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Nagaya et al. Published OnlineFirst June 6, 2017; DOI: 10.1158/1541-7786.MCR-17-0164 Discussion PSMA is the prototypic cell-surface marker of prostate cancer and provides an attractive target for mAb targeted therapies. The first mAb that received FDA approval for clinical use in prostate cancer was capromab pendetide, a murine, 111In-labeled, mAb (7E11) directed to PSMA (13, 30). However, results were disappointing as the mAb targeted an internal domain of PSMA (31, 32). Several mAbs targeting the external domain of PSMA are currently under- going clinical investigation in prostate cancer. Although there was some potential clinical utility of radiolabeled mAb for imaging and diagnostic purposes (33), therapeutic radioisotopic labeling of the mAb have proven disappointing (7, 34). The conjugate anti-PSMA–IR700 proved to be an effective agent for treating a PSMA-expressing prostate cancer model with NIR- PIT. Unlike other mAb-mediated therapies, NIR-PIT with anti- PSMA–IR700 led to rapid cell death in vitro and tumor growth reduction and survival improvement in vivo. Thus, anti-PSMA- IR700 could be an effective platform for NIR-PIT in PSMA- expressing tumors. IR700 conjugation minimally alters the anti- body due to the small size and hydrophilic nature of the IR700 dye (19). As a result, these APCs show high target accumulation with minimal distribution in normal tissue and minimal binding to nontarget-expressing cells. The effectiveness of NIR-PIT has been demonstrated in a variety of different tumor types with a variety of antibodies (19, 21–26, 35). The anti-PSMA antibody–IR700 conjugate achieved adequate tumor TBRs as shown in Fig. 2, indicating that it may be practical for clinical application during surgical, endoscopic, or trans- needle procedures because of its high TBR on the PSMA-expres- sing tumors. Efficient binding and distribution of the antibody in the tumor are important for APCs to be effective as agents for NIR- PIT. This also holds for antibody–toxin or antibody–drug con- jugates since, to be effective, the drugs and toxins must be internalized after cell binding. Our results showed that anti-PSMA antibody bound to PSMA on cells specifically and was internal- ized within 6 hours of incubation in PSMA-expressing cancer cells as shown in Fig. 1. These results suggest that anti-PSMA antibody has favorable characteristics for an antibody–drug conjugate. Rapid and massive cancer cell killing adjacent to tumor vessels with NIR-PIT leads to an immediate increase in vascular perme- ability after therapy (36–38). The delivery of various nano-sized or macromolecular drugs into a NIR-PIT–treated tumor increases up to 24-fold compared with that in a control nontreated tumor immediately after the initial NIR light exposure, a phenomenon that is known as the super enhanced permeability and retention (SUPR) effect induced by NIR-PIT (36–38). After the first NIR-PIT, circulating APCs can enter the treated tumor bed with greater permeability and penetration than prior to NIR-PIT. There, they bind homogeneously to the surviving fraction of cancer cells (39). Therefore, the second exposure to NIR light can further enhance therapeutic effects of NIR-PIT (40). Thus, we chose the current therapeutic regimen with a single injection of the APC and two light exposures to maximize therapeutic effectiveness. Fractionated dosing of the APC with repeated light exposure is also likely to increase effectiveness. For instance, in a model utilizing EGFR-targeted NIR-PIT, repeated dosing of the APC and NIR light dosing was reported to improve the therapeutic effect compared with a single shot approach (40, 41). Therefore, we investigated this regimen of repeated APC and NIR light exposure. This proved to be an effective therapy for treating a PSMA- 1160 Mol Cancer Res; 15(9) September 2017 expressing prostate cancer model. Looking forward to NIR-PIT use in humans, splitting the APC dose and using repeated light exposures will reduce toxicity of drugs because NIR light exposure by itself is harmless. Therefore, repeated NIR-PIT will optimize efficacy without increasing toxicity. In cancer therapy, anticancer drugs often fail because hetero- geneous cellular density and vascularity, increased interstitial pressure, and other structural barriers imposed by the extracellular matrix prevent the drug from reaching its target in sufficient concentrations to be effective (42, 43). Moreover, naturally occur- ring tumors usually are phenotypically and functionally hetero- geneous (44, 45). Repeated NIR-PIT with additional various types of APC or delivery of higher doses of nontargeted anticancer drugs by taking advantage of the SUPR effect are good strategies to improve the therapeutic effect of cancer (38). Another aspect of NIR-PIT is its immunogenic nature. Cells treated with NIR-PIT undergo rapid volume expansion leading to rupture of the cell membrane and extrusion of cell contents into the extracellular space (20). Thus, NIR-PIT induces nearly imme- diate immunogenic cell death rather than apoptotic cell death which is induced by most other cancer therapies (46–48). As the immune effects of NIR-PIT are currently unknown it is difficult to know whether this will be of benefit to patients, although it is anticipated that immunogenic cell death will augment the ther- apeutic effect of NIR-PIT as it selectively kills target cells while nontarget cells immediately adjacent, including effector immune cells, show no toxic effects (19). In one specific example, targeting of local regulatory T cells with NIR-PIT (35) induced a rapid antitumor immune activation and regression of the PIT-treated tumor. Moreover, NIR-PIT could enable activated cytotoxic effec- tor cells to attack other tumors of a similar nature located distant from the NIR-PIT–treated lesion. While NIR-PIT shows highly selective cytotoxicity, and NIR light exposure can be easily applied to superficial tumors, an obvious limitation is the inability to deliver NIR light to the tumor located deep in the tissue such as bone. Skin, fat, and other organs will absorb NIR light before it reaches the tumor. There are several potential solutions to this problem. For instance, NIR light exposure could be delivered to a tumor and to adjacent structures while the tissues are still exposed during a surgical resection, thus treating residual tumor in the tumor margin or in regional lymph nodes. Such procedures have been proposed in the past with PDT (49, 50); however, we believe that NIR-PIT would be much more effective with lower toxicity than PDT. Alternatively, fiber optic light probes could be placed within or nearby tumor using endoscopes, laparoscopes, catheters, or image-guided percutane- ous needles. This would enable lesions such as prostate cancer recurrences or regional lymph nodes to be effectively treated as the depth of penetration of NIR light is at least 2 cm. For instance, it is entirely feasible that locally recurrent prostate cancer adjacent to the urethra could be treated with NIR-PIT via a transparent transuretheral catheter. Conclusion The fully human anti-PSMA antibody–IR700 conjugate showed accumulation in PSMA-expressing prostate cancer cells. Subsequent NIR-PIT using anti-PSMA–IR700–induced remark- able therapeutic responses after repeated NIR-PIT cycles in a PSMA-expressing prostate cancer and cured more than two third of cancers. Thus, NIR-PIT utilizing PSMA as the targeting antigen Molecular Cancer Research Downloaded from mcr.aacrjournals.org on December 1, 2020. © 2017 American Association for Cancer Research.PDF Image | Near-Infrared Photoimmunotherapy Targeting Prostate Cancer
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