Nature's in-depth review: Improving cancer immunotherapy targeted DNA damage response is promising

Immunotherapy has brought revolutionary changes to cancer treatment and also improved the treatment results for patients with multiple cancer types

In recent years, more and more evidence supports that targeted DNA damage response (DNA Damage Response, DDR) therapies can enhance the anti-tumor immune response

Multiple relationships between DDR and tumor cell immunogenicity

The immunogenicity of tumor cells can include three parts: first, how many neoantigens the tumor cells can produce that can be recognized by the immune system; second, whether the tumor cells will release aids including type 1 interferon and pro-inflammatory cytokines Molecules attract the infiltration and activation of T cells; thirdly, whether tumor cells can activate the killing function of T cells

Research in recent years has shown that DDR has a close relationship with these three parts

The US FDA has approved Keytruda to treat cancer patients with these characteristics based on the molecular characteristics of MMR defects and elevated MSI

However, the level of neoantigens is not the only factor that determines the anti-tumor immune response

Studies have shown that the immune signaling pathway stimulated by cytosolic nucleic acid (cNA) in the cytoplasm is an important part of the anti-tumor immune response.

Studies have shown that when tumor cells increase DNA damage due to DNA damage drugs or endogenous DDR loss, the cGAS-STING signaling pathway will be activated

In addition, DDR defects can also affect the expression of immune checkpoint proteins.

DDR deficiency can also affect the expression of many costimulatory molecules, including CD80, LAG3, TIM3 immune checkpoint protein and so on

▲DDR regulates multiple immune checkpoint proteins expressed on the surface of tumor cells (picture source: reference [1])

Clinical development based on the interaction between DDR and immune response

The review pointed out that there are currently more than 80 clinical trials evaluating the effects of DDR-targeted therapies in combination with immune checkpoint inhibitors

For example, in a phase 2 clinical trial called TOPACIO, the PARP inhibitor niraparib was combined with Keytruda to treat metastatic triple-negative breast cancer (TNBC) or recurrent ovarian cancer

In a phase 2 clinical trial called MEDIOLA, the PARP inhibitor olaparib, a triple combination therapy consisting of the PD-L1 inhibitor durvalumab and the VEGF inhibitor bevacizumab, is used in the treatment of non-germline BRCA-mutated ovarian cancer patients who are sensitive to platinum-containing chemotherapy It showed an objective response rate of 87% and a median progression-free survival of 15 months, which is better than PARP inhibitor or VEGF inhibitor monotherapy

In patients with metastatic trend-resistant prostate cancer, the combination of olaparib and durvalumab resulted in a biochemical response in 53% of patients (reduction of prostate-specific antigen levels by more than 50%), and no progression at 12 months in patients with DDR deficiency The survival rate was significantly higher than that of patients with normal DDR (83.

As a neoadjuvant therapy, olaparib and durvalumab also show encouraging anticancer activity in the treatment of patients with early myometrial invasive bladder cancer

In addition to PARP inhibitors, a number of clinical trials are also evaluating the effects of other therapies that target DDR in combination with immune checkpoint inhibitors, including ATR inhibitors, WEE1 inhibitors, and so on

The review authors pointed out that, overall, a number of independent early clinical trials have shown that the combination of DDR-targeting therapies and immune checkpoint inhibitors is safe and has shown encouraging anti-cancer efficacy
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A prospective randomized trial with a larger number of patients and longer follow-up time is currently needed to further validate this strategy
.

Open up an exciting new direction in immuno-oncology

The review pointed out that in the past 10 years, researchers have used a variety of treatment strategies to explore the relationship between DDR and immune response
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Their main goals can be divided into four categories: to enhance tumor immunogenicity by generating tumor neoantigens (Figure a below); activating cytoplasmic immune signaling pathways (Figure b below); and regulating immunity by stimulating the expression of immune checkpoint molecules Synapse (Figure c below); and trigger immunogenic cell death (Figure d below)
.

▲Clinical development strategy using the interaction between DDR and immune response (picture source: reference [1])

The review author pointed out that at present, our understanding of the "dialogue" between DDR and anti-cancer immunity is still in its infancy
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Future research needs to explore the effects of the combination of DDR-targeted therapies and immunotherapies other than immune checkpoint inhibitors, and it is necessary to optimize biomarker-based patient selection and combination therapies
.

Nevertheless, the interaction between DDR and anti-cancer immunity has opened up an exciting and innovative therapeutic area in immuno-oncology, and encouraging clinical results have paved the way for the broader development of this strategy
.

Reference materials:

[1] Chabanon et al.
, (2021).
Targeting the DNA damage response in immuno-oncology: developments and opportunities.
Nature Reviews Cancer, https://doi.
org/10.
1038/s41568-021-00386-6

[2] Brown et al.
, (2021).
Combining DNA damaging therapeutics with immunotherapy: more haste, less speed.
British Journal of Cancer, https://doi.
org/10.
1038/bjc.
2017.
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