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Nov.
14, 2022 /eMedClub News/-NK cells are cytotoxic lymphocytes of the innate immune system capable of killing viral infections and/or cancer cells and can be engineered using CAR and gene editing to increase targeting and activation
.
However, after culture expansion, NK cells typically lose some of their ability
to deliver, localize, and proliferate in vivo.
This is thought to be the main reason for the low survival rate of NK cells of adoptive metastasis and their inability to overcome immune resistance in the
tumor microenvironment.
To this end, Gamida Cell, a NAM engineered cell therapy development company, has developed a proprietary NAM (nicotinamide) platform for in vitro expansion of allogeneic NK cells, enhancing NK cell function
by preventing cell failure, improving cytotoxic activity, producing protection against oxidative stress, and exhibiting better homing to lymphoid tissue.
These properties provide an opportunity
to enhance the therapeutic potential of NK cells in the clinic.
Recently, Gamida Cell presented excellent preclinical data
for its CAR-NK cell therapy GDA-501 based on NAM platform technology at the 37th Annual Meeting of the Cancer Immunotherapy Association.
For HER2+ solid tumors, it shows strong anti-cancer effect
In a poster presentation titled "Engineered NAM-NK cells with HER2-CAR expression demonstrate increased cytotoxicity against HER2-expressing solid tumors", the company introduced the genetically modified HER2-CAR NAM-NK cell GDA-501.
It has shown significant enhancement and durability of in vitro cytotoxicity and potency when cultured with HER2+ cancer cells, and has shown significant efficacy in inhibiting the growth of HER2+ solid tumors in mice
.
In addition, the investigators observed elevated levels of the degranulation marker CD107a and pro-inflammatory cytokines (including interferon (IFN)-γ and tumor necrosis factor (TNF)-α), indicating that GDA-501 was more potent than control cells
.
After electroporation, increased cytotoxicity and potency persist for up to 5 days
.
These preclinical data show that GDA-501 has potent antitumor activity and suggest that GDA-501 is a unique potential treatment option for cancer patients
with poor prognosis expressing HER2.
Dr.
Yona Geffen, Vice President of R&D at Gamida Cell, is looking for a senior medical editor with a salary of 10-20k per month, click to view>>>
"Our proprietary NAM technology enhances the ideal anti-cancer properties of a wide range of innate and adaptive cell types
, including NK cells 。 As shown in our SITC poster, GDA-501 is genetically modified by chimeric antigen receptors (CARs) to directly enhance the cellular activity
of GDA-501 by optimizing downstream signaling.
In vitro data show strong cytotoxicity
to HER2-expressing cells.
Therefore, HER2-CAR can be used to target a variety of HER2+ solid tumors
.
"
According to the report, this CAR-NK cell was developed
based on a single-stranded variable fragment (scFv) of the widely used humanized monoclonal antibody trastuzumab.
The developers used the same binding domains present in trastuzumab and designed different constructs in a modular manner, optimized by modifying the hinge region, transmembrane region, and cytoplasmic domain with NK cell-associated activating molecules to specifically enhance the cytotoxicity
of NK cells.
The researchers also assessed the specificity of cytotoxic effects: when cultured with normal lymphocytes, no significant elevation in
HER2-CAR NK cell activation was detected.
Platform technology integrating expansion, stability and enhancement
Gamida's proprietary NAM technology platform improves the amplification of small molecules in vitro culture while preserving their characteristics and functions by
harnessing the epigenetic regulatory function of small molecules NAM (nicotinamide).
This NAM technology, on the one hand, can inhibit the rapid differentiation of cultured cells, thereby improving the expansion of stem cells and progenitor cells in cell culture; On the other hand, it reduces changes in cell characteristics, thereby improving the function of CD34-positive cells expanded under culture conditions, including their migration, homing, and colonization
in the bone marrow.
▲ NAM platform technology can improve the homing and colonization efficiency
of CD34+ cellsIn addition to GDA-501, which is still in the preclinical stage, Gamida's other NK cell therapy based on the NAM technology platform, GDA-201, has been approved by the FDA for clinical trials
.
This is a congenital NK cell immunotherapy that is combined with standard treatment antibody therapy for the treatment of hematologic tumors and solid tumors
.
▲ Mock map prepared by NK cells (GDA-201).
According to a Gamida press release, a 57-year-old man with chronic lymphocytic leukemia (CLL) and a history of Richter translational (large cell lymphoma) experienced tumor shrinkage by 80%
after 6 months of GDA-201 treatment.
▲Typical cases (i.
before treatment ii.
6 months after treatment)
The results of phase I clinical trials showed that it was generally well tolerated in the 35 patients enrolled
.
Most of the 19 NHL response patients had multiple relapses, with a median age of 64 years, of which 13 had a complete response (CR) and 1 had a partial response (PR), that is, a complete response rate of 68%, and an overall response rate of 74%.
Two-year follow-up data showed progression-free survival (PFS) of 50% and 35% at 1 and 2 years, respectively, and an overall survival (OS) of 78%
at 2 years.
In addition, it is worth mentioning that the biological product license (BLA) application for Gamida's product omidubicel has been accepted by the FDA for the treatment of blood cancer patients
who require allogeneic hematopoietic stem cell transplantation.
This is an investigational stem cell therapy with "first-in-class" potential for the treatment of patients
with hematologic malignancies.
The press release states that it is the first bone marrow transplant treatment product to receive breakthrough therapy designation from the U.
S.
FDA and has received orphan drug designation in both the United States and the European Union
.
Recommended reading: The first allogeneic stem cell transplantation therapy was declared for marketing
Resources:
1.
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https://jitc.
bmj.
com/content/10/Suppl_2/A288
3.
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