Photochemical Internalization for Intracellular Drug Delivery. From Basic Mechanisms to Clinical Research
Fantastisk rykende fersk artikkel. Sjekk hva som står om dyreforsøk under fimaNac… publikasjon på gang. Er det AZ forsøkene?
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Ikke dårlig denne om Vacc heller:
"In conclusion, PCI is demonstrated preclinically to enhance MHCI crosspresentation and to be a
very promising method for strong enhancement of cancer vaccine efficacy [219,220,222].
PCI-enhanced vaccination has also recently been validated in a Phase I study on healthy volunteers,
with the objective to assess safety, tolerability and immune response after PCI of human papilloma
virus E7 (HPV E7) and keyhole limpet hemocyanin (KLH) antigens (ClinicalTrials.gov Identifier:
NCT02947854). This study (Høgset et al. manuscript in preparation) confirmed preclinical results
(unpublished data) showing that PCI significant enhances cellular immune responses to HPV
peptide antigens. "
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Strålende gravearbeid på en fredagskveld, @solvoll. Takk også til @Investor og @sjog for høyst interessante utdrag fra artikkelen.
Ferten av suksess blir stadig sterkere. Men enn så lenge er det bare de med nese for det som er i stand til å forstå hva som kan være i ferd med å skje.
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Vi hadde en diskusjon her tidligere vedr om carriers som feks lipofectamine var konkurrent eller ikke til fimaNac.
Det som står om naked delivery, “very promising results”, kan tyde på at fimaNac kan få anvendelse også uten å bruke en carrier.
Enig?
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The PCI-induced enhancement of nucleic acid delivery across a wide range of nucleic acid and delivery vehicle type confirms the central role of endosomal escape as a barrier for intracellular nucleic acid delivery. Even for several delivery systems believed to be quite efficient in endosomal escape, such as adenovirus, and lipidic vehicles such as lipofectamine significant improvement could be induced by PCI, strongly indicating endosomal escape as an important limitation also for
J. Clin. Med. 2020, 9, 528 23 of 52
such vehicles. Both for adenoviral and for lipidic delivery vehicles there however seem to by substantial differences in the PCI effect between different cell types [196,214], indicating differences in endocytic trafficking and the processing of such vehicles in different cell types.
Mildt sagt ganske interresant.
Fantastisk gravearbeid solvoll.
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Hvis artikkelen blir lang og tung for noen, er oppsummeringen og fremtiden med PCI overbevisende nok.
- 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. "
“Beam me up, Scotty” Nå tar det av…
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Edit
Sletter denne posten.
Var ikke kla over det, men ser faktisk ut som 46 pasienter har fått pci-bleomycin fordelt på 2 studier . Trodde de bare hadde ca 20 totalt.
I så fall stemmer det med 70, ikke medregnet RELEASE.
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Nå tar jeg helt sikkert feil, men skulle ikke dette ha blitt kommunisert via børsmelding?
Ja, nå er alle artiklene som viser hvor forferdelig synd det var at H&N-studien ikke ble gjennomført publisert. Det må jo bli tatt opp igjen, i kombinasjon med en CPI!
Dette er altså først og fremst rGelonin som ble diskutert for en stund siden her på fundamentaltråden. Så vidt jeg har forstått et foreløpig fullstendig uutforsket felt klinisk, som ligger åpent for PCIB. Det jeg foreslo å kalle FimaCHEM 2.0.
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Ja, det kan man ikke være uenig i. NAc kan brukes med eller uten carrier, og der applikasjonen muliggjør uten, så er det det beste. De viktigste samarbeidene innen NAc er åpenbart med levering av mRNA uten carrier.
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Og det er positivt pga…? Mindre bivirkninger?
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Exakt
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Voldsomt imponerende å lese denne artikkelen.
Forstår nå uttrykket “virker på alt”.
Hvorledes definerer du “konkurrent” når det meste som utvikles med gode resultater bare blir enda bedre ved å legge til PCI-teknologien?
Og et hav av anvendelsesområder.
Grunnen til at PCI-teknologien er så enestående er slik jeg oppfatter det at delivery er en fysisk prosess (ikke biologisk) og at en kan levere druget presist på mengde (effekt) sted og tid mens andre har problemer med denne presisjonen og i tillegg strir med bivirkninger.
En kan også grunnet delivery er så presist senke mengde medisin samtidig med fortsatt øket effekt.
Kan ikke forstå annet enn at PCIB fremtidig burde vært blandt de selskapene som skal utvikle vaksiner mot pandamier.
PCIB og AZ er i forhandlinger nå , har forhandlet i 6 uker og har tilgode 18 uker.
Det er svært kort tid i Biotek.
lykke til
Fantastiske billedserier fig 14 side 36 + flere fra Head & Neck studien.
Er meget spent på effekten av dobbel behandling.
Kan bli alvorlig mange CR’r.
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Ingen som så langt har kommentert de svært spennende resultatene som presenteres i dyremodeller på hjernesvulst.
Kontrollen her (svart kurve) er bleomycin, mens grønn er PCI,
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Ang hode/hals. Søker man på PCIA202/10 på https://reec.aemps.es/reec/public/detail.html
og skroller til bunnen får man opp en rapport fra fase 2 -studien på hode hals.
Den studien ble som nevnt stoppet pga forventet konkurranse fra immunterapi.
Hvordan gikk det så med immunterapi? Fant denne som viste ingen effekt av nivolumab. på progression free survival
https://www.nejm.org/doi/full/10.1056/NEJMoa1602252
The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32).
De mener å vise til økt overlevelse, men det ser marginalt ut, spør du meg.
The median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy.
Uansett- i den nevnte rapporten framkommer noen interessante Kaplan-Meier plots, som viser OS og PFS ved data cut-off (studiet ble jo stoppet). Små tall, selvsagt men det gruser jo Nivolumab ned i støvlene!
Etter å ha sett hvor gode data PCIB har her ble jeg litt mistenksom. Er Nivolumab studien på en svært syk pasientpopulasjon som ikke er sammenliknbar? Nei, skal vi tro denne artikkelen er forventet overlevelse for “Recurrent Squamous-Cell Carcinoma of the Head and Neck” 6-9 mnd:
The survival rate at 3 years after potentially curative surgical or radiation treatment for locally advanced squamous cell carcinoma of head and neck (SCCHN) remains quite poor at 30 to 50%. Over 50% of these patients relapse locally or at distant sites and with a median survival of 6-9 months.
Og så dobbeltsjekker vi mot rapporten og ganske riktig er dette samme indikasjon som PCIB:
Indication: Recurrent head and neck squamous cell
carcinoma
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La ut ditt flotte sammendrag på /stockaholics med link, så får vi håpe på nye 3 tusen klikk og at kjøpsbølgen kommer.Beklager det er Søndag i dag og jeg glemte opphavsrett så jeg slettet sammendraget,men linken ligger.
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En fersk aksjonærliste for PCIB er tilgjengelig for Insider-medlemmer. Ikke Insider? Les mer og prøv gratis
Utdrag från senaste artikeln.
When using the fimaporfin (TPCS2a) photosensitizer [51], which is currently being developed in clinical studies [106], the photosensitizer molecule is added as a separate entity, not being chemically
or physically attached to the other components of the delivery system. For many applications it
could however seem advantageous to have the photosensitiser attached to the nucleic acid cargo, the delivery vehicle or both. Such systems have been developed both for oligonucleotides [162,163] and
for plasmid [186] delivery, and has been shown to work well. While there are obvious advantages of having all components in one cargo, it however also makes the synthesis and formulation processes more complicated, and for some covalent systems it may also be a problem to achieve optimal doses
of all components in the system at the same time. Thus, using PCI with small molecule
photosensitizer like fimaporfin constitutes a flexible and efficient system for nucleic acid delivery.
Enkelheten är genial. Amphinex är som ni vet autoklaverbar och kan sedan stå lång tid på en hylla i väntan på användning. Behöver inte administreras samtidigt eller i en och samma komplex som carriern för att fungera vilket underlättar.
Angående leverering mha virus:
However, many viral systems have severe safety concerns, and in general it
would be very advantageous to be able to target virus-mediated gene delivery to the desired sites in the body, and also to use as low doses of virus as possible to diminish production problems, safety concerns and the induction of unwanted immune reactions.
It was therefore somewhat surprising that PCI could strongly enhance adenovirus-mediated transduction, with an enhancement of >20 times achieved by the employment of PCI [204,205]. In the same study dose response experiments showed that the
transduction-enhancing effect of PCI was especially good at low virus doses, something that may be very valuable in the clinical use of adenovirus mediated therapies.
Återigen den stora fördelen med fimaporfin, låg dos ger minskade biverkningar men 20ggr förstärkning.
Kanske är det pga olika bra resultat i olika celltyper som Astra Zeneca ville testa ut i så många olika celltyper som möjligt?
Both for adenoviral and for lipidic delivery vehicles there however seem to by
substantial differences in the PCI effect between different cell types [196,214], indicating differences in endocytic trafficking and the processing of such vehicles in different cell types.
Many polymeric delivery vehicles (e.g., PEI) are believed to effect endosomal escape through a
so-called “proton sponge” effect [215], where protons are captured by the vehicles leading to
endosomal swelling and rupture of the endosomes. For this mechanism to be effective it is necessary with a minimum amount of vehicle inside the endosomes to induce the necessary endosomal
swelling. While this may be easy to achieve in vitro, it is much more difficult in vivo, especially since such vehicles often induce toxic reactions strongly limiting the amount of vehicle that can be injected. It is therefore very interesting that PCI is able to enhance nucleic acid delivery with such vehicles in amounts far below what is needed for the induction of endosomal escape by the “proton sponge” effect [214,216], potentially making it possible to use the vehicles also for in vivo
applications where vehicle toxicity would normally be of concern.
Samma visa igen: mycket lägre doser ger mindre biverkningar men ökad effekt. 
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