Photochemical Internalization: Light Paves Way for New Cancer Chemotherapies and Vaccines
<p>Photochemical internalization. The drug is co-administered with the photosensitizer. The photosensitizer accumulates in cell membranes and the drug is taken up through endocytosis. ROS are generated during illumination, which leads to disruption of the endocytic membrane and release of the drug into the cytosol (modified with courtesy from PCI Biotech: <a href="http://pcibiotech.no/what-is-pci/" target="_blank">http://pcibiotech.no/what-is-pci/</a>).</p> "> Figure 2
<p>Antigen uptake, processing, and T-cell presentation in PCI-based vaccination. Photosensitizer and antigen are endocytosed into an antigen-presenting cell (APC). The photosensitizer is attached to the endosomal membrane and the antigen is contained in the endosomal lumen. After a wash-out period, where excess photosensitizer dissociates from the outer plasma membrane, light exposure causes endosomal eruption and cytosolic release of antigen for proteasomal degradation and MHC class-I presentation to CD8 T cells. In the absence of the photosensitizer and light, endosomes mature and fuse with lysosomes for MHC class-II presentation of digested antigens to CD4 T cells.</p> "> Figure 3
<p>PRISMA flow diagram for systematic selection and review of studies.</p> ">
Abstract
:1. Introduction
1.1. Cancer Therapy Development
1.2. Methods for Cytosolic Targeting
1.3. Photodynamic Therapy (PDT)
1.4. PCI—A Photosensitizer—And Light-Driven Technology for Cellular Internalization of Molecules
1.5. Photosensitizers in Use
1.6. PCI in Immunotherapy
1.7. Cancer Vaccines
1.8. Objective
2. Results
2.1. Study Selection and Study Characteristics
2.2. Preclinical Studies with PCI of Cytotoxic Therapeutics
2.3. Clinical Studies with PCI of Cytotoxic Therapeutics
2.4. PCI Immunotherapy
3. Discussion
3.1. PCI of Cytotoxic Therapeutics
3.2. PCI in Immunotherapy
3.3. Strength and Limitations
4. Materials and Methods
4.1. Eligibility Criteria
4.2. Information Sources and Search
4.3. Study Selection
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Name | Ex Wave-Length (nm) | Manufacturer | Application |
---|---|---|---|
FIRST GENERATION PHOTOSENSITIZERS | |||
Porfimer sodium | 630 | Axcan Pharma | PDT of esophageal cancer, lung adenocarcinoma, and endobronchial cancer |
SECOND GENERATION PHOTOSENSITIZERS/Prodrugs | |||
5-aminolaevulinic acid | 635 | DUSA Stabiopharma | PDT of mild to moderate actinic keratosis Fluorescence guided resection of glioma |
Methyl-aminolevulinic acid | 579–670 | Galderma | PDT of non-hyperkeratotic actinic keratosis and basal cell carcinoma |
Temoporfin | 652 | Biolitec | PDT of advanced head and neck cancer |
Talaporfin | 664 | Meiji Seika Novartis | PDT of early centrally located lung cancer |
Verteporfin | 690 | Novartis | PDT of age-related macular degeneration |
Redaporfin | 749 | Luzitin | PDT of biliary tract cancer |
PHOTOSENSITIZERS UNDER CLINICAL INVESTIGATIONS | |||
Fotolon | 665 | Apocare Pharma | PDT of nasopharyngeal, sarcoma |
Hexylaminolevulinate | 635 | Photocure | PDT of HPV-induced cervical precancerous lesions and non-muscle invasive bladder cancer |
Radachlorin | 662 | Rada-pharma | PDT of skin cancer |
Photochlor (HTTP) | 664 | Rosewell Park | PDT of head and neck cancer |
Padeliporfin | 762 | Negma-Lerads | PDT of prostate cancer |
Motexafin lutetium | 732 | Pharmacyclics | PDT of coronary artery disease |
Rostaprofin | 664 | Miravant | PDT of age-related macular degeneration |
Talaporfin | 664 | Meiji Seika | PDT of colorectal neoplasms, liver metastasis |
Fimaporfin | 435 | PCI Biotech | PCI of cutaneous or sub-cutaneous malignancies, cholangiocarcinoma and PCI of vaccine antigens |
Author, Year, Country | Tested Tissue/Cells | PCI-Internalized Molecule and Photosensitizer | Study Model | Primary Outcome | Reference |
---|---|---|---|---|---|
PRECLINICAL STUDIES | |||||
Olsen et al., 2013 | Dox-resistant human sarcoma cell line MES-SA/Dx5 and non-resistant MES-SA line | rGel and TPCS2a | In vitro: Cell culture | PCI circumvents the mechanisms of PDT resistance in dox-resistant human sarcoma cell lines | [25] |
O’Rourke et al., 2017 | Rat cortical mixed glial cells, DRG, and satellite glia, HNSCC cell line | Bleomycin and TPPS2a or TPCS2a | In vitro: Cell culture | DRG neurons can survive TPCS2a and TPPS2a-mediated PCI at doses enough to kill the carcinoma cell line | [26] |
Martínez-Jothar et al., 2019 | Human HER2+ and HER2− breast cancer cell lines | Saporin or placebo in PEGylated NP and TPPS2a, functionalized with 11A4 nanobody | In vitro: Cell culture | PCI of saporin-loaded PEGylated NP can be used to selectively induce cell death of HER2+ breast cancer cells | [27] |
Norum et al., 2017 | Murine CC and murine MGC cells in athymic and thymic BALB/c mice | Bleomycin and AlPcS2a | In vivo: Murine allograft model | PCI of bleomycin had a curative effect on tumor cells in thymic, but not in athymic mice and induced immune responses sufficient to reject new tumor cells for up to two months | [28] |
Stratford et al., 2013 | Human sarcoma cell line and human fibrosarcoma cell line, human sarcoma cells in athymic nude mice | CD133-targeting immunotoxins and TPCS2a | In vitro: Cell culture In vivo: Murine xenograft model | Proof-of-concept: PCI of CD133-targeting immunotoxins reduces cellular viability and proliferative capacity of sarcoma cells and inhibits tumor grafting | [29] |
Bostad et al., 2015 | Human CA, ALL, malignant melanoma, and TNBC (CD133+ and CD133−) cell lines, human CA cells in athymic nude mice | CD133-targeting immunotoxin and TPCS2a | In vitro: Cell culture In vivo: Murine xenograft model | Efficient PCI of CD133-targeting immunotoxins in human cancer cell lines in vitro. Proof-of-concept: Anti-tumor response after PCI of CD133-targeting immunotoxins in vivo | [30] |
Eng et al., 2018 | Human TNBC, amelanotic human melanoma, human Melmet cell lines, amelanotic human melanoma cells in athymic nude mice | CSPG4-targeting toxin and TPCS2a | In vitro: Cell culture In vivo: Murine xenograft model | PCI of CSPG4-based immunotoxins induces death of CSPG4-positive and drug-resistant cells of TNBC and malignant melanoma origin, in vitro and in vivo | [32] |
Berstad et al., 2015 | Head and neck squamous cell carcinoma cell line. A-431or SCC-026 cells in athymic nude mice | rGel/EGF (an EGFR-targeted fusion protein) | In vitro: Cell culture In vivo: Murine xenograft model | PCI increased the cytotoxicity of rGel/EGF in EGFR-expressing cells. PCI of rGel/EGF induced significant antitumor effects in A-431 xenograft mice | [31] |
Weyergang et al., 2018 | VEGFR2-expressing endothelial cells, murine colon carcinoma, and breast carcinoma cell lines in vitro and in BALB/c and athymic nude mice | VEGF121/rGel and TPPS2a (in vitro) or TPCS2a (in vivo) | In vitro: Cell culture In vivo: Murine allograft model | PCI of VEGF121/rGel directly targets tumor cells and induces T-cell mediated tumor remission, reduced perfusion, and produced tumor protection in vivo | [63] |
CLINICAL TRIALS IN HUMAN | |||||
Sultan et al., 2016, England | Patients (18 to 85 years) with local recurrent, advanced, or metastatic cutaneous or subcutaneous malignancies | Bleomycin and TPCS2a | Phase I, First-in-human | Administration of TPCS2a was found to be safe and tolerable by all patients. No significant systemic adverse events related to photochemical internalization treatment occurred. | [52,64] |
Jerjes et al., 2019, England | 57-year-old male with end-stage recurrent and therapy-resistant chondroblastic osteosarcoma in the right mandible | Bleomycin and TPCS2a | Case report | Illuminated areas responded favorably to treatment. PCI anti-tumor activity was superior to PDT, clinically and histopathologically. Peri-illumination pain | [65] |
Author, Year, Country | PCI-Internalized Molecule and Photosensitizer | Study Model | Primary Outcome | Reference |
---|---|---|---|---|
PCI IN IMMUNOTHERAPY, preclinical studies | ||||
Waeckerle-Men et al., 2013 | OVA and TPCS2a | In vitro: DCs In vivo: Autologously immunized C57BL/6 mice | Proof-of-concept: Feasibility of PCI of OVA in DCs for stimulation of CTL responses in vitro. Autologous vaccination of mice with PCI-treated DCs led to improved MHC class-I-restricted and antigen-specific CTL response | [33] |
Håkerud et al., 2014 | OVA and TPCS2a | In vitro: DCs In vivo: Allograft model, B16-OVA-melanoma cells in C57BL/6 mice | Proof-of-concept: Photosensitization and immunization directly in vivo. PCI-vaccination stimulated antigen-specific CD8 memory cells and prevented tumor growth | [34] |
Håkerud et al., 2015 | OVA and TPCS2a | In vitro: DCs In vivo: Allograft model, B16-OVA-melanoma cells in C57BL/6 mice | Prophylactic PCI-based vaccination prevented tumor grafting and therapeutic vaccination reduced tumor growth and improved mouse survival | [35] |
Hjálmsdóttir et al., 2016 | DPPC Liposomes loaded with OVA or TPCS2a | In vitro: TPCS2a-and OVA-loaded liposomes Ex vivo CTL in blood and spleen of C57BL/6 mice | Liposomes can be used for PCI-based cytosolic antigen targeting and CTL cross priming and may protect photosensitizers from light-induced inactivation | [20] |
Bruno et al., 2015 | PLGA microparticles loaded with OVA and TPCS2a | In vivo: Allograft model, B16-OVA-melanoma cells in C57BL/6 mice | The combination of PLGA microparticle–based antigen delivery and photosensitization induces stimulation of antigen-specific CTL in a mouse model | [22] |
Haug et al. | In vitro: OVA and TPCS2a. In vivo: HPV 16 E7 protein (HPV43–78) and from tyrosinase-related protein 2 (TRP2 180–188) and TPCS2a | In vitro: Macrophages In vivo: C57BL/6 mice | PCI promotes delivery of peptide antigens to the cytosol of APCs in vitro. Successful induction of antigen-specific CTL responses following intradermal peptide vaccination using PCI in vivo | [36] |
Varypataki et al., 2019 | OVA and TPCS2a or lethally irradiated B16-OVA and TPCS2a | In vivo: Allograft model, B16-OVA-melanoma cells in C57BL/6, congenic CD45.1, MHC class II- and CD40L-deficient mice | PCI-based vaccination caused tumor regression independent of MHC class II or CD4 T cells in melanoma-bearing mice | [37] |
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Šošić, L.; Selbo, P.K.; Kotkowska, Z.K.; Kündig, T.M.; Høgset, A.; Johansen, P. Photochemical Internalization: Light Paves Way for New Cancer Chemotherapies and Vaccines. Cancers 2020, 12, 165. https://doi.org/10.3390/cancers12010165
Šošić L, Selbo PK, Kotkowska ZK, Kündig TM, Høgset A, Johansen P. Photochemical Internalization: Light Paves Way for New Cancer Chemotherapies and Vaccines. Cancers. 2020; 12(1):165. https://doi.org/10.3390/cancers12010165
Chicago/Turabian StyleŠošić, Lara, Pål Kristian Selbo, Zuzanna K. Kotkowska, Thomas M. Kündig, Anders Høgset, and Pål Johansen. 2020. "Photochemical Internalization: Light Paves Way for New Cancer Chemotherapies and Vaccines" Cancers 12, no. 1: 165. https://doi.org/10.3390/cancers12010165
APA StyleŠošić, L., Selbo, P. K., Kotkowska, Z. K., Kündig, T. M., Høgset, A., & Johansen, P. (2020). Photochemical Internalization: Light Paves Way for New Cancer Chemotherapies and Vaccines. Cancers, 12(1), 165. https://doi.org/10.3390/cancers12010165