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Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients.
Davar, D, Dzutsev, AK, McCulloch, JA, Rodrigues, RR, Chauvin, JM, Morrison, RM, Deblasio, RN, Menna, C, Ding, Q, Pagliano, O, et al
Science (New York, N.Y.). 2021;(6529):595-602
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Abstract
Anti-programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti-PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti-PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti-PD-1 in patients with PD-1-refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti-PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8-expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti-PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 in a subset of PD-1 advanced melanoma.
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Anti-PD-1 monoclonal antibody MEDI0680 in a phase I study of patients with advanced solid malignancies.
Naing, A, Infante, J, Goel, S, Burris, H, Black, C, Marshall, S, Achour, I, Barbee, S, May, R, Morehouse, C, et al
Journal for immunotherapy of cancer. 2019;(1):225
Abstract
BACKGROUND The safety, efficacy, pharmacokinetics, and pharmacodynamics of the anti-programmed cell death-1 antibody MEDI0680 were evaluated in a phase I, multicenter, dose-escalation study in advanced solid malignancies. METHODS MEDI0680 was administered intravenously once every 2 weeks (Q2W) or once every 3 weeks at 0.1, 0.5, 2.5, 10 or 20 mg/kg. Two cohorts received 20 mg/kg once a week for 2 or 4 weeks, then 20 mg/kg Q2W. All were treated for 12 months or until progression. The primary endpoint was safety. Secondary endpoints were efficacy and pharmacokinetics. Exploratory endpoints included pharmacodynamics. RESULTS Fifty-eight patients were treated. Median age was 62.5 years and 81% were male. Most had kidney cancer (n = 36) or melanoma (n = 9). There were no dose-limiting toxicities. Treatment-related adverse events occurred in 83% and were grade ≥ 3 in 21%. Objective clinical responses occurred in 8/58 patients (14%): 5 with kidney cancer, including 1 with a complete response, and 3 with melanoma. The relationship between dose and serum levels was predictable and linear, with apparent receptor saturation at 10 mg/kg Q2W and all 20 mg/kg cohorts. CONCLUSIONS MEDI0680 induced peripheral T-cell proliferation and increased plasma IFNγ and associated chemokines regardless of clinical response. CD8+ T-cell tumor infiltration and tumoral gene expression of IFNG, CD8A, CXCL9, and granzyme K (GZMK) were also increased following MEDI0680 administration. TRIAL REGISTRATION NCT02013804 ; date of registration December 12, 2013.
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Sorafenib in metastatic uveal melanoma: efficacy, toxicity and health-related quality of life in a multicentre phase II study.
Mouriaux, F, Servois, V, Parienti, JJ, Lesimple, T, Thyss, A, Dutriaux, C, Neidhart-Berard, EM, Penel, N, Delcambre, C, Peyro Saint Paul, L, et al
British journal of cancer. 2016;(1):20-4
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Abstract
BACKGROUND The aim of the study was to analyse efficacy, safety, and health-related quality of life (HRQoL) for sorafenib treatment in patients with metastatic uveal melanoma. METHODS A multicentre, single-arm phase II trial was conducted. The primary objective was to determine the non-progression rate (RECIST) at 24 weeks for patients receiving sorafenib at a dose of 800 mg per day. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and HRQoL. RESULTS Thirty-two patients were included. Ten patients showed non-progression at 24 weeks (31.2%) without objective tumour responses. The estimated 24-week PFS was 31.2% (95% CI: 14.8%-47.6%) and the estimated 24-week OS was 62.5% (95% CI: 45.4%-79.6%). Ten patients (34.3%) had at least one grade 3 or 4 adverse reaction and 12 patients (41.4%) required dose modifications due to toxicity. At 24 weeks, no patient had an improvement in global HRQoL and 87.5% experienced a permanent increase in physical fatigue. CONCLUSIONS Sorafenib demonstrated non-progression at 24 weeks in 31.2% of patients. However, 41.4% of patients required dose modifications due to toxicity and no improvement in HRQoL was demonstrated.
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Safety, efficacy, pharmacokinetics, and pharmacodynamics of the combination of sorafenib and tanespimycin.
Vaishampayan, UN, Burger, AM, Sausville, EA, Heilbrun, LK, Li, J, Horiba, MN, Egorin, MJ, Ivy, P, Pacey, S, Lorusso, PM
Clinical cancer research : an official journal of the American Association for Cancer Research. 2010;(14):3795-804
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Abstract
PURPOSE Heat shock protein (Hsp) 90 inhibition affects the Raf kinase signaling pathway and could enhance antitumor effects of sorafenib, a Raf kinase inhibitor. The combination of sorafenib and tanespimycin [17-allyl-amino-geldanamycin (17-AAG); NSC 330507/KOS-953] was evaluated in a phase I trial with the primary objective of defining a phase II dose. PATIENTS AND METHODS The dose cohorts consisted of fixed continuous oral dosing of 400 mg sorafenib twice daily, starting at 14 days before tanespimycin, which was administered intravenously at escalating doses (starting at 300 mg/m,(2) with 50 mg/m(2) increments), on days 1, 8, and 15 in a 28-day cycle. Toxicity was assessed weekly, and response was evaluated every two cycles. RESULTS Twenty-seven toxicity-evaluable patients were enrolled and treated at four dose levels. Predominant primary malignancies were renal cancer (12), melanoma (6), and colorectal cancer (4). Dose-limiting toxicities of grade 4 transaminitis and grade 3 hand-foot syndrome in one patient each were observed at 450 mg/m(2) of tanespimycin. One hundred fourteen cycles were administered with a median of four cycles (range 1-17 cycles). Plasma concentrations of sorafenib and metabolites reached steady state after 7 days. Tanespimycin did not alter sorafenib concentrations. Pharmacodynamics showed a decrease in Hsp90 levels and induction of Hsp70. Clinical efficacy was observed in 9 of 12 renal cancer patients and 4 of 6 melanoma patients CONCLUSIONS Recommended phase II doses of this combination are 400 mg sorafenib twice daily and 400 mg/m(2) tanespimycin on days 1, 8, and 15, every 28 days. Clinical and pharmacodynamic activity was observed in kidney cancer and melanoma.
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A phase II trial of sorafenib in metastatic melanoma with tissue correlates.
Ott, PA, Hamilton, A, Min, C, Safarzadeh-Amiri, S, Goldberg, L, Yoon, J, Yee, H, Buckley, M, Christos, PJ, Wright, JJ, et al
PloS one. 2010;(12):e15588
Abstract
BACKGROUND Sorafenib monotherapy in patients with metastatic melanoma was explored in this multi-institutional phase II study. In correlative studies the impact of sorafenib on cyclin D1 and Ki67 was assessed. METHODOLOGY/PRINCIPAL FINDINGS Thirty-six patients treatment-naïve advanced melanoma patients received sorafenib 400 mg p.o. twice daily continuously. Tumor BRAF(V600E) mutational status was determined by routine DNA sequencing and mutation-specific PCR (MSPCR). Immunohistochemistry (IHC) staining for cyclin D1 and Ki67 was performed on available pre- and post treatment tumor samples. The main toxicities included diarrhea, alopecia, rash, mucositis, nausea, hand-foot syndrome, and intestinal perforation. One patient had a RECIST partial response (PR) lasting 175 days. Three patients experienced stable disease (SD) with a mean duration of 37 weeks. Routine BRAF(V600E) sequencing yielded 27 wild-type (wt) and 6 mutant tumors, whereas MSPCR identified 12 wt and 18 mutant tumors. No correlation was seen between BRAF(V600E) mutational status and clinical activity. No significant changes in expression of cyclin D1 or Ki67 with sorafenib treatment were demonstrable in the 15 patients with pre-and post-treatment tumor samples. CONCLUSIONS/SIGNIFICANCE Sorafenib monotherapy has limited activity in advanced melanoma patients. BRAF(V600E) mutational status of the tumor was not associated with clinical activity and no significant effect of sorafenib on cyclin D1 or Ki67 was seen, suggesting that sorafenib is not an effective BRAF inhibitor or that additional signaling pathways are equally important in the patients who benefit from sorafenib. TRIAL REGISTRATION Clinical Trials.gov NCT00119249.
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Safety and efficacy of arsenic trioxide for patients with advanced metastatic melanoma.
Tarhini, AA, Kirkwood, JM, Tawbi, H, Gooding, WE, Islam, MF, Agarwala, SS
Cancer. 2008;(5):1131-8
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Abstract
BACKGROUND Arsenic trioxide (ATO) cytotoxicity and apoptosis induction has been demonstrated with numerous cancer cell lines, including human melanoma. METHODS A second-line, phase 2, single-arm study of ATO was conducted in patients with inoperable American Joint Committee on Cancer (AJCC) stage IV melanoma. One cycle consisted of a loading dose of 0.32 mg/kg/day for 4 days in Week 1, followed by 0.25 mg/kg/day twice per week for 6 weeks, followed by 1 week of rest, at which time response assessment was performed. RESULTS Twenty-one patients (median age, 63.8 years) were accrued. All had stage IV melanoma including M1a (2 patients), M1b (6 patients), and M1c (13 patients) disease. One patient had metastatic choroidal melanoma and 20 patients had cutaneous melanoma. Twenty patients had received prior therapy. Possible treatment-related grade 3 of 4 toxicities (using the National Cancer Institute Common Toxicity Criteria) included 1 case of idiopathic thrombocytopenic purpura and 1 case of elevated lactate dehydrogenase. Four patients did not complete the first cycle of therapy and were not evaluable for response. Among 17 evaluable patients, 1 patient (6%; 95% confidence interval [95% CI], 0-29%) achieved a partial response lasting 7 months, and 10 patients (59%) had disease stabilization after at least 1 cycle, but all eventually developed disease progression. The median time to disease progression was 17 weeks (95% CI, 11-38 weeks) and the median survival was 13 months (95% CI, 12-26 months). CONCLUSIONS ATO as tested in the current trial was found to be well tolerated and had limited activity in patients with metastatic melanoma. The application of this agent in combination with either chemotherapy or agents that target recognized critical signaling and antiapoptotic pathways of melanoma has not yet been performed.
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Depletion of normal B cells with rituximab as an adjunct to IL-2 therapy for renal cell carcinoma and melanoma.
Aklilu, M, Stadler, WM, Markiewicz, M, Vogelzang, NJ, Mahowald, M, Johnson, M, Gajewski, TF
Annals of oncology : official journal of the European Society for Medical Oncology. 2004;(7):1109-14
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BACKGROUND We postulated that in patients with metastatic renal cell carcinoma (RCC) or melanoma, depletion of normal B cells using the anti-CD20 mAb rituximab before treatment with low-dose interleukin (IL)-2 would improve clinical outcome. PATIENTS AND METHODS Rituximab (375 mg/m(2)) weekly for 4 weeks. IL-2 [11 (million units) daily] s.c., 4 days a week for weeks 5-8, followed by a 2-week rest (weeks 9 and 10). Patients without disease progression continued on IL-2. Disease re-evaluation was performed after rituximab and after every course of IL-2. RESULTS Fifteen patients with RCC and six with melanoma were enrolled. One patient had a partial response and seven patients had stable disease. Toxicities were similar to those expected with IL-2 alone, and there were no grade 4 events. Circulating B cells were depleted in all patients. The subsequent low-dose IL-2 increased absolute numbers of natural killer cells, activated CD4(+) and activated CD8(+) T cells. Expanded T cells produced interferon-gamma, but not IL-4. Proliferation of peripheral blood lymphocytes to phytohemagglutinin was diminished following rituximab treatment, suggesting that B cells participate in this response in vitro. CONCLUSIONS Our results suggest that depletion of circulating B cells with rituximab does not increase the response rate, alter the toxicity profile or change the biological activity in response to low-dose IL-2 in patients with RCC or melanoma.
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Recombinant fowlpox viruses encoding the anchor-modified gp100 melanoma antigen can generate antitumor immune responses in patients with metastatic melanoma.
Rosenberg, SA, Yang, JC, Schwartzentruber, DJ, Hwu, P, Topalian, SL, Sherry, RM, Restifo, NP, Wunderlich, JR, Seipp, CA, Rogers-Freezer, L, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2003;(8):2973-80
Abstract
PURPOSE The purpose of this study was to evaluate the immunological responses and therapeutic effectiveness of immunization with fowlpox vaccines encoding the gp100 melanoma antigen in patients with metastatic melanoma. EXPERIMENTAL DESIGN In three consecutive clinical trials, patients were immunized with recombinant fowlpox viruses encoding three different forms of the melanoma/melanocyte-associated antigen gp100: (a) the native, full-length gp100 molecule; (b) the gp100 molecule with two amino acids modified to increase binding to HLA-A*0201 molecules; and (c) a "minigene" construct encoding a single, modified epitope gp100:209-217(210M) targeted to the endoplasmic reticulum. The immunogenicity of these constructs was studied using peripheral blood mononuclear cells to measure epitope-specific release of IFN-gamma. RESULTS Reactivity against gp100 was not seen in any patient before receiving fowlpox immunization. Whereas just one of seven patients developed reactivity after receiving fowlpox encoding native gp100, 10 of 14 patients who received fowlpox encoding the anchor modified full-length gp100 exhibited reactivity against the native gp100 molecule, and 12 of 16 patients were successfully immunized after inoculation with the modified minigene construct (p2 = 0.02). There was no difference in the latter group between those randomized to vaccination by i.v. or i.m. routes. There was one partial cancer regression in the group of 46 patients receiving virus in the absence of interleukin (IL)-2. Once patients showed evidence of progressive disease, they were eligible for "cross-over" treatment to IL-2 alone or with the fowlpox virus. None of the 13 patients receiving the full-length or modified full-length forms of gp100 responded when receiving IL-2, whereas 6 of 12 patients who received the fowlpox containing the minigene construct and then received IL-2 showed objective cancer regressions, including three patients with complete regression. CONCLUSIONS These data underscore the importance of modifying anchor residues of nonmutated self-antigen peptides to generate cellular immune responses after immunization and support the further investigation of recombinant fowlpox viruses encoding modified epitopes administered in combination with IL-2.