A new small and less costly molecule could make immunotherapy available to all cancer patients
- Researchers from Tel Aviv University and the University of Lisbon have joined forces to create an immunotherapy molecule that will be available to all cancer patients.
- Patients will be able to take it at home instead of in hospitals.
- The new molecule is based on an antibody developed by the Nobel Prize winners of 2018, James Allison and Tasuku Honjo.
Researchers from Tel Aviv University and the University of Lisbon have synthesized and identified a small molecule that will be a less costly and more effective alternative to an antibody that can treat various types of cancers.
Taking an existing antibody to the next level, researchers have published their findings in Journal for ImmunoTherapy of Cancer.
"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. "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."
A smaller yet smarter alternate
While the discovery made by the Nobel Prize winners of 2018 is greatly promising when it comes to fighting against cancer, there are some setbacks to consider. Firstly, antibodies are costly to produce; hence they don't appeal to all patients. Secondly, antibodies are too large to penetrate through a solid tumor; therefore, the treatment falls behind, affecting all parts of the cancer.
Researchers, however, have combined bioinformatic and data analysis tools to come up with a smaller yet smarter alternate.
"Post-doctoral researcher Dr. Rita Acúrcio 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 tumor 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."
Experiments reveal that the new, small molecule helps with the activation of immune cells inside the solid tumor mass.
"The surface area of a solid tumor is heterogeneous," explains Prof. Satchi-Fainaro. "If there are fewer blood vessels in a particular area of the tumor, 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 tumor'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."
Background: Inhibiting programmed cell death protein 1 (PD-1) or PD-ligand 1 (PD-L1) has shown exciting clinical outcomes in diverse human cancers. So far, only monoclonal antibodies are approved as PD-1/PD-L1 inhibitors. While significant clinical outcomes are observed on patients who respond to these therapeutics, a large proportion of the patients do not benefit from the currently available immune checkpoint inhibitors, which strongly emphasize the importance of developing new immunotherapeutic agents.
Methods: In this study, we followed a transdisciplinary approach to discover novel small molecules that can modulate PD-1/PD-L1 interaction. To that end, we employed in silico analyses combined with in vitro, ex vivo, and in vivo experimental studies to assess the ability of novel compounds to modulate PD-1/PD-L1 interaction and enhance T-cell function.
Results: Accordingly, in this study we report the identification of novel small molecules, which like anti-PD-L1/PD-1 antibodies, can stimulate human adaptive immune responses. Unlike these biological compounds, our newly-identified small molecules enabled an extensive infiltration of T lymphocytes into three-dimensional solid tumor models, and the recruitment of cytotoxic T lymphocytes to the tumor microenvironment in vivo, unveiling a unique potential to transform cancer immunotherapy.
Conclusions: We identified a new promising family of small-molecule candidates that regulate the PD-L1/PD-1 signaling pathway, promoting an extensive infiltration of effector CD8 T cells to the tumor microenvironment.
The system, which uses Tesla technology, went online earlier than originally planned due to predicted energy shortages.