Williams Cancer Institute

Blocking DNA Repair to Enhance Immunotherapy

Blocking DNA repair to enhance immunotherapy is an emerging approach to cancer treatment that aims to increase the effectiveness of immunotherapy by inhibiting the ability of cancer cells to repair DNA damage caused by immune-mediated cell death.

The immune system recognizes cancer by the differences it has from normal cells, due to mutations, However, cancer cells also have the ability to repair DNA damage that reduces mutations, which can reduce the effectiveness of immunotherapy.

By inhibiting DNA repair pathways, it is possible to increase the accumulation of DNA damage in cancer cells, which can enhance the effectiveness of immunotherapy. For example, preclinical studies have shown that combining immunotherapy with inhibitors of DNA repair pathways, such as PARP inhibitors or ATR inhibitors, can result in enhanced tumor regression and prolonged survival in mouse models of cancer. Patients who have mutations in the DNA repair, known as Mismatch Repair Deficiency (dMMR) have a better response to immunotherapy. Unfortunately, these are the minority of patients. There are other DNA repair genes, such as ATM, ATR, RAD-3 and CHEK2. Mutations in DNA repair genes leads to increased mutations and can be associated with and improved response to immunotherapy. Patients who don’t have mutations in these genes can achieve improved responses to immunotherapy by blocking some of these DNA repair mechanisms. This allows a better response, closer to what was seen in people who naturally have mutations, like those in the MSK dostarlimab study for rectal cancer, reported to be 100% cured in 14/14 patients.

Several clinical trials are currently underway to evaluate the efficacy and safety of combining immunotherapy with DNA repair inhibitors in various types of cancer. While the results of these trials are still preliminary, they suggest that this approach has the potential to improve the response rate and duration of response to immunotherapy, particularly in patients with tumors that are resistant to conventional therapies.

Reference: Ariosto Silva de Campos , J., & Demaria, P. (January de 2018). Blocking DNA repair to enhance immunotherapy: a promising combination strategy. Journal for ImmunoTherapy of Cancer, 6(1). Obtenido de https://jitc.biomedcentral.com/articles/10.1186/s40425-018-0314-1

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