Researchers from Tel Aviv University and the University of Lisbon worked together to find and synthesise a tiny chemical that may replace an antibody that is now used to treat a range of tumours in a more practical and efficient way.
Scientists on Cancer
A global team of scientists, led by Prof. Ronit Sachi-Fainaro, Head of the Center for Cancer Biology Research and the Laboratory for Cancer Research and Nanomedicine at the Sackler Faculty of Medicine, Tel Aviv University, as well as Prof. Helena Florindo and Prof. Rita Guedes from the Research Institute for Medicines at the Faculty of Pharmacy, University of Lisbon, is responsible for the ground-breaking discovery. The Journal for ImmunoTherapy of Cancer reported the study’s findings.
“In 2018, the Nobel Prize in Medicine was awarded to James Allison and Tasuku Honjo for their contribution to the study of immunotherapy, the treatment of cancer through activation of the immune system,” says Prof. Satchi-Fainaro, a 2020 Kadar Family Award recipient. “Honjo discovered that immune cells called T cells express the protein PD-1 that disables the T-cells’ own activity when it binds to the protein PD-L1 expressed in cancer cells. In fact, the interaction between PD-1 and PD-L1 allows cancer cells to paralyze the T cells, preventing them from attacking the cancer cells. Honjo developed antibodies that neutralize either PD-1 or PD-L1, thereby releasing the T cells to fight cancer effectively.”
The antibodies against PD-1/PD-L1 proteins are already approved for clinical use and are considered the great promise in the fight against cancer. This immunotherapy can significantly improve patient outcome, without the severe side effects that accompany treatments such as chemotherapy. But the antibodies are expensive to produce, hence not available to all patients. Moreover, the treatment does not affect all parts of the solid tumours because the antibodies are too large to penetrate and reach less accessible and less exposed areas of the tumour. Now, researchers at Tel Aviv University and the University of Lisbon have used bioinformatic and data analysis tools to find a smaller, smarter alternative to these antibodies.
“Post-doctoral researcher Dr. Rita Acurcio started with thousands of molecular structures, and by using computer-aided drug design (CADD) models and databases, we narrowed down the list of candidates until we reached the best structure,” says Prof. Satchi-Fainaro. “In the second stage, we confirmed that the small molecule controls tumour growth as effectively as the antibodies – it inhibits PD-L1 in animals engineered to have human T cells. In other words, we have developed a molecule that can inhibit PD-1/PD-L1 binding and remind the immune system that it needs to attack the cancer. Moreover, the new molecule has some major advantages over the antibody treatment.
First of all, the cost: since the antibody is a biological rather than a synthetic molecule, it requires a complex infrastructure and considerable funds to produce, costing about $200,000 per year per patient. In contrast, we have already synthesized the small molecule with simple equipment, in a short time and at a fraction of the cost. Another advantage of the small molecule is that patients will probably be able to take it at home, orally, without the need for IV administration in the hospital.”
In addition to accessibility issues, our tests demonstrate that the tiny molecule enhances immune cell activation within the solid tumour mass.
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“The surface area of a solid tumour is heterogeneous,” explains Prof. Satchi-Fainaro. “If there are fewer blood vessels in a particular area of the tumour, the antibody will not be able to get inside. The small molecule, on the other hand, diffuses, and is therefore not entirely dependent on the tumour’s blood vessels or on its hyperpermeability. I believe that in the future, the small molecule will be commercially available and will make immunotherapy affordable for cancer patients.”
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