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iNature
Glioblastoma (GBM) is the most aggressive and lethal human brain tumor, and despite combination therapies including surgical resection, radiotherapy, and chemotherapy, the prognosis for patients remains poor
.
Chimeric antigen receptor (CAR)-T therapy combines the specific recognition of tumor antigens by monoclonal antibodies and the tumor-killing function of T cells, providing a new strategy
for cancer treatment.
Ganglioside GD2 is mainly expressed on neuronal cell membranes in normal tissues and is also highly expressed
in many malignant tumors.
In brain tumors, GD2 is enriched
on the tumor surface of 80% of diffuse intrinsic pontine gliomas (DIPG).
In animal studies, CAR-T cells against GD2 can effectively eliminate GD2-positive human GBM and DIPG tumors implanted in situ in mice without obvious neurotoxicity or off-target effects
.
Recently, 4 patients with DIPG gene encoding histone H3 (H3K27M) mutations or patients with diffuse midline glioma (DMG) in the spinal cord have been reported with
GD2-specific CAR-T cell therapy.
These early results underscore the safety and clinical benefit
of GD2-specific CAR-T for the treatment of H3K27M mutated DIPG and spinal DMG.
Considering that GD2 is expressed in normal neural tissue, and anti-GD2 antibody therapy for neuroblastoma is associated with neuropathic pain, further clinical exploration of GD2-specific CAR-T cell therapy for GBM is necessary
.
On January 9, 2023, the Mao Jie team of Shenzhen People's Hospital, the Wu Dinglan team of Shenzhen Hospital of Southern Medical University, and the team of Zhang Longji of Shenzhen Institute of Immunogene Therapy published an online report entitled "Safety and antitumor activity of GD2-Specific 4SCAR-T cells in patients with" in Molecular Cancer magazine glioblastoma" research paper, which aims to verify whether GD2-specific fourth-generation safety-designed CAR (4SCAR)-T cells are safe and whether CAR-T cells have antiglioblastoma activity
.
Studies have shown that GD2-specific 4SCAR-T cell targeting GBM alone and in combination is safe, well tolerated, and has no serious adverse events
.
In addition, GD2-specific 4SCAR-T cells partially mediate antigen loss and activate the immune response
in the tumor microenvironment.
for hematologic cancers, including non-Hodgkin lymphoma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia.
Recently, in the longest follow-up study of CAR-T therapy to date, 60% of patients with B-cell lymphoma who received CAR-T therapy were still in remission at 5 years
.
However, the challenge of CAR-T in treating solid tumors remains, and only a small number of patients have a good
prognosis.
Previous studies have identified four major barriers, including heterogeneous antigen expression, impaired CAR-T cell adaptation, limited homing and penetration of CAR-T cells, and immunosuppressive microenvironment
.
Antigen selection is critical for CAR-T cell function, and heterogeneous antigen expression results in limited targeted antigens for CAR-T cells
.
Adequate and effective transport of CAR-T cells to the tumor site is essential
for CAR-T therapy.
However, the fitness of CAR-T cells after infusion is impaired, and the homing and penetration of CAR-T cells to solid tumors are limited, which greatly hinders the tumor killing effect
.
Immunosuppressive cells accumulate in the tumor microenvironment, impairing the tumor-killing effect
of CAR-T cells.
In addition, immunosuppressive cells produce an environment
that is unfavorable to CAR-T cells by secreting a variety of inhibitory cytokines.
Immunotherapy
for GBM with transgenic T cells expressing different CAR is currently being studied.
Clinical trials of CAR-T cells targeting interleukin-13Rα2, epidermal growth factor receptor variant III (EGFRvIII) and human epidermal growth factor receptor 2 (HER2) for the treatment of GBM have been completed
。 Although the safety of CAR-T cells in GBM has been demonstrated in these three trials, CAR-T cells are not particularly effective
as monotherapy in GBM due to antigen escape and tumor heterogeneity.
In addition to IL-13Rα2, EGFRvIII, and HER2, various targets for CAR-T therapy for GBM have been identified
.
To address safety concerns and improve anti-tumor efficacy, this study used a fourth-generation safe-designed CAR (4SCAR).
4SCAR consists of
CD28 transmembrane and cytoplasmic domains, co-stimulated 4-1BB intracellular TRAF-binding domains, CD3z chain intracellular domains, and the caspase 9 gene that induces suicide.
A phase I trial was conducted by injecting GD2-specific 4SCAR-T cells in patients with progressive GBM and reported their safety, persistence, and tumor-killing efficacy
.
Figure 1.
The results of the GD2-specific 4SCAR-T cell design and kill assay (Figure from Molecular Cancer) showed that 4SCAR-T cells expanded for 1-3 weeks and persisted
at low frequencies in peripheral blood.
Of the 8 evaluable patients, 4 had partial remission 3 to 24 months after infusion, 3 progressed 6 to 23 months after infusion, and 1 was stable
4 months after infusion.
For the entire cohort, median overall survival was 10 months
post-infusion.
GD2 antigen deletion and T cell infiltration were observed in tumors resected after infusion
.
Figure 2.
Regulation of peripheral blood cytokines after GD2-specific 4SCAR‐T cell transfusion (Figure from Molecular Cancer) In summary, this study shows that the infusion of autologous GD2-specific 4SCAR-T cells into GBM-patients through two different routes is safe and well tolerated
.
In addition, GD2-specific 4SCAR-T cells partially mediate antigen loss and activate the immune response
in the tumor microenvironment.
Although increased life expectancy and loss of GD2-specific antigen were observed in some patients, the study was unable to determine clinical benefit
due to the small sample size.
Preliminary clinical trials of the study highlight the safety of GD2-specific 4SCAR-T cells targeting GBM, and further evaluation of the Phase II study
of GD2-specific 4SCAR-T cells is warranted.
Original link: https://molecular-cancer.
biomedcentral.
com/articles/10.
1186/s12943-022-01711-9
—END—
The content is [iNature]
