-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
-
Cosmetic Ingredient
- Water Treatment Chemical
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
October 12, 2022 /eMedClub News/--Over the past few years, cellular immunotherapy has emerged as a new treatment option
for certain types of hematologic malignancies.
With the entry of a number of CAR-T therapies into the clinic, the limitations of autologous cell products and the challenges of CAR-T cytotoxicity have also become prominent
.
There is an urgent need for new cell therapy products
that are more convenient, safe and effective.
CAR-NK cell immunotherapy emerged as a safer, faster, and more cost-effective method without signs
of severe toxicity in CAR-T cells.
Due to the unique biological characteristics and multiple mechanisms of action of NK cells, CAR-NK cell therapy is a strong clinical candidate
.
Despite the multiple advantages, CAR-NK treatment faces many challenges that can trigger drug resistance and affect its efficacy
.
Therefore, we need to pay attention to these mechanisms, especially the CAR-NK dysfunction that causes hematological tumors to evade immune surveillance, so as to formulate effective strategies to overcome CAR-NK failure and migration barriers and ensure the persistence
of CAR-NK effects.
Double CAR structure, outside and inside
Researchers at the University of Texas MD Anderson Cancer Center have developed a new natural killer (NK) cell engineering method that uses two signals to eliminate one target cellby adding a second chimeric antigen receptor (CAR) as a logic gate.
In preclinical studies, these new dual CAR-NK cells improved tumor specificity and enhanced anti-tumor activity
by overcoming processes that lead to NK cell dysfunction and tumor recurrence.
The study, published in Nature Medicine, found that a normal physiological process known as trogocytosis[Note 1] contributed to tumor escape and poor
response after CAR-NK cell therapy by causing tumor antigen loss, NK cell failure, and cannibalism.
During cytognawing, the surface proteins of the target cell are transferred to the surface of immune cells, such as NK cells or T cells, to regulate their activity
.
▲ Gnawing, adhesion and phagocytosis (Image source: Reference 2)
.
"
Using a variety of in vivo tumor models and clinical data, the study found that CAR activation in NK cells promotes the metastasis of CAR homologous antigens from tumors to NK cells through cytognawing.
This antigen metastasis not only reduces tumor antigen density, but also impairs the contact ability of CAR-NK cells with targets.
In turn, self-recognition and sustained CAR-mediated contact are induced, leading to cannibalism between NK cells and low reactivity of NK cells
.
Simply put, the target antigen between tumor cells and CAR-NK cells is reduced, and the engineered cells target each other instead of the tumor
.
At the same time, this self-attack leads to intracellular depletion and accelerated exhaustion of NK, metabolic dysfunction and weakening
of the antitumor response.
The team used clinical samples from patients with lymphatic malignancies treated with anti-CD19 CAR-NK cells in a clinical trial to confirm that higher levels of CD19 antigen on CAR-NK cells correlated
with lower levels of CD19 on tumor cells and a higher probability of recurrence.
To prevent cannibalism between NK cells caused by this factor, the researchers then added an inhibitory CAR designed to identify a marker unique to NK cells that signals "don't kill me" to each other when CAR-NK cells interact, even if they have tumor antigens
on their surface.
After applying this dual-CAR-structured CAR-NK cell to a preclinical tumor model, the researchers observed that these logic-gated CAR-NK cells were better able to focus and attack tumor cells, while reducing NK cell depletion and cannibalism, greatly improving anti-tumor activity
.
Rezvani also pointed out: "It is also important to prevent tumor escape after CAR-NK treatment, and the recurrence of some patients is inseparable from this
.
" But by stopping the exhaustion and cannibalism of CAR-NK cells, we can further improve their activity and function
.
This study provides further understanding of the biology of CAR-NK and supports the development process
of a dual CAR strategy.
The same thing: bispecific CAR-T
In CAR-T cell therapy, the concept of this dual CAR structure has been applied
.
For example, through its proprietary TruUCAR technology platform, Ganxi Biotech has designed a bispecific CAR, CAR1 for "defense", targeting T cells and NK cells that will carry out allogeneic reactive killing of patients to protect CAR-T cells from rejection; CAR2, on the other hand, is used for "attack," targeting tumor antigens to clear tumor cells
.
In this way, with a single CAR design, bispecific CAR can perform dual functions, achieving the effect
of being outside and inside.
Taking the CD19/CD7 dual-target universal CAR-T cell therapy GC502, a representative product of this technology platform, as an example, the CD19 CAR on the product cells can specifically target malignant tumor cells, while the CD7 CAR can inhibit host anti-graft rejection (HvG).
In addition, Quadrux Biotech has embedded an enhanced molecule in the basic structure of TruUCAR to enhance the expansion capacity
of TruUCAR-T cells.
Not long ago, during the 2022 annual meeting of the American Association for Cancer Research (AACR), Genxi Biotech disclosed the early clinical data
of GC502 in the form of a poster report.
In terms of efficacy, 3 of the 4 patients achieved a complete response with a negative minimal residual lesion/a complete response with incomplete recovery of blood cell count (MRD-CR/CRi); One patient achieved a partial remission at 1 month and subsequently received an allogeneic hematopoietic stem cell transplant
on day 39.
In terms of safety, patients developed grade 2/3 cytokine release syndrome (CRS) in treatment, and did not develop grade 4/5 CRS
.
At the same time, no immune effector cell-associated neurotoxicity syndrome (ICANS) or acute graft-versus-host disease (aGvHD)
were observed.
Note [1]: Trogo in trogocytosis (translated as "gnawing") is Greek, which means "to gnaw" in Greek
.
Specifically, in the early stage of the immune response, antigen-presenting cells capture antigen molecules and present them on the cell surface for receptor recognition
on B cells, T cells, NK cells and other lymphocytes.
These lymphocytes come into contact with antigen-presenting cells to extract these antigen molecules, as well as part of the cell membrane
of antigen-presenting cells.
This process is called the Trogocytosis effect
.
Resources:
1.
style="margin-right: 16px;margin-left: 16px;white-space: normal;max-width: 100%;line-height: normal;overflow-wrap: break-word !important;box-sizing: border-box !important;margin-bottom: 0px;">2.
style="outline: 0px;max-width: 100%;color: rgb(34, 34, 34);font-family: system-ui, -apple-system, BlinkMacSystemFont, "Helvetica Neue", "PingFang SC", "Hiragino Sans GB", "Microsoft YaHei UI", "Microsoft YaHei", Arial, sans-serif;letter-spacing: 0.
544px;white-space: normal;background-color: rgb(255, 255, 255);text-align: center;box-sizing: border-box !important;overflow-wrap: break-word !important;margin-bottom: 0px;">
——List of recent popular events——
▼October 13, Sino-US Double Report Cell Bank Verification Strategy Seminar
▼October 18, the application and development trend of biopharmaceutical safety detection technology
