Near-InfraRed PhotoImmunoTherapy (NIR-PIT) for the local control of solid cancers: Challenges and potentials for human applications

Abstract

Near-InfraRed PhotoImmunoTherapy (NIR-PIT) is a novel cancer-targeted treatment effected by a chemical conjugation between a photosensitiser (e.g. the NIR phthalocyanine dye IRDye700DX) and a cancer-targeting moiety (e.g. a monoclonal antibody, moAb). Delivery of a conjugate in vivo leads to accumulation at the tumour cell surface by binding to cell surface receptors or antigens. Upon deployment of focal NIR-light, irradiation of the conjugate results in a rapid, targeted cell death. However, the mechanisms of action to produce the cytotoxic effects have yet to be fully understood. Herein, we bring together the current knowledge of NIR-PIT from preclinical and clinical studies in a variety of cancers highlighting the key unanswered research questions. Furthermore, we discuss how to enhance the local control of solid cancers using this novel treatment regimen.

Keywords: Clinical trials; In vitro; In vivo; Local control; Monoclonal antibodies; Near-InfraRed fluorophores; PhotoImmunoTherapy; Solid cancers.

Graphical abstract

Fig. 1

Direct cytotoxic effects of NIR-PIT on tumour cells expressing cancer specific antigens. 1A) Upon NIR-light irradiation, the IR700 dye changes shape and solubility, becoming hydrophobic and showing a tendency to aggregate. This APC physical modification significantly stress the cell membrane with a consequent disruption of its transmembrane osmotic gradient. 1B) The following disruption of the transmembrane osmotic gradient leads to cell swelling, blebbing and bursting. The release of intracytoplasmatic antigens and Damage-Associated Molecular Patterns (DAMPs) in the extracellular space activates the host immune system against the dying tumour cells. The overall process has been named Immunogenic Cell Death (ICD).

Fig. 2

In vitro morphological changes following affibody-based PIT. Incubation of U87-MGvIII spheroids with the ZEGFR:03115–IR700DX for 6 h and irradiation with a red LED (16 J/cm2) induced phototoxic cell death and disintegration of the architectural structure of the spheroid population (Courtesy of Dr Gabriela Kramer-Marek) (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).

Fig. 3

Cytotoxic effects of NIR-PIT induced by the activation of the host anti-cancer immune response. Following the exposure to NIR light, dying tumour cells rapidly release cancer-specific antigens and membrane damage danger signals which promote the maturation of Dendritic Cells. The consequent activation of tumour infiltrating CD8 + T cells result in the selective killing of residual tumour cells.