Treatment of Retinoblastoma: What Is the Latest and What Is the Future

Abstract

The management of retinoblastoma, the most common intraocular malignancy in children, has changed drastically over the last decade. Landmark developments in local drug delivery, namely, safer techniques for intravitreal chemotherapy injection and ophthalmic artery chemosurgery, have resulted in eye globe salvages that were not previously attainable using systemic chemotherapy or external beam irradiation. Novel drugs, oncolytic viruses, and immunotherapy are promising approaches in the treatment of intraocular retinoblastoma. Importantly, emerging studies of the pattern of tumor dissemination and local drug delivery may provide the first steps toward new treatments for metastatic disease. Here, we review recent advances in retinoblastoma treatment, especially with regard to local drug delivery, that have enabled successful conservative management of intraocular retinoblastoma. We also review emerging data from preclinical and clinical studies on innovative approaches that promise to lead to further improvement in outcomes, namely, the mechanisms and potential uses of new and repurposed drugs and non-chemotherapy treatments, and discuss future directions for therapeutic development.

Keywords: adenovirus; chemotherapy; innovative treatments; intra-arterial chemotherapy; intravitreal injections; pharmacology; retinoblastoma.

Figure 1

Workflow for tumor sampling and genomic and pharmacological characterization. Samples obtained from enucleated eyes with retinoblastoma, cerebrospinal fluid, and/or bone marrow are subjected to multi-omic analysis to identify deregulated pathways that may be subjected to targeted agents. Also, these samples may be used to establish tumor cell lines and patient-derived xenografts in immunocompromised animals to evaluate tumor invasiveness and pharmacological sensitivity to novel agents, repositioned drugs, or combination therapies.

Figure 2

Drug discovery in retinoblastoma. Left: Pathways shown to be deregulated in retinoblastoma and drugs targeting them that may represent future candidates for translation into the clinic. These include agents that disrupt the interaction between MDM2/MDM4 and p53 (e.g., nutlin); proteasome, and histone deacetylase (HDAC) inhibitors; bromodomain extra-terminal (BET) proteins inhibitors, which may be selectively active against tumors with MYCN amplification; and a genetically modified adenovirus that selectively replicates in cells with high levels of free E2F transcription factor resulting from a dysfunctional RB1 pathway. Right: Proposed immunotherapy approaches in retinoblastoma, namely, anti-GD2 and anti-NcGM3 monoclonal antibodies, anti-GD2CART cells, and inhibitors of immune checkpoints as PD-1/PD-L1 and B7H3 (omburtamab). In the presence of anti-GD2 monoclonal antibodies, retinoblastoma cells may be targeted by the immune system, as described in neuroblastoma, via a response including granulocyte- and natural killer-mediated antibody-dependent cellular cytotoxicity (ADCC) and complement- and macrophage-mediated cytotoxicity.