MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial

Dréno, Brigitte; Thompson, John F.; Smithers, B. Mark; Santinami, Mario; Jouary, Thomas; Gutzmer, Ralf; Levchenko, Evgeny; Rutkowski, Piotr; Grob, Jean‐Jacques; Коровін, С.І.; Drucis, Kamil; Grange, Florent; Machet, L.; Hersey, Peter; Krajsová, Ivana; Testori, Alessandro; Conry, Robert M.; Guillot, B.; Kruit, Wim; Демидов, Лев В.; Thompson, John A.; Bondarenko, Igor; Jaroszek, Jaroslaw; Puig, Susana; Cinat, Gabriela; Hauschild, Axel; Goeman, Jelle J.; Houwelingen, Hans C. van; Ulloa‐Montoya, Fernando; Callegaro, Andrea; Dizier, Benjamin; Spiessens, Bart; Debois, Muriel; Brichard, Vincent G.; Louahed, Jamila; Therasse, Patrick; Debruyne, Channa; Kirkwood, John M.

doi:10.1016/s1470-2045(18)30254-7

Cited by 147 publications

(92 citation statements)

References 29 publications

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“…Therefore, its further development for use in NSLCs has been stopped (Vansteenkiste et al, 2016). Similar conclusions were drawn from a phase III trial of a MAGE-A3/AS015 vaccine in patients with resected, MAGE-A3-positive, stage III melanoma, which led to the arrest of the clinical development of this vaccine for use in melanoma (Dreno et al, 2018).…”

Section: Therapeutic Vaccines Cancermentioning

confidence: 83%

Updated insights into the mechanism of action and clinical profile of the immunoadjuvant QS-21: A review

2019

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Background: Vaccine adjuvants are compounds that significantly enhance/prolong the immune response to a coadministered antigen. The limitations of the use of aluminium salts that are unable to elicite cell responses against intracellular pathogens such as those causing malaria, tuberculosis, or AIDS, have driven the development of new alternative adjuvants such as QS-21, a triterpene saponin purified from Quillaja saponaria. Purpose: The aim of this review is to attempt to clarify the mechanism of action of QS-21 through either receptors or signaling pathways in vitro and in vivo with special emphasis on the co-administration with other immunostimulants in new adjuvant formulations, called adjuvant systems (AS). Furthermore, the most relevant clinical applications will be presented. Methods: A literature search covering the period 2014-2018 was performed using electronic databases from Sci finder, Science direct, Medline/Pubmed, Scopus, Google scholar. Results: Insights into the mechanism of action of QS-21 can be summarized as follows: 1) in vivo stimulation of Th2 humoral and Th1 cell-mediated immune responses through action on antigen presenting cells (APCs) and T cells, leading to release of Th1 cytokines participating in the elimination of intracellular pathogens. 2) activation of the NLRP3 inflammasome in mouse APCs with subsequent release of caspase-1 dependent cytokines, Il-1β and Il-18, important for Th1 responses. 3) synthesis of nearly 50 QS-21 analogs, allowing structure/activity relationships and mechanistic studies. 4) unique synergy mechanism between monophosphoryl lipid A (MPL A) and QS-21, formulated in a liposome (AS01) in the early IFN-γ response, promoting vaccine immunogenicity. The second part of the review is related to phase I-III clinical trials of QS-21, mostly formulated in ASs, to evaluate efficacy, immunogenicity and safety of adjuvanted prophylactic vaccines against infectious diseases, e.g. malaria, herpes zoster, tuberculosis, AIDS and therapeutic vaccines against cancer and Alzheimer's disease. Conclusion: The most advanced phase III clinical applications led to the development of two vaccines containing QS-21 as part of the AS, the Herpes Zoster vaccine (HZ/su) (Shingrix™) which received a license in 2017 from the FDA and a marketing authorization in the EU in 2018 and the RTS,S/AS01 vaccine (Mosquirix™) against malaria, which was approved by the EMA in 2015 for further implementation in Sub-Saharan countries for routine use.2014 have made the research on vaccines very attractive in the last decades (Lee and Nguyen, 2015). Modern subunit vaccines comprising homogeneous molecular antigens have been developed to prevent and treat many human diseases, but they are weakly immunogenic and must be administered with an adjuvant to elicit a potent immune response. Adjuvants whose name originates from the Latin word adjuvare https://doi.

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Section: Therapeutic Vaccines Cancermentioning

confidence: 83%

Updated insights into the mechanism of action and clinical profile of the immunoadjuvant QS-21: A review

2019

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“…Other methods of immunotherapy (e.g. interleukin 2), vaccinations or cytotoxic medication do not have any application in post-operative adjuvant treatment [1,4,5,30].…”

Section: Discussionmentioning

confidence: 99%

New developments in the perioperative treatment of melanomas with locoregional advancement

Rutkowski

Wysocki

Świtaj

et al. 2019

Nowotwory. Journal of Oncology

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Surgical intervention is the treatment of choice for patients with melanomas. However, the prognoses of the patients with melanomas at the IIC-IV stage, even after a complete resection of the lesions, is very diverse and, to a great degree, connected with a high risk of disease recurrence. The positive results of the studies in this area have resulted in systemic adjuvant therapy becoming the standard for patients in this group. New methods of systemic treatment-both the molecularly targeted treatment with BRAF and MEK inhibitors (dabrafenib with trametinib) and anti-PD-1 immunotherapy (nivolumab or pembrolizumab)-are already registered in the United States and the European Union. Also the results of the studies concerning the use of preoperative systemic treatment in patients with loco-regionally advanced melanomas seem to be very promising.

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“…CT genes were first observed and considered to be candidate targets for immunotherapy due to their immunogenicity. However, 19 of the 24 phase II/III clinical trials that tested 17 distinct therapeutic anticancer vaccines failed to achieve their primary objectives (20)(21)(22)(23); this included a trial for the vaccine targeting MAGEA3 in non-small cell lung cancer (NSCLC) and melanoma. A recent study reported that the aneuploidy level can predict the reduced level of cytotoxic infiltrating immune cells (8).…”

Section: Discussionmentioning

confidence: 99%

Meiosis related cancer-testis genes correlate with tumor aneuploidy and immune infiltration in 21 cancer types

Wang

Chang

et al. 2019

Preprint

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The meiosis stage of spermatogenesis and the aneuploidy generation in tumorigenesis are highly linked. Cancer-testis genes (CT genes) were specifically expressed in testis and cancers and may serve as the molecular basis of the shared features between spermatogenesis and tumorigenesis. In the present study, we integrated multi-omics data from bulk samples and cell lines, and single cell RNA-Seq data from testis and two tumors to systematically investigate the association between CT genes and aneuploidy. After ranking genes according to their association with aneuploidy level, we found that CT genes, especially CT genes specifically expressed in meiosis, showed a consistently positive correlation with aneuploidy and homologous recombination deficiency (HRD) level. Similar results were also found in the CT non-coding genes. Then, we constructed a regulatory network based on the single cell RNA-seq data and revealed that the gain of accelerator transcriptional factors (TFs) E2F7 and E2F8 and the loss of the stabilizer TFs RFX2 and NFYA aberrantly activated CT genes in the cancers and were associated with the increase of HRD level. Finally, we found that the association between CT genes and cytotoxic infiltrating lymphocytes can be influenced by the HRD level. In sum, our results revealed the evidence of pseudomeiotic functions of CT genes in the aneuploidy generation process in the cancer cells. The results may help illuminate the origin of aneuploidy in cancers and guide future immunotherapy targeting CT antigens.

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MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial

Abstract: GlaxoSmithKline Biologicals SA.

Cited by 147 publications

References 29 publications

Updated insights into the mechanism of action and clinical profile of the immunoadjuvant QS-21: A review

Updated insights into the mechanism of action and clinical profile of the immunoadjuvant QS-21: A review

New developments in the perioperative treatment of melanomas with locoregional advancement

Meiosis related cancer-testis genes correlate with tumor aneuploidy and immune infiltration in 21 cancer types

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