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- Summary
PCI has been shown to be a versatile tool for the cytotsolic delivery of endocytosed drugs unable to escape the endolysosomal compartmentalization. The recent and currently ongoing clinical trials are based on PCI activation of approved drugs that are only partly accumulating in lysosomes and therefore not optimal for obtaining high specificity and efficacy. Despite these limitations good clinical outcome has been documented.
TPCS2a-based PCI of bleomycin may provide an effective and localised anti-cancer therapy due to the synergistic action from both photodynamic and chemotherapeutic treatments. The first-in-human phase I trial dealt with very difficult-to-treat group of patients who exhausted all the available treatment options of surgery, radiotherapy and chemotherapy. Significant anti-tumour effects were seen with all the doses tested on several different types of tumours in patients with life expectancy not exceeding few months, yet some of them still lived four years after the end of the trial. The PCI-related adverse events were negligible. It was very interesting to see the uniform PCI effect causing tumour death on a number of patients with very aggressive malignancies including squamous cell carcinoma, sarcoma, eccrine (adnexal) carcinoma, and chemo-resistant ductal carcinoma.
The PCI technology, still in the clinical research phase has been used so far in managing advanced and recurrent tumours with high levels of success in eliminating tumours with minimal morbidity and adverse events. Future application of this technology in managing primary disease is yet to come although a phase II pivotal clinical trial on inoperable cholangiocarcinoma has recently been initiated (clinicaltrials.gov identifier NCT04099888).
PCI can be an option specifically when dealing with end-stage disease when the patient has exhausted all conventional treatment options. However, a potential application may also include managing primary disease, which should be considered in future trials. Managing of such an aggressive and widespread form of disease is a real challenge to any clinician. The PCI anti-tumour activity was highly effective and this was proven by randomly surgical biopsies acquired at two different times.
The current experimental and preclinical directions are selecting or designing drugs or drug formuations that are solely activated by PCI. As reviewed here many approaches are under evaluation. The most active area appears to be for PCI to release drugs carried by nanoparticles that in most cases end up in lysosomes. One of the most interesting appears to be the double unwrapping strategy where light of the same wavelength ruptures the endolyosomes and cleaves a photolable bond on the NP simultaneously.
The utilization of immunotoxins may also flourish in combination with PCI. The immunotoxin strategy has struggled with the need to use type II protein toxins that exert an intrinsic ability to penetrate acidic endolysosomal membranes. The specificity will therefore completely rely on the
J. Clin. Med. 2020, 9, 528 39 of 52
targeting moiety which is usually not fully specific for the cancer cells and thus very few drugs, e.g., mexetumomab, are currently approved for clinical use, but limited by many side effects. The use of immunotoxins based on type I protein toxins will not be dependent on a highly selective targeting moiety and preclinical studies are very promising. PCI of immunotoxins may also be attractive for targeting treatment resistant tumors since these protein toxins are targeting pathways independent of the resistant mechanisms evolving by previous chemo- or other therapies.
PCI has also shown promise in improved antigen presentation at least partly due to better cross-presentation and the results in preclinical and healthy volunteers appear very promising.
The use of PCI to translocate nucleic acids into cytosol and the nucleus is also very promising, depending on the approach in particular in cancer research. It is generally difficult to transfect/transduce all tumor cells so bystander effects in various ways including mRNA expression of tumor antigens in antigen presenting cells may become an interesting approach.
For brain tumors alternative approaches to utilize the PCI technology has been presented as examples on how PCI may be utilized in clinical practice.
The PCI technology has evolved strongly the last 20 years and approximately 70 patient and 90 healthy volunteers have so far been included in evaluating this technology. There is clearly a need for more preclinical and clinical research to develop all the alternative uses of the technology that is encouraged by the promising initial clinical studies.
13. Future Directions
The PCI technology, which combines photodynamic therapy and chemotherapy, aims to target multiple pathways to increase response to treatment. This intervention without doubt led to tumour cell death, with minimal collateral damage allowing the healthy tissue to regenerate and restore form and function. The clinical application of this technology in the field of clinical oncology is at its early stages, but the preliminary results are beyond impressive. The uniform effect of PCI against a number of malignancies represents an area of high interest in the molecular genetics of these pathologies. The phase I trial data showed that nearly all the recruited patients had life expectancy not exceeding weeks to few months, yet many have survived for many months to few years after only one round of PCI (average survival about 12 months). Reduction in morbidity and mortality was achieved in many aggressive advanced and/or recurrent malignancies of the head and neck and breast areas. The applications of PCI can extend beyond this to involve other malignancies that are resistant to conventional therapies. Moreover, the role of PCI in managing primary disease is another potential that would allow direct comparisons with chemo-radiation or immunotherapy. «
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" the preliminary results are beyond impressive. "
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