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Experimental treatment of patients with disseminated malignant melanoma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. (Gustav J. Ullenhag)ORCID iD: 0000-0002-5514-3637
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
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.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. , p. 80
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1382
Keyword [en]
Malignant melanoma, AdCD40L, immunotherapy, proteomics, DW-MRI, FDG-PET/CT, prediction, early response, BRAF-inhibitor, vemurafenib
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:uu:diva-330710ISBN: 978-91-513-0107-5 (print)OAI: oai:DiVA.org:uu-330710DiVA, id: diva2:1149354
Public defence
2017-12-02, Hedstrandsalen, Akademiska sjukhuset ingång 70, Uppsala, 09:30 (Swedish)
Opponent
Supervisors
Available from: 2017-11-09 Created: 2017-10-15 Last updated: 2017-11-09
List of papers
1. Immunostimulatory AdCD40L gene therapy combined with low-dose cyclophosphamide in metastatic melanoma patients
Open this publication in new window or tab >>Immunostimulatory AdCD40L gene therapy combined with low-dose cyclophosphamide in metastatic melanoma patients
Show others...
2016 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 114, no 8, p. 872-880Article in journal (Refereed) 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.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-295735 (URN)10.1038/bjc.2016.42 (DOI)000374129200004 ()27031851 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2016-06-09 Created: 2016-06-09 Last updated: 2018-02-20Bibliographically approved
2. Adenovirus-mediated CD40L gene transfer increases Teffector/Tregulatory cell ratio and upregulates death receptors in metastatic melanoma patients
Open this publication in new window or tab >>Adenovirus-mediated CD40L gene transfer increases Teffector/Tregulatory cell ratio and upregulates death receptors in metastatic melanoma patients
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2017 (English)In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 15, no 79Article in journal (Refereed) 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.

Keyword
AdCD40L, Malignant melanoma, Immunotherapy, Proteomics, T regulatory cells, Myeloid-derived suppressor cells
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-322800 (URN)10.1186/s12967-017-1182-z (DOI)000399786900002 ()28427434 (PubMedID)
Available from: 2017-06-20 Created: 2017-06-20 Last updated: 2018-02-20Bibliographically approved
3. Diffusion-Weighted MRI may be better than FDG-PET/CT to assess immunotherapy response in patients with metastatic melanoma
Open this publication in new window or tab >>Diffusion-Weighted MRI may be better than FDG-PET/CT to assess immunotherapy response in patients with metastatic melanoma
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-330709 (URN)
Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2018-02-20
4. Treatment of metastatic malignant melanoma with vemurafenib during pregnancy
Open this publication in new window or tab >>Treatment of metastatic malignant melanoma with vemurafenib during pregnancy
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2013 (English)In: Journal of Clinical Oncology, ISSN 0732-183X, Vol. 31, no 11, p. e192-e193Article in journal (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-328673 (URN)10.1200/JCO.2012.45.2870 (DOI)23401457 (PubMedID)
Available from: 2017-08-29 Created: 2017-08-29 Last updated: 2017-10-15Bibliographically approved
5. A case report of a patient with metastatic ocular melanoma who experienced a response to treatment with the BRAF inhibitor vemurafenib
Open this publication in new window or tab >>A case report of a patient with metastatic ocular melanoma who experienced a response to treatment with the BRAF inhibitor vemurafenib
2016 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 16, article id 634Article in journal (Refereed) 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.

Keyword
BRAF inhibitor, BRAF mutation, Conjunctival malignant melanoma, Ocular melanoma, Vemurafenib
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-305937 (URN)10.1186/s12885-016-2657-7 (DOI)000384169800001 ()27520988 (PubMedID)
Available from: 2016-11-11 Created: 2016-10-24 Last updated: 2018-02-20Bibliographically approved

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