Phototruncation cell tracking with near-infrared photoimmunotherapy using heptamethine cyanine dye to visualise migratory dynamics of immune cells.

BACKGROUND: Noninvasive in vivo cell tracking is valuable in understanding the mechanisms that enhance anti-cancer immunity. We have recently developed a new method called phototruncation-assisted cell tracking (PACT), that uses photoconvertible cell tracking technology to detect in vivo cell migration. This method has the advantages of not requiring genetic engineering of cells and employing tissue-penetrant near-infrared light. METHODS: We applied PACT to monitor the migration of immune cells between a tumour and its tumour-draining lymph node (TDLN) after near-infrared photoimmunotherapy (NIR-PIT). FINDINGS: PACT showed a significant increase in the migration of dendritic cells (DCs) and macrophages from the tumour to the TDLN immediately after NIR-PIT. This migration by NIR-PIT was abrogated by inhibiting the sphingosine-1-phosphate pathway or Gαi signaling. These results were corroborated by intranodal immune cell profiles at two days post-treatment; NIR-PIT significantly induced DC maturation and increased and activated the CD8+ T cell population in the TDLN. Furthermore, PACT revealed that NIR-PIT significantly enhanced the migration of CD8+ T cells from the TDLN to the tumour four days post-treatment, which was consistent with the immunohistochemical assessment of tumour-infiltrating lymphocytes and tumour regression. INTERPRETATION: Immune cells dramatically migrated between the tumour and TDLN following NIR-PIT, indicating its potential as an immune-stimulating therapy. Also, PACT is potentially applicable to a wide range of immunological research. FUNDING: This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Centre for Cancer Research (grant number: ZIA BC011513 and ZIA BC011506).

Near-infrared photoimmunotherapy targeting Nectin-4 in a preclinical model of bladder cancer.

Enfortumab vedotin (EV), an antibody-drug conjugate (ADC) that targets Nectin-4, has shown promising results in the treatment of bladder cancer. However, multiple resistance mechanisms that are unique to ADCs limit the therapeutic potential of EV in clinical practice. Here, we developed and tested a Nectin-4-targeted near-infrared photoimmunotherapy (NIR-PIT) that utilizes the same target as EV but utilizes a distinct cytotoxic and immunotherapeutic pathway in preclinical models of bladder cancer. NIR-PIT was effective in vitro against luminal subtype human bladder cancer cell lines (RT4, RT112, MGH-U3, SW780, and HT1376-luc), but not against other subtype cell lines (UMUC3 and T24). In vivo, the tumor site was clearly visible by Nectin-4-IR700 fluorescence 24 h after its administration, suggesting the potential as an intraoperative imaging modality. NIR-PIT significantly suppressed tumor growth and prolonged survival in SW780 and RT112 xenograft models. Weekly treatment with NIR-PIT further improved tumor control in RT112 xenograft models. The effectiveness of NIR-PIT was also confirmed in HT1376-luc orthotopic xenograft models. Histological analysis verified that NIR-PIT induced a significant pathologic response. Taken together, Nectin-4-targeted NIR-PIT shows promise as a treatment for luminal subtype bladder cancers.

A multi-institutional survey of the effectiveness of chemotherapy combined with radiotherapy for patients with nasopharyngeal carcinoma.

BACKGROUND: Previous randomized trials have shown a survival advantage of concurrent platinum-based chemoradiotherapy with or without adjuvant chemotherapy for advanced nasopharyngeal cancer. Applicability of these data to a Japanese population is an important issue which remains to be solved. METHODS: A retrospective survey of treatment of patients with nasopharyngeal cancer in 17 institutions in Japan was done with special reference to the relationship between the type of chemotherapy and survival outcome. Chemotherapy used was classified according to: (i) whether > or =2 courses of platinum plus 5-fluorouracil (FP) was given; or (ii) whether platinum was administered concurrently with radiotherapy (RT). This resulted in three groups being produced consisting of (i)/(ii) = YES/YES, other miscellaneous (MISC) and RT alone. RESULTS: Of 333 evaluable replies, 67 patients (20%) corresponded to the YES/YES, 192 (58%) to the MISC and 74 (22%) to the RT alone group. The YES/YES group achieved a better overall survival than RT alone for patients with intermediate stage (T3N0 or T1-3N1, 81.9 versus 60.7% at 5 years, P = 0.042) and advanced stage (T4 or N2/3, 56.6 versus 31.5%, P = 0.017) disease. The MISC group achieved an almost identical survival rate to that in the YES/YES group for patients with intermediate stage disease (81.9% at 5 years, P = 0.968), whereas it was not significantly different from that of the RT alone group for patients with advanced stage disease (44.0%, P = 0.261). CONCLUSION: The results of this survey mirrored the data from previous randomized trials for patients with intermediate and advanced stage nasopharyngeal cancer in Japan. However, confirmatory prospective trials are required to test the efficacy of less toxic approaches for patients with intermediate stage disease.