MYCN-targeting vaccines and immunotherapeutics

Abstract

Amplification and concomitant overexpression of the MYCN oncogene is a frequent event in many malignancies including the childhood tumors, neuroblastoma and medulloblastoma. MYCN is only expressed in a defined time frame during early developmental processes, 1 which is beneficial for approaches combatting tumor-specific MYCN. However, MYCN is a transcription factors that was considered a poor drug target, until recent approaches suggested that down-regulation of MYCN could be possible by indirect targeting using Aurora kinase inhibitors or BET inhibitors. These concepts were proven using preclinical models [2][3][4][5][6] and are now entering clinical trials. KEYWORDS DNA vaccination; minigene; MYCN; neuroblastomaIn neuroblastoma (NB), a common solid tumor of childhood, the MYCN oncogene is amplified in~20 % of cases. 7 Following induction chemotherapy and consolidation with high dose chemotherapy and stem cell rescue, maintenance treatment regimens focus on passive immunotherapy by targeting NB-specific expression of the disialoganglioside GD2 with GD2-specific monoclonal antibodies (MAbs). As GD2 is devoid of any intracellular signal transduction component, the mechanism of action of this approach is the induction of complement-dependent (CDC) and antibody-dependent cellular cytotoxicity (ADCC). In this context, treatment with mouse-human chimeric Mab ch14.18 showed superior survival rates when used as a single agent approach 8 or in combination with IL-2 and GM-CSF. 9 These two studies from independent cooperative groups demonstrated the potential of targeted immunotherapies in neuroblastoma. Ongoing clinical trials in the context of passive immunotherapy address the role of cytokines as well as the potential of novel delivery methods by long term continuous infusion. The specific components of ch14.18 were also used to design GD2-specific chimeric antigen receptor-engineered (CAR) T cells. These were generated and administered to NB patients in the context of a phase I study. Complete remission was achieved in 3/11 patients with active disease and persistence of CARs in vivo > 6 weeks was found to correlate with clinical outcome. 10 One disadvantage of passive immunotherapy is the absence of long lasting and persistent immunity against the malignancy. Based on the high relapse rate in NB combined with limited strategies for therapeutic intervention new approaches are urgently needed. 11 Globally, neuroblastomas escape from destruction by the immune system using a combinatorial strategy involving MYCN-dependent downregulation of MHC molecules 12 and inhibition of NKT cells, which in turn causes up-regulation of tumor-associated macrophages (TAMs, 13,14 Earlier reports also indicated that MYCN-specific cytotoxic T cells (CTLs) are present in neuroblastoma patients harboring tumor-specific MYCN amplification. 15 Surprisingly, little is known on the usefulness of MYCN as a target for cancer immunotherapy. 16 Peptide vaccination using a HLA-A2 restricted peptide derived from MYCN has been shown to effecti...

Embryonal Tumors of the Central Nervous System in Children: The Era of Targeted Therapeutics

“…Early studies have shown that most MB tumors have only nominal immune-cell infiltration and tumor cells have absent or deficient antigen-presenting machinery [62,63]. Despite the apparent lack of tumor surveillance, there is growing evidence that checkpoint inhibition, immunization, or viral therapy may be of benefit [64,65,66].…”

An In Vitro Study of Saffron Carotenoids: The Effect of Crocin Extracts and Dimethylcrocetin on Cancer Cell Lines

“…MYCN belongs to the MYC family of proto-oncogenes and transcription factors, encoding a helix-loop-helix (bHLH) domain-based protein, implicated in the progression of the cell cycle through the G1/S transition. MYCN represents a critical oncogene, maintaining the tumorigenic state in several cancer types, implicated in cancer initiation, progression and invasion [ 141 , 191 , 192 ]. C-Myc downregulation at 72 h in the presence of CRCs and DMCRT for A172 cells and in the presence of DMCRT for TE671 cells could represent another mode of saffron cytotoxicity and induction of apoptosis in a MYCN-dependent manner.…”

The Scaffold Protein p140Cap as a Molecular Hub for Limiting Cancer Progression: A New Paradigm in Neuroblastoma

“…However, the compounds that can interfere with MYCN interaction with its partner MAX as a way to block its transcriptional action, were not efficient in vivo [57], dampening their development in clinical testing. Strategies to exploit MYCN as a tumor-associated antigen for immunotherapy deserve further functional validation [58]. The ALK gene is altered by gain-of-function point mutations in around 14% of high-risk NB and represents an ideal therapeutic target given its low or absent expression in healthy tissue postnatally [59].…”