Theranostic Near-Infrared Photoimmunotherapy
Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cell-selective cancer therapy with enormous potential for treating cancer in a variety of ways. NIR-PIT not only kills cancer cells, but can also eliminate other unfavorable cells including cancer stem cells and immune-suppressor cells, among others, without damaging favorable cells such as immune cells, vascular cells and tissue stem cells. This technique can efficiently activate anti-tumor host immunity in a way that can even cure untreated distant metastasis.
KeywordsNear-infrared photoimmunotherapy Cancer Tumor immunity
Targeted cancer therapies offer the promise of highly effective tumor control with fewer side-effects than conventional cancer treatments. In this approach, drugs or radioisotopes are directed to a tumor by coupling to monoclonal antibodies (mAbs) against specific targets on the cancer cell surface. These antibody–drug conjugates (ADCs) have had modest commercial success, but side-effects remain problematic. We have greatly advanced targeted cancer detection that assists surgical or endoscopic therapy by developing a series of optical imaging probes (‘activatable probes’) that only fluoresce when they are bound to or inside tumors (Kobayashi et al. 2010; Kobayashi and Choyke 2011), enabling precise tracking of cancer cells and drugs in the tissue (Urano et al. 2009). With these probes, cancer-specific fluorescence has been achieved in animal models and in fresh surgical specimens from cancer patients.
From a physics perspective, excitation energy can be dissipated in the form of fluorescent light for diagnosis. Alternatively, it can be exchanged for heat, oxidation or photochemical reactions to induce cytotoxic treatment. Our work is to be differentiated from conventional photodynamic therapy (PDT). PDT has been in limited clinical use for several decades. Photofrin (porfimer) is the most commonly employed PDT agent and has been used to treat endobronchial, esophageal and bladder cancers. Photofrin and related compounds passively permeate into cells based on their hydrophobicity which is non-specific but slightly favors uptake in cancer cells and when exposed to light in the presence of oxygen, generate reactive oxygen species. Reactive oxygen species are typically toxic to the cell, resulting in cell death, however, this typically occurs within the cytoplasm and results in apoptosis rather than necrosis. Although PDT is used in specific cases, widespread adoption has been limited because the current compounds distribute rather non-specifically and permeate into normal cells leading to off-target toxicities. For instance, patients are often unable to go outside into direct sunlight for several months and even room light for several days. Incidental exposure to strong light, for instance, from a copy machine, can be catastrophic. Moreover, PDT is notorious for inducing serious inflammatory changes at the treatment site, limiting its utility. This relates to the non-specific biodistribution and slow clearance rates (half-life of 23 days) of PDT agents. More general use of PDT is thus limited by its potential side effects. Targeted PDT has been attempted but delivery issues related to the large number of photosensitizer molecules in each conjugate, limits the achievable concentrations of the photosensitizer.
22.2 NIR-PIT Can Selectively Kill Various Cancer Cells
22.3 NIR-PIT Rapidly Enhances Nano-Drug Delivery
In addition, NIR-PIT has a desirable side-effect: it initially causes enlargement of the tumor vasculature, increasing blood flow and permeability that induces enhanced delivery of various size of nano-drugs ranging from 5 to 300 nm in diameter.
22.4 NIR-PIT Initiates Anti-Tumor Host Immunity and Promotes Rapid Healing
Three-dimensional dynamic quantitative phase-contrast microscopy (QPM) and dual selective plane illumination microscopy (dSPIM) of tumor cells undergoing PIT showed rapid swelling in treated cells immediately after light exposure suggesting rapid water influx into cells, followed by irreversible morphologic changes such as bleb formation, and rupture of cellular membrane and vesicles. Furthermore, biological markers of ICD including relocation of HSP70/90 and calreticulin from cytosol to cellular membrane, and release of calreticulin, ATP and High Mobility Group Box 1 (HMGB1), were clearly detected immediately after NIR-PIT. When NIR-PIT was performed in a mixed culture of cancer cells and immature dendritic cells, maturation of immature dendritic cells was strongly induced rapidly after NIR-PIT against cancer cells.
Because cell membranes across mammalian species exhibit virtually identical physico-chemical properties, they are equally susceptible to the photochemical damage induced by NIR-PIT. Thus, new NIR-PIT conjugates can be developed in vitro, ex vivo or in animal models with a very high likelihood of successful translation to human patients. This translatability is an important advantage of our chemistry- and photophysics-based approach to cancer treatment. NIR-PIT technology opens the doors for many clinical applications and we hope it will lead to new treatments for numerous different cancer types. In addition, we have found that intact tissue stem cells in the tumor bed greatly contribute to clean wound healing, vital for improving the prognosis and quality of life of cancer patients treated with NIR-PIT.
22.5 Targeting Systemic Metastases
NIR-PIT shows immense promise for practical and clinical applications. Several NIR-PIT-related patents were licensed to the start-up biotech company Aspyrian Therapeutic Inc., which started a phase I clinical trial in June 2015 and currently advanced to phase II, using the cetuximab–IR700 conjugate (RM-1929) to treat head and neck cancer patients who had failed to respond to all conventional cancer therapies including surgery, chemotherapy and radiation therapy (https://clinicaltrials.gov/ct2/show/NCT02422979). Similar trials are planned for lung, esophageal, bladder and pancreatic cancer, some precancerous conditions including leukoplakia and papillomatosis, and others by targeting cancer cells or immune-suppressor cells in the near future. We have engaged researchers internationally to further explore the possibilities of NIR-PIT and to expedite its introduction into the clinic.
This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.
(MP4 933398 kb)
Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.
The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.