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Experimental treatment of patients with disseminated malignant melanoma
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. (Gustav J. Ullenhag)ORCID-id: 0000-0002-5514-3637
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Fritextbeskrivning
Abstract [en]

Malignant melanoma (MM) is the deadliest skin cancer with an ever-increasing incidence. New treatments have improved the prognosis for patients with advanced MM. Still, most patients do not respond, and the side effects can be severe, underlining the need for better therapies.

The overall aim of this thesis was to evaluate new means to improve the treatment for patients with advanced MM. Immunostimulatory gene therapy (AdCD40L) was evaluated in a clinical study and BRAF-inhibitory treatment in rare cases of BRAF-mutated MM.

Due to its immunogenicity, MM is an attractive target for immunostimulatory gene therapy. AdCD40L is an adenovirus carrying the human gene for CD40 ligand, which in different ways can stimulate the immune system to combat cancer. We conducted a Phase I/IIa study with AdCD40L in patients with metastatic MM having received established treatments. In cohort 1 (n=6), four weekly, intratumoural AdCD40L injections were given. In cohort 2 (n=9), low dose cyclophosphamide was added to increase the immune response. Since irradiation may act synergistically with immunotherapy, patients in cohort 3 (n=9) also received a single fraction of radiotherapy (8 Gy). This fraction was given towards the lesion selected for injections.

The primary objectives were to assess the feasibility and safety of AdCD40L-treatment and secondarily its anti-tumour effects. Patients were thoroughly assessed for toxicity. The anti-tumour response was evaluated by imaging techniques (FDG-PET/CT, DW-MRI scans), tumour biopsies and blood tests. Plasma protein markers were measured with a multiplex platform. Another objective was to evaluate the potential of DW-MRI and FDG-PET/CT for prediction of AdCD40L treatment response, in terms of overall survival (OS).

AdCD40L was well tolerated with mild transient reactions. Local and distant responses in PET/CT scans along with a significantly better 6-month survival in the cohorts that received cyclophosphamide conditioning were observed. Effector lymphocyte responses were elicited. All patients had an increased T effector/T regulatory-cell ratio and death receptors were significantly up-regulated post therapy. Inflammatory cytokines and other plasma proteins were altered in favourable ways by the AdCD40L treatment. The analyses support that the functional DWI parameters may be better early predictors of OS than the established metabolic and morphologic criteria of FDG-PET/CT and CT/MRI, respectively.

In conclusion, the stimulation of the CD40 pathway to initiate anti-tumour immunity is a promising treatment alternative for MM patients. However, further studies with developed treatment schemes are warranted.

In the first report ever on treatment of a pregnant patient with a BRAF-inhibitor, the therapy was initiated in the second trimester. The treatment with vemurafenib enabled prolonged gestation, hence reducing the risk of immaturity-related complications. Further, we report the first case worldwide of a patient with metastatic conjunctival melanoma who benefitted from treatment with vemurafenib. Additional studies are needed to assess the efficacy of BRAF -inhibitors in the different subtypes of ocular melanoma.

 

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2017. , 80 s.
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1382
Nyckelord [en]
Malignant melanoma, AdCD40L, immunotherapy, proteomics, DW-MRI, FDG-PET/CT, prediction, early response, BRAF-inhibitor, vemurafenib
Nationell ämneskategori
Cancer och onkologi
Forskningsämne
Onkologi
Identifikatorer
URN: urn:nbn:se:uu:diva-330710ISBN: 978-91-513-0107-5 (tryckt)OAI: oai:DiVA.org:uu-330710DiVA: diva2:1149354
Disputation
2017-12-02, Hedstrandsalen, Akademiska sjukhuset ingång 70, Uppsala, 09:30 (Svenska)
Opponent
Handledare
Tillgänglig från: 2017-11-09 Skapad: 2017-10-15 Senast uppdaterad: 2017-11-09
Delarbeten
1. Immunostimulatory AdCD40L gene therapy combined with low-dose cyclophosphamide in metastatic melanoma patients
Öppna denna publikation i ny flik eller fönster >>Immunostimulatory AdCD40L gene therapy combined with low-dose cyclophosphamide in metastatic melanoma patients
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2016 (Engelska)Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 114, nr 8, 872-880 s.Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

BACKGROUND: Current approaches for treating metastatic malignant melanoma (MM) are not effective enough and are associated with serious adverse events. Due to its immunogenicity, melanoma is an attractive target for immunostimulating therapy. In this phase I/IIa study, local AdCD40L immunostimulatory gene therapy was evaluated in patients with MM.

METHODS: AdCD40L is an adenovirus carrying the gene for CD40 ligand. Patients that failed standard treatments were enrolled. Six patients received four weekly intratumoral AdCD40L injections. Next, nine patients received low-dose cyclophosphamide conditioning before the first and fourth AdCD40L injection. The blood samples were collected at multiple time points for chemistry, haematology and immunology evaluations. Radiology was performed at enrolment and repeated twice after the treatment.

RESULTS: AdCD40L was safe with mild transient reactions. No objective responses were recorded by MRI, however, local and distant responses were seen on FDG-PET. The overall survival at 6 months was significantly better when cyclophosphamide was added to AdCD40L. The patients with the best survival developed the highest levels of activated T cells and experienced a pronounced decrease of intratumoral IL8.

CONCLUSIONS: AdCD40L therapy for MM was well tolerated. Local and distant responses along with better survival in the low-dose cyclophosphamide group are encouraging.

Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:uu:diva-295735 (URN)10.1038/bjc.2016.42 (DOI)000374129200004 ()27031851 (PubMedID)
Forskningsfinansiär
Cancerfonden
Tillgänglig från: 2016-06-09 Skapad: 2016-06-09 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
2. Adenovirus-mediated CD40L gene transfer increases Teffector/Tregulatory cell ratio and upregulates death receptors in metastatic melanoma patients
Öppna denna publikation i ny flik eller fönster >>Adenovirus-mediated CD40L gene transfer increases Teffector/Tregulatory cell ratio and upregulates death receptors in metastatic melanoma patients
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2017 (Engelska)Ingår i: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 15, nr 79Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background and aims: Malignant melanoma is an aggressive tumor sensitive for immunotherapy such as checkpoint blockade antibodies. Still, most patients with late stage disease do not respond, and the side effects can be severe. Stimulation of the CD40 pathway to initiate anti-tumor immunity is a promising alternative. Herein, we demonstrate immune profiling data from melanoma patients treated with an adenovirus-based CD40 ligand gene therapy (AdCD40L). Methods: Peripheral blood mononuclear cells and plasma were collected from malignant melanoma patients (n = 15) enrolled in a phase I/IIa study investigating intratumoral delivery of AdCD40L with or without low dose cyclophosphamide. Cells were analyzed by flow cytometry while plasma samples were analyzed by a multi-array proteomics. Results: All patients had an increased Teffector/Tregulatory cell ratio post therapy. Simultaneously, the death receptors TNFR1 and TRAIL-R2 were significantly up-regulated post treatment. Stem cell factor (SCF), E-selectin, and CD6 correlated to enhanced overall survival while a high level of granulocytic myeloid-derived suppressor cells (gMDSCs), IL8, IL10, TGFb1, CCL4, PlGF and Fl3t ligand was highest in patients with short survival. Conclusions: AdCD40L intratumoral injection induced desirable systemic immune effects that correlated to prolonged survival. Further studies using CD40 stimulation in malignant melanoma are warranted.

Nyckelord
AdCD40L, Malignant melanoma, Immunotherapy, Proteomics, T regulatory cells, Myeloid-derived suppressor cells
Nationell ämneskategori
Immunologi inom det medicinska området
Identifikatorer
urn:nbn:se:uu:diva-322800 (URN)10.1186/s12967-017-1182-z (DOI)000399786900002 ()28427434 (PubMedID)
Tillgänglig från: 2017-06-20 Skapad: 2017-06-20 Senast uppdaterad: 2017-10-15Bibliografiskt granskad
3. Diffusion-Weighted MRI may be better than FDG-PET/CT to assess immunotherapy response in patients with metastatic melanoma
Öppna denna publikation i ny flik eller fönster >>Diffusion-Weighted MRI may be better than FDG-PET/CT to assess immunotherapy response in patients with metastatic melanoma
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:uu:diva-330709 (URN)
Tillgänglig från: 2017-10-03 Skapad: 2017-10-03 Senast uppdaterad: 2017-10-15
4. Treatment of metastatic malignant melanoma with vemurafenib during pregnancy
Öppna denna publikation i ny flik eller fönster >>Treatment of metastatic malignant melanoma with vemurafenib during pregnancy
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2013 (Engelska)Ingår i: Journal of Clinical Oncology, ISSN 0732-183X, Vol. 31, nr 11, e192-e193 s.Artikel i tidskrift (Refereegranskat) Published
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-328673 (URN)10.1200/JCO.2012.45.2870 (DOI)23401457 (PubMedID)
Tillgänglig från: 2017-08-29 Skapad: 2017-08-29 Senast uppdaterad: 2017-10-15Bibliografiskt granskad
5. A case report of a patient with metastatic ocular melanoma who experienced a response to treatment with the BRAF inhibitor vemurafenib
Öppna denna publikation i ny flik eller fönster >>A case report of a patient with metastatic ocular melanoma who experienced a response to treatment with the BRAF inhibitor vemurafenib
2016 (Engelska)Ingår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 16, 634Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: Conjunctival malignant melanoma (CMM) is a rare malignancy and in the advanced setting there is no effective treatment. In contrast, half of cutaneous melanomas have BRAF mutations and treatment with BRAF inhibitors is established for patients with disseminated disease. The most common form of ocular melanoma, uveal melanoma, lacks these mutations, however, their presence has been reported for CMM. Case presentation: We used the BRAF inhibitor vemurafenib to treat a 53 year-old female suffering from a BRAFV600E mutated metastatic CMM. The patient benefited from the treatment, a response was evident within a week and she experienced a progression free survival of four months. Conclusions: To our knowledge, this is the first described case of response to vemurafenib treatment in a patient with ocular melanoma.

Nyckelord
BRAF inhibitor, BRAF mutation, Conjunctival malignant melanoma, Ocular melanoma, Vemurafenib
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:uu:diva-305937 (URN)10.1186/s12885-016-2657-7 (DOI)000384169800001 ()27520988 (PubMedID)
Tillgänglig från: 2016-11-11 Skapad: 2016-10-24 Senast uppdaterad: 2017-11-29Bibliografiskt granskad

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