Drug release mechanism of continuous action in tumors Prolongs survival through administration in combination with an immune checkpoint inhibitor, demonstrating the synergistic effect
Liposomes are artificially constructed vesicles made from organic phospholipids that make up cellularmembranes. They provide a type of drug delivery system (DDS) technology that delivers the required amount of a drug to the specific area of the body in timely manner. In some cases, anti-cancer agents can act on healthy tissues instead of the tumor, leading to adverse side effects. However, by encapsulating the drug in a liposome, it is expected that the drug will be selectively delivered to the tumor, suppressing side effects and enhancing the pharmacological efficacy of the drug.
Gemcitabine has a very short elimination half-life*3 in the blood. FF-10832, a liposome based agent, can stabilize the gemcitabine in the blood, accumulating and releasing the blood at tumores with an enhanced permeability and retention (EPR) effect*4. The study in mice demonstrated that when administered as theliposome based agent with a low dose amounting to 1/60 of a dose, the pharmacological benefit of FF-10832 had a significantly better outcome compared to simply administering gemcitabine alone. The pharmacological benefit of FF-10832 was also found in mice where certain types of cancer cells were transplanted, in which gemcitabine did not demonstrate much effectiveness.
While Fujifilm began U.S. Phase I clinical trials on FF-10832 in May this year, they also conducted the studies in mice, elucidating the drug release mechanism in tumores and continuing research on synergistic effects with an immune checkpoint inhibitor. These studies yielded the following results.
[Research Results 1] Drug release mechanism of continuous action in tumors
•FF-10832 was labeled with a fluorescent dye and administered to mice transplanted with human-derived pancreatic cancer cells (Capan-1). Analysis of the behavior of FF-10832 revealed that it had accumulated in those pancreatic cancer cells, and it was observed that immune cells called macrophages*5 within the cancer cells had taken up FF-10832.
• After incorporating FF-10832, the macrophages released the gemcitabine outside of the cell.
• It was observed that FF-10832 had a greater pharmacological efficacy compared to when administeringgemcitabine alone, inhibiting DNA synthesis for cell proliferation over a longer period of time.
From the above, the mechanism for longer exposure of cells was explicated. FF-10832 accumulates in tumor tissue through the EPR effect, and after being incorporated into macrophage, the gemcitabine is gradually released from the liposomes.
[Research Results 2] Improved pharmacological efficacy observed when administered in combination with an immune checkpoint inhibitor
(1) Experiment:
Mice transplanted with mouse-derived breast cancer cells (EMT6) were used to perform single agentadministration and concomitant administration of FF-10832 and immune checkpoint inhibitor to confirm efficacy and tolerability. The administration period was three cycles of the immune checkpoint inhibitor (30mg/m2) twice a week, and three cycles of FF-10832 (12 mg/m2) once a week.
(2) Results:
• When administered as a monotherapy, the median value for mouse survival periods was 15 days for the immune checkpoint inhibitor and 27 days for FF-10832. Meanwhile, when administered as a combination therapy, the median value for mouse survival periods exceeded 46 days, demonstrating a statistically significant difference when compared with the monotherapies. Mouse survival rates for the combination therapy were 100% at 46 days after the 1st administration.
• Even when administered as a combination therapy, noticeable side effects such as weight loss were not observed, and there were no issues with tolerability.
Based on the above, FF-10832 is expected to further suppress tumor proliferation through administration in combination with an immune checkpoint inhibitor and prolong survival periods.
Fujifilm will present its research results on FF-10832 at the “30th EORTC-NCI-AACR SYMPOSIUM”, one of the world’s most prominent cancer related academic conferences, to be held in Dublin, Ireland from November 13th to 16th, 2018.
Fujifilm is harnessing its advanced technologies such as the nano-dispersion technology and ability to synthesize and design compounds to undertake the development of new drugs in the key areas of cancer, central nervous system diseases, and infectious diseases. The company is also focusing on developing drug delivery system (DDS) technologies including liposome drugs, undertaking research and development to apply DDS technologies not only to low-molecular-weight drugs but also to next-generation drugs such as nucleic acid drugs and gene therapy drugs. Going forward, the company will contribute to the resolution of social issues by developing and delivering innovative, high value-added pharmaceutical products.
*1The general term for drugs that have an effect by enabling activated immune cells to attack cancer cells by inhibiting the mechanism (immune checkpoints) that weakens the action of immune cells. Widely used in the treatment of malignant melanomas, lung cancer, stomach cancer, and kidney cancer. The immune checkpoint inhibitor used in the combination therapy with FF-10832 was an anti-CTLA-4 antibody.
*2An anti-cancer drug (generic name: gemcitabine, product name: Gemzar) developed by the U.S. company Eli Lilly and Company. It is used as a drug of first choice for the treatment of pancreatic cancer, and is also indicated for the treatment of a wide range of other cancers (such as lung cancer and ovarian cancer).
*3The time required for the concentration of a drug in the blood to be reduced to half.
*4As they grow, tumors generate surrounding blood vessels, but these newly generated blood vessels are not fully developed and have larger gaps that are much smaller in normal blood vessels. When liposomes and polymers are retained within the blood, they do not permeate the walls of normal blood vessels, which have small gaps, permeating only the vascular walls around the tumor. In addition, as lymphatic vessels are not fully developed in tumors, the liposomes and polymers that have permeated are not easily eliminated, resulting in the accumulation of these liposomes and polymers in the tumor. This is called the enhanced permeability and retention (EPR) effect.
*5Immune cells that phagocytize foreign substances in the body such as bacteria and waste products.
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