibitor with desirable pharmaceutical properties, is poised to start clinical trials in cancer patients. Mol Cancer Ther; 9(2); 489-98.

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“…Thus, the effective and global coverage of metastatic cells represents a critical factor for optimizing therapeutic outcome. Although novel targeted therapies such as BRAF inhibitors (Yang et al, 2010) and anti-CTLA4 antibodies (Camacho et al, 2009) are showing promising results in melanoma clinical trials, resistance to these compounds and patient relapse are rapidly emerging (Poulikakos et al, 2010). Small interfering RNA-mediated therapies, such as targeting BCL2 with the antisense oligonucleotide Oblimersen (Jansen et al, 2000), also had limited success.…”

Section: Introductionmentioning

confidence: 99%

Efficient in vivo microRNA targeting of liver metastasis

et al. 2010

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Targeting oncogenic microRNAs (miRNAs) is emerging as a promising strategy for cancer therapy. In this study, we provide proof of principle for the safety and efficacy of miRNA targeting against metastatic tumors. We tested the impact of targeting miR-182, a pro-metastatic miRNA frequently overexpressed in melanoma, the in vitro silencing of which represses invasion and induces apoptosis. Specifically, we assessed the effect of anti-miR-182 oligonucleotides synthesized with 2 0 sugar modifications and a phosphorothioate backbone in a mouse model of melanoma liver metastasis. Luciferase imaging showed that mice treated with anti-miR-182 had a lower burden of liver metastases compared with control. We confirmed that miR-182 levels were effectively downregulated in the tumors of anti-miR-treated mice compared with tumors of control-treated mice, both in the liver and in the spleen. This effect was accompanied by an upregulation of multiple miR-182 direct targets. Transcriptional profiling of tumors treated with anti-miR-182 or with control oligonucleotides revealed an enrichment of genes controlling survival, adhesion and migration modulated in response to anti-miR-182 treatment. These data indicate that in vivo administration of anti-miRs allows for efficient miRNA targeting and concomitant upregulation of miRNAcontrolled genes. Our results demonstrate that the use of anti-miR-182 is a promising therapeutic strategy for metastatic melanoma and provide a solid basis for testing similar strategies in human metastatic tumors.

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Phase I/II Trial of Tremelimumab in Patients With Metastatic Melanoma

Abstract: Multiple infusions of tremelimumab were generally tolerable and demonstrated single-agent antitumor activity. Both phase II regimens generated durable tumor responses. Based on its more favorable safety profile, 15 mg/kg every 3 months was selected for further clinical testing.

Cited by 287 publications

References 23 publications

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

Hydroxyamidine Inhibitors of Indoleamine-2,3-dioxygenase Potently Suppress Systemic Tryptophan Catabolism and the Growth of IDO-Expressing Tumors

Efficient in vivo microRNA targeting of liver metastasis

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