Precision drugs can reveal cancers in the immune system and enhance the effects of immunotherapy
A precise cancer drug called a PARP inhibitor has previously unknown ability to boost the immune system and can help more patients benefit from immunotherapy, a new study shows.
Scientists have discovered that PARP inhibitors can elicit a strong immune response when used against cancer cells and lack the ability to repair DNA.
This study changed our understanding of how PARP inhibitors work - and suggests that they can be used with immunotherapy to increase their effectiveness. Clinical trials have begun to evaluate this combination.
Some patients benefit from a new generation of immunotherapy - but usually only 10% to 20% of patients will respond, and many other patients' cancers can evade the immune system.
Scientists at the London Cancer Institute and the Gustavusi Institute in France, led by Professor Chris Lord and Dr. Sophie Postal-Vinay, have found that PARP inhibitors can reveal some of the cancers that currently evade immune cell detection.
Their research was published in the Journal of Clinical Research, funded by the British Breast Cancer and the British Cancer Institute.
One of the systems in which PARP inhibitors, such as olaparib, block cells for repairing their DNA. They are designed to attack tumors that have been defective in DNA repair, particularly in women with ovarian and breast cancers with hereditary BRCA mutations.
The researchers studied lung tumors obtained from patients and found that those with DNA repair defects had significantly more immune cells in the tumor than those with functional DNA repair systems. This suggests that DNA repair mutations stimulate an immune response against the tumor.
They also studied cancer cells from non-small cell lung cancer and triple-negative breast cancer, which have mutations in DNA repair genes (such as ERCC1 or BRCA) to assess whether PARP inhibitors can increase this immune response.
When cancer cells with defective repair systems are treated with PARP inhibitors to block their remaining DNA repair system, they are no longer able to repair any DNA damage, thus accumulating more and more DNA mutations until they die.
The researchers found that the accumulation of DNA damage in cancer cells treated with PARP inhibitors triggers the release of various molecular signals that may attract immune cells to the tumor, suggesting that treatment with PARP inhibitors can enhance these cancer cells. Immune response.
In an ERCC1-deficient cancer cell line, 24 of the 50 signaling pathways activated after exposure to a PARP inhibitor are associated with the immune system.
Scientists have found that PARP inhibitors may be used to treat lung cancer with DNA repair gene defects, in part because of these newly discovered immune system effects. This immune response can be further enhanced by the use of PARP inhibitors and immunotherapy to kill cancer cells more effectively.
Since 30% to 50% of patients with non-small cell lung cancer lack the ERCC1 DNA repair system, this can open up a new and more effective way to treat most patients with non-small cell lung cancer.
Professor Chris Lord, Professor of Cancer Genomics at the London Cancer Institute, said: "The results of this study have dramatically changed our understanding of how PARP inhibitors work. We now know that they not only kill tumors by destroying DNA, but also attack them by attracting immune cells - as a two-pronged attack."
