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Photoimmunotherapy Inhibits Tumor Recurrence After Surgical Resection on a Pancreatic Cancer Patient-Derived Orthotopic Xenograft (PDOX) Nude Mouse Model

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Photoimmunotherapy (PIT) uses a target-specific photosensitizer based on a near-infrared (NIR) phthalocyanine dye, IR700, to induce tumor necrosis after irradiation with NIR light to kill cancer cells, such as those that remain after surgery. The purpose of the present study was to sterilize the surgical bed after pancreatic cancer resection with PIT in carcinoembryonic antigen (CEA)-expressing, patient-derived, orthotopic xenograft (PDOX) nude mouse models.

Methods

After confirmation of tumor engraftment, mice were randomized to two groups: bright light surgery (BLS)-only and BLS + PIT. Each treatment arm consisted of seven tumor-bearing mice. BLS was performed under standard bright-field with an MVX10 long-working distance, high-magnification microscope on all mice. For BLS + PIT, anti-CEA antibody conjugated with IR700 (anti-CEA-IR700) (50 µg) was injected intravenously in all mice 24 h before surgery. After the surgery, the resection bed was then irradiated with a red-light-emitting diode at 690 ± 5 nm with a power density of 150 mW/cm2.

Results

Anti-CEA-IR700 labelled and illuminated the pancreatic cancer PDOX. Minimal residual cancer of the PDOX was detected by fluorescence after BLS. The local recurrence rate was 85.7 % for BLS-only and 28.6 % for BLS + PIT-treated mice (p = 0.05). The average recurrent tumor weight was 1149.0 ± 794.6 mg for BLS-only and 210.8 ± 336.9 mg for BLS + PIT-treated mice (p = 0.015).

Conclusion

Anti-CEA-IR700 was able to label and illuminate a pancreatic cancer PDOX nude mouse model sufficiently for PIT. PIT reduced recurrence by eliminating remaining residual cancer cells after BLS.

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Acknowledgment

This study was supported in part by National Cancer Institute grants CA132971 and 142669 (to Michael Bouvet and AntiCancer, Inc.) and JSPS KAKENHI Grant Numbers 26830081 to Yukihiko Hiroshima, 26462070 to Itaru Endo and 24592009 to Kuniya Tanaka.

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Author notes

    Authors and Affiliations

    1. Department of Surgery, Moores Cancer Center, University of California San Diego, San Diego, CA, USA

      Yukihiko Hiroshima MD, Ali Maawy MD, Robert M. Hoffman PhD & Michael Bouvet MD

    2. AntiCancer, Inc., San Diego, CA, USA

      Yukihiko Hiroshima MD, Yong Zhang PhD & Robert M. Hoffman PhD

    3. Yokohama City University Graduate School of Medicine, Yokohama, Japan

      Yukihiko Hiroshima MD, Kuniya Tanaka MD & Itaru Endo MD

    4. Aspyrian Therapeutics, Inc., San Diego, CA, USA

      Miguel Garcia Guzman PhD, Roger Heim PhD & Lew Makings PhD

    5. OncoFluor, Inc., San Diego, CA, USA

      George A. Luiken MD

    6. National Institutes of Health, Bethesda, MD, USA

      Hisataka Kobayashi MD, PhD

    7. VA San Diego Healthcare System, San Diego, CA, USA

      Michael Bouvet MD

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    1. Yukihiko Hiroshima MD
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    2. Ali Maawy MD
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    Corresponding author

    Correspondence to Michael Bouvet MD.

    Additional information

    Yukihiko Hiroshima and Ali Maawy have contributed equally to this work.

    Electronic supplementary material

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    10434_2015_4553_MOESM1_ESM.tif

    Supplemental Figure 1. Image of photoimmunotherapy (PIT) in a mouse after resection of orthotopic pancreatic cancer. (TIFF 1674 kb)

    10434_2015_4553_MOESM2_ESM.tif

    Supplemental Figure 2. Characterization of the patient-derived pancreatic tumors. Both SDXPC1 and SDXPC2 were diagnosed as moderately differentiated adenocarcinoma with H & E staining (A and C). SDXPC2 was strongly stained with anti-CEA antibody (D), but the signal was minimally detected in SDXPC1 (A). Scale bars: 100 μm. (E - H) Whole body images of subcutaneous pancreatic tumors labeled with anti-CEA-IR700. Anti-CEA-IR700 (50 μg) was injected from the tail vain of the mice with subcutaneous SDXPC1or SDXPC2 tumors. Twenty-four hours later, whole body images were obtained with the OV100 (Olympus). Yellow arrow heads indicate subcutaneous tumors. SDXPC2 was brightly labeled with anti-CEA-IR700 (H), but the specific fluorescence signal from SDXPC1 labeled with anti-CEA-IR700 was minimally detected (F). Scale bars: 10 mm (TIFF 7708 kb)

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    Hiroshima, Y., Maawy, A., Zhang, Y. et al. Photoimmunotherapy Inhibits Tumor Recurrence After Surgical Resection on a Pancreatic Cancer Patient-Derived Orthotopic Xenograft (PDOX) Nude Mouse Model. Ann Surg Oncol 22 (Suppl 3), 1469–1474 (2015). https://doi.org/10.1245/s10434-015-4553-9

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    • DOI: https://doi.org/10.1245/s10434-015-4553-9

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