Long-term survival of high-risk melanoma patients immunized with a Hyper-IL-6-modified allogeneic whole-cell vaccine after complete resection

Maćkiewicz, Andrzej; Mackiewicz, Jacek; Wysocki, Piotr J.; Wiznerowicz, Maciej; Kapcińska, Małgorzata; Łaciak, Maria; Rose-John, Stefan; Iżycki, Dariusz; Burzykowski, Tomasz; Karczewska-Dzionk, A.

doi:10.1517/13543784.2012.684753

Cited by 24 publications

(42 citation statements)

References 41 publications

(28 reference statements)

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“…In all HLA-A2 positive long living patients, ALDH1A1-specific CD8 + T cells were detected. Since ETAM trial is a continuation of treatment study, 8,9 we could not evaluate the baseline level of these specific CD8 + T cells before immunization. Accordingly, we have investigated ALDH1A1-specific CD8 + T cells before and following vaccine dose administrations in long-living treated patients.…”

Section: Discussionmentioning

confidence: 99%

“…In our study protocol in case of progression, we applied more frequent dosing, what resulted in many cases metastatic tumor eradication. 9 In the fraction of cases, we excised returning tumors first and continued immunization until patients’ death. Above strategy resulted in long-term survival of a significant number of advanced melanoma patients.…”

Section: Discussionmentioning

confidence: 99%

“…Above strategy resulted in long-term survival of a significant number of advanced melanoma patients. 9 On the other hand blockade of immune checkpoints prevents elimination of specific CTL entering the tumor. However, these CTL may become exhausted and lose the effectiveness.…”

Section: Discussionmentioning

confidence: 99%

“…8,9 ETAM was initiated in November 2008, and all 138 surviving patients from trials 2-5 were transferred. The Regional Bioethics Committee approved the clinical study; all patients signed the informed consent.…”

Section: Methodsmentioning

confidence: 99%

“…8,9 In patients with resected metastases vaccination was combined with surgery of recurring metastases, which were surgically removed, and vaccination continued. A significant fraction of AGI-101H treated melanoma patients is still alive (from 11 to 19 years) and are the subjects of the study.…”

Section: Introductionmentioning

confidence: 99%

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Whole cell melanoma vaccine genetically modified to stem cells like phenotype generates specific immune responses to ALDH1A1 and long-term survival in advanced melanoma patients

Kwiatkowska-Borowczyk

Czerwińska

Mackiewicz

et al. 2018

OncoImmunology

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Allogeneic whole cell gene modified therapeutic melanoma vaccine (AGI-101H) comprising of two melanoma cell lines transduced with cDNA encoding fusion protein composed of IL-6 linked with the soluble IL-6 receptor (sIL-6R), referred to as H6 was developed. H6 served as a molecular adjuvant, however, it has altered vaccine cells phenotype towards melanoma stem cells (MSC)-like with high activity of aldehyde dehydrogenase isoenzyme (ALDH1A1). AGI-101H was applied in advanced melanoma patients with non-resected and resected disease. In the adjuvant setting, it was combined with surgery in case of recurring metastases, which were surgically removed and vaccination continued. A significant fraction of AGI-101H treated melanoma patients is still alive (11–19 years). Out of 106 living patients, 39 were HLA-A2 positive and were the subject of the study. Immunization of melanoma patients resulted in the generation of cytotoxic CD8+ T cells specific for ALDH1A1, which were detected in circulation by HLA-A0201 MHC dextramers loaded with ALDH1A188-96(LLYKLADLI) peptide. Phenotypically they were central memory CD8+ T cells. Re-stimulation with ALDH1A188-96 ex vivo resulted in IFN-γ secretion and cells degranulation. Following each vaccine dose administration, the number of ALDH1A1-CD8+ T cells increased in circulation and returned to the previous level until next dose injection (one month). ALDH1A1-CD8+ T cells were also found, however in the lower number than in vaccinated patients, in the circulation of untreated melanoma with stage IV but were not found in stage II or III and healthy donors. Specific anti-ALDH1 antibodies were present in treated patients. Long-term survival suggests immuno-targeting of MSC in treated patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Whole cell melanoma vaccine genetically modified to stem cells like phenotype generates specific immune responses to ALDH1A1 and long-term survival in advanced melanoma patients

Kwiatkowska-Borowczyk

Czerwińska

Mackiewicz

et al. 2018

OncoImmunology

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Immunomodulatory Factors Control the Fate of Melanoma Tumor Initiating Cells

et al. 2016

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Melanoma is a highly heterogeneous tumor for which recent evidence supports a model of dynamic stemness. Melanoma cells might temporally acquire tumor-initiating properties or switch from a status of tumor-initiating cells (TICs) to a more differentiated one depending on the tumor context. However, factors driving these functional changes are still unknown. We focused on the role of cyto/chemokines in shaping TICs isolated directly from tumor specimens of two melanoma patients, namely Me14346S and Me15888S. We analyzed the secretion profile of TICs and of their corresponding melanoma differentiated cells and we tested the ability of cyto/chemokines to influence TIC self-renewal and differentiation. We found that TICs, grown in vitro as melanospheres, had a complex secretory profile as compared to their differentiated counterparts. Some factors, such as CCL-2 and IL-8, also produced by adherent melanoma cells and melanocytes did not influence TIC properties. Conversely, IL-6, released by differentiated cells, reduced TIC self-renewal and induced TIC differentiation while IL-10, produced by Me15888S, strongly promoted TIC self-renewal through paracrine/autocrine actions. Complete neutralization of IL-10 activity by gene silencing and antibody-mediated blocking of the IL-10Rα was required to sensitize Me15888S to IL-6-induced differentiation. For the first time these results show that functional heterogeneity of melanoma could be directly influenced by inflammatory and suppressive soluble factors, with IL-6 favoring TIC differentiation, and IL-10 supporting TIC self-renewal. Thus, understanding the tumor microenvironment (TME) role in modulating melanoma TIC phenotype is fundamental to identifying novel therapeutic targets to achieve long-lasting regression of metastatic melanoma. Stem Cells 2016;34:2449-2460.

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Cancer Stem Cell Challenges in Melanoma Characterization and Treatment

Tuccitto

Castelli

Alison³

et al. 2019

Resistance to Targeted Anti-Cancer Therapeutics

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Long-term survival of high-risk melanoma patients immunized with a Hyper-IL-6-modified allogeneic whole-cell vaccine after complete resection

Abstract: Continuous vaccination, regardless of the disease progression, re-induction, and immunization of patients until death resulted in patients a long-term survival.

Cited by 24 publications

References 41 publications

Whole cell melanoma vaccine genetically modified to stem cells like phenotype generates specific immune responses to ALDH1A1 and long-term survival in advanced melanoma patients

Whole cell melanoma vaccine genetically modified to stem cells like phenotype generates specific immune responses to ALDH1A1 and long-term survival in advanced melanoma patients

Immunomodulatory Factors Control the Fate of Melanoma Tumor Initiating Cells

Cancer Stem Cell Challenges in Melanoma Characterization and Treatment

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