Recently, it has been elucidated that blocking immunosuppressive networks and immune checkpoints realizes a successful immunotherapeutic modality for the treatment of cancer.42–45 Therefore, a combination of Ad-REIC with inhibition of immune checkpoint and/or suppressor cells will offer a more promising strategy for the next generation of can­cer immunotherapy. It has been reported that the two main immune checkpoint pathways involve signaling through cyto­toxic T-lymphocyte-associated antigen 4 (CTLA-4) or pro­grammed cell death protein 1 (PD-1). The CTLA-4 pathway is more important in the early phase of the immune system activation (priming phase), while the PD-1 pathway is more important in the tumor microenvironment during the effec­tor phase.46 A combination of Ad-REIC with PD-1 pathway blockade seems to be more appropriate, since Ad-REIC gen­erates a strong antitumor immunity, as demonstrated in this patient. One of the most important findings (from early clini­cal trials of PD-1 pathway blockade for advance solid cancers) reveals that programmed death-ligand 1 (PD-L1) expression on tumor cells reflects an immune-active microenvironment and is the single factor most closely correlated with response to anti-PD-1 blockade.43,47 Therefore, in our future study it is crucial to investigate PD-L1 expression status in tumors, before and after Ad-REIC as well in metastatic tumors, if recurrence occurs. In terms of blocking immunosuppressive networks, targeted therapies and cytotoxic agents also modulate immune responses.44 Among them, sunitinib, vascular endothelial growth factor A (VEGF-A), and low-dose cyclophosphamide are possible candidates to combine with Ad-REIC in order to improve clinical outcomes in the treatment of CRPC.

Apart from this combination strategy, the second gen­eration of Ad-REIC using a super gene expression (SGE) system (Ad-SGE-REIC) has already been developed in order to augment the therapeutic effects of in situ Ad-REIC.48 The SGE system is a new plasmid vector, developed by placing three enhancers in tandem after poly A to realize extremely high expression of the targeted REIC gene.49 A Phase I/IIa clinical trial of Ad-SGE-REIC for localized prostate cancer is being conducted at two institutions in the United States ( Similarly, a Phase I/IIa clinical trial for malignant pleural mesothelioma will be initiated in the near future at three institutions in Japan. In addition, preclinical studies of Ad-REIC on various intractable solid cancers including pancreatic cancer,36 lung cancer,37 and malignant glioma38 have been conducted successfully.

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A 63-year-old man with mCRPC after docetaxel failure was successfully treated for two years with in situ Ad-REIC gene therapy. Repeated injections of Ad-REIC into metastatic LNs showed remarkable safety profiles and induced potent direct and indirect antitumor effects, thus paving the way for a new, future cancer therapeutic vaccine against a variety of intrac­table solid cancers.


We thank Dr. Sabina Mahmood, Dr. Shigeru Kobayashi (Okayama University Graduate School, Okayama, Japan), and Mr. Hitoshi Shiomi (Momotaro-Gene Inc., Okayama, Japan) for providing valuable suggestions and help with the prepara­tion of this manuscript.

Author Contributions

Conceived and designed the study: HK, MW, YN. Performed medical operations: HK, KS, YA, TS, HY, MW. Analyzed the data: HK, KS, YA. Wrote the first draft of the manuscript: HK. Contributed to the writing of the manuscript: HK, KS, YA, TS, MW. Agree with manuscript results and conclusions: HK, KS, YA, SE, TH, SK, HY, MW, YN. Jointly developed the structure and arguments for the paper: HK, KS, YA, MW, YN. Made critical revisions and approved final version: HK, HY, MW, YN. All authors reviewed and approved of the final manuscript.


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Source: Clinical Medicine Insights: Oncology.
Originally published on March 23, 2015.