NK cell (Natural killer cell)을 활성화시키는 Combi. therapy

1. 내용 Key Highlights

 

When cancer drugs fail, a unique combination of already existing drugs could harness an under-targeted part of the immune system to join the fight

A new study led by Penn State College of Medicine scientists finds that another type of immune cell — natural killer cells — can be harnessed to pick up the slack when T cells no longer work and may also reinvigorate T cells to attack melanoma tumors. 

 

 The team has identified a unique combination drug strategy to activate this natural killer cell-mediated immunity in mice. The individual agents are clinically used but not in combination, and the combination still must be demonstrated to be effective in humans.

 

The individual agents are clinically used but not in combination, and the combination still must be demonstrated to be effective in humans.

 

Robertson explained that natural killer cells can be lacking in solid tumors, likely due to limitations of signals attracting them into tumors, activation once in the tumor, and the general immunosuppressive microenvironment that occurs in tumors. He said that therapies that can increase natural killer cell infiltration and/or activation in tumors are urgently needed.

 

“Emerging evidence suggests that restoration of p53 signaling within tumor cells can lead to natural killer cell infiltration and activation in the tumor,” said Robertson, a Penn State Cancer Institute researcher. “Yet, studies have found that drugs targeting MDM proteins in order to restore p53’s tumor-suppression activities tend to be toxic.”

 

Instead, he said, targeting a different set of proteins — AKT and WEE1 — may be a potentially non-toxic and novel approach to increase p53 activity.

 

What they found is that targeting both AKT and WEE1 uniquely reverses the effects of the MDM proteins, reactivating the p53 pathways in a way that does not occur when using MDM inhibitors. Thus, the effect is better p53 pathway activation without the toxic effects seen with MDM inhibitors.

 

In their study, which published on June 3 in the journal Cancer Immunology Research, Robertson and his colleagues tested the abilities of two AstraZeneca cancer drugs — capivasertib (AZD5363), which is known to inhibit AKT, and adavosertib (MK1775), which is known to inhibit WEE1 — to solicit a natural killer cell immune response.

 

“We found that simultaneous inhibition of both AKT and WEE1 with capivasertib and adavosertib synergistically reduced melanoma cell proliferation and increased melanoma cell death mediated by the natural killer cells,” said Robertson. By contrast, he added, inhibiting the proteins individually was not effective at causing the natural killer cell response.

 

The team conducted a similar study in live mice with melanoma tumors and found that the drug combination reduced tumor volumes by approximately 80% compared to mice in the control group. In addition, the researchers found that the drug combination was not toxic to the animals.

 

Importantly, not only did the scientists identify drugs that are effective against melanomas, but they also determined the specific mechanisms of the drugs’ actions. The team found that the drugs inhibited AKT and WEE1, which in turn resulted in restoration of p53 pathway activity and increased the abilities of natural killer cells to infiltrate tumors. This occurred because the drugs changed the surfaces of tumor cells, and the tumor cells produced factors that attracted natural killer cells into the tumors and activated them once there.

 

“When we used these drugs to draw natural killer cells into the tumors, the natural killer cells also pulled in T-cells, whose activity could then be triggered with an additional agent, called an immune checkpoint inhibitor,” said Robertson. “Using this approach, we were able to completely eliminate tumors in mice.”

 

 

https://www.psu.edu/news/research/story/novel-drug-combo-activates-natural-killer-cell-immunity-destroy-cancer-cells/

Novel drug combo activates natural killer cell immunity to destroy cancer cells | Penn State University

 

 

2. 내 생각

 

1) NK cell-mediated immunity에 관련된 새롭고 안전한 MOA를 밝힌 것에 큰 의의가 있음

 

This resarch is very meaningful because it proved the MOA which targeting AKT and WEE1 can active NK cell-mediated immunity by restoring p53 signalling pathway in a safe way.

 

2) Human translation 가능한지가 궁금. 특히 실제 human cancer에서 efficacy가 얼마나 개선될지 여부가 관건

 

As the article mentioned, I am wondering if this anti-tumor efficacy can be traslated in a human body. How much efficacy improvement it will show compared to the standard of care treatment?

 

3) 기출시 약물의 combi.로 NK cell을 활성화하는 효과를 밣혀냈다는 점이 고무적임 

 - 신약 개발에는 오랜 시간 및 금전적 자원 소요

 - 기출시 약물끼리의 combi. 는 해당 시간 및 금전적 자원을 절약해줄 수 있는 방법

 

This research is inspiring because it proved the efficacy of activating NK cells by combination therapy of marketed drugs so it can save the time and money for developing novel drugs

 

4) Melanoma의 경우 immune cell mediated treatment가 많이 사용되는 것 같은데, 관련 내용 추가 리서치 필요

  - 타 cancer 와 차별화되게 immuen cell mediated treatment 효과가 좋아서 first-line therapy로 사용되는 중인가?

  - T cell meidated treatment는 CAR-T를 의미하는 것인지? 아니면 T cell을 activation 하는 interferon 등인지? 

 

Is melanoma a type of cancer that immune cell-mediated treatment is widely utilized?

 

5) T cell for hema. tumor vs NK cell (natural killer cell) for solid tumor 구도에서 벗어난 T cell + nk cell 의 관점으로 접근할 수 있지 않을까? 

 

 - NK cell activation -> T cell activation, + immune checkpoint inhibitor

 

It is widely hypothesized that T cell is effective for hematological tumor and NK cell is effective for solid tumor. However, I want to check the possibiity which t cell and nk cell collaborate together in a human body and show high efficacy. I want to check the combi. therapy of T cell and nk cell under development. 

 

추가 리서치 포인트 : T cell + nk cell combi. 조합으로 개발 중인 therapy 있는지 여부

 - off- the shelf Car-T 및 off the shelf Car-NK 조합으로 개발 중인 therapy 있을 것 같음