New cell immunotherapy!

Article source: Pharmaceutical Guanlan

From the sky to the sea, viruses and bacteria are almost everywhere
.

In the body's immune system, T cells as "special forces" that can accurately and efficiently attack on bacteria, viruses, cancer cells and so on
.

So, what are the advantages of CAR-NK products? What is the prospect of its development? This article will take you to find out in conjunction with public information
.

What is unique about NK cells?

NK cells are an important immune cell in the human body and participate in physiological processes such as anti-tumor, anti-viral infection and immune regulation
.

Unlike T cells and B cells, NK cells belong to the innate immune system, which can target a variety of pathogenic antigens and have stronger cytotoxicity
.

In addition to acting as cytotoxic effector cells, activated NK cells can also secrete some cytokines and chemokines to regulate the immune response and inflammation, and these factors in turn will recruit and activate other immune cells, such as T cells and dendritic cells.
And macrophages
.

▲The anti-tumor mechanism mediated by NK cells (picture source: reference [1])

Based on these unique biological characteristics, NK cells have become one of the ideal choices for researchers to develop new immunotherapies
.

Potential advantages of CAR-NK products

Up to now, 5 CAR-T products have been approved by the US FDA for the treatment of blood cancers
.

According to a review published in EBioMedicine, a subsidiary of The Lancet, CAR-NK cell therapy products have the following potential advantages:

First, CAR-NK cell immunotherapy has better safety
.

Second, CAR-NK cells still have natural anti-tumor cell toxicity.
In addition to killing tumor target cells in a CAR-dependent manner, CAR-NK cells can also eliminate cancer cells in a non-CAR-dependent manner
.
In addition, NK cells can eliminate tumor cells through the CD16-mediated ADCC mechanism
.
Therefore, CAR-modified NK cells can effectively eliminate certain tumor cells that do not express the target antigen on CAR through multiple mechanisms of action that are CAR-dependent and NK cell receptor-dependent
.

Third, it has the potential to become a "universal" product
.
Since the source of NK cells is relatively wide, and the safety of allogeneic NK cells is better, CAR-NK cells are expected to provide a "universal" product to solve the long production cycle and individual problems of CAR-T products.
Difficulties in demand for globalization
.

▲The source and production process of CAR-NK cells (picture source: reference [1])

The world has entered the clinical trial stage, and many studies come from China

According to the information published on the ClinicalTrials.
gov website, many CAR-NK product clinical trials are currently in progress, most of which are in the phase 1/2 clinical trial stage
.
From the target point of view, and CAR-T is similar to the majority of CAR-NK cell therapy products targeted are common malignant blood cancer targets, such as CD19, CD22, BCMA, CD33 and so on
.
Some CAR-NK targeted product is a solid tumor-associated antigens, such as PSMA, mesothelin, ROBO1, NKG2D the like
.

The potential advantages of CAR-NK products have been initially verified in preclinical studies and some clinical studies
.
A study published in the New England Journal of Medicine (NEJM) in 2020 showed that 11 cancer patients received a CAR-NK product that targets CD19, and 7 patients experienced complete remission (CR), and all There are no common side effects such as cytokine release syndrome (CRS) and neurotoxicity in the treatment of CAR-T products
.
"Nature-Medical" also listed this progress as one of the ten notable developments in the field of biomedicine in 2020
.

It is worth mentioning that among these studies registered on ClinicalTrials.
gov, there are many scientific research institutions and companies from China
.
Including precision biology’s CD19 targeting CAR-NK, ASCO’s ROBO1 targeting CAR-NK, BCMA targeting CAR-NK, and Nuovo’s CD19/CD22 dual target CAR-NK and PSMA targeting CAR- NK, Boshengji Pharmaceutical’s CD33 targets CAR-NK and so on
.
These candidate products are basically in the phase 1 / phase 2 clinical trials.
The indications targeted include not only non-Hodgkin's lymphoma (NHL), multiple myeloma, acute myeloid leukemia and other blood cancers, but also prostate cancer and ovarian cancer.
And other solid tumors
.

▲Part of the clinical trials of CAR-NK in the treatment of solid tumors (picture source: reference [1])

In general, the development of CAR-NK cell therapy products is still in the early stage of research, and there is not much clinical trial data released yet
.

Challenges and potential coexist

Although CAR-NK cell therapy products have considerable application prospects, as a class of cutting-edge therapies, they still face many challenges in their research and development
.
A major challenge is how to generate sufficient numbers of NK cells
.
No matter which cell source is selected, a single therapeutic infusion requires a large number of NK cells, so the expansion and activation of NK cells in vitro is very important
.
The use of traditional cytokine-based in vitro amplification methods is not only costly, but also time-consuming
.
Therefore, it is of great significance to explore more effective and lower-cost methods to expand NK cells in vitro
.

Secondly, what method should be chosen to transfer CAR into NK cells
.
Currently, the commonly used transduction methods are viral vectors and non-viral vectors, each of which has advantages and disadvantages
.
For example, viral vectors can stably integrate CAR into the genome, but there are high-risk and high-cost shortcomings in clinical applications
.
Although retroviral vectors have relatively high transduction efficiency, they may cause problems such as insertion mutations
.
Although lentiviral vectors have a low probability of causing insertional mutations, they have a low transduction rate for NK cells derived from peripheral blood
.
Therefore, it is also important to choose a suitable method to transfer CAR into NK cells
.

Despite the huge challenges, the therapeutic potential of CAR-NK cells is still worth looking forward to
.
It is hoped that with the development and progress of technologies such as iPSC and gene editing, CAR-NK product research can make more breakthroughs and progress in the future, and provide new weapons for humans to overcome cancer
.

Reference

[1]Faroogh Marofi, Alaa S Al-Awad, et al (2021).
CAR-NK Cell: A New Paradigm in Tumor Immunotherapy.
.
Frontiers in Oncology .
DOI:10.
3389/fonc.
2021.
673276

[2] Xie, Guozhu, Dong, Han, et al.
(2020).
CAR-NK cells: A promising cellular immunotherapy for cancer.
EBioMedicine.
doi:10.
1016/j.
ebiom.
2020.
102975

[3] Clintrials gov.
Retrieved July 01, 2021, From https://clinicaltrials.
gov/ct2/results?cond=&term=CAR-NK&cntry=&state=&city=&dist=

[4] Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors.
New England Journal of Medicine (2020).
doi:10.
1056/NEJMoa1910607

[5] Myers, JA, Miller, JS Exploring the NK cell platform for cancer immunotherapy.
Nat Rev Clin Oncol 18, 85–100 (2021).
https://doi.
org/10.
1038/s41571-020-0426-7

[6]Shi Ruifang.
(2020).
CAR-NK: A new strategy for tumor immune cell therapy.
Chinese Journal of Cancer Biotherapy.
DOI: 10.
3872/j.
issn.
1007-385x.
2020.
04.
016