CAR T-cell therapy is revolutionizing cancer treatment by harnessing the body’s immune system to specifically target and destroy cancer cells. While it has shown outstanding success in blood cancers, its application in solid tumors—like gastric cancer—presents new challenges and opportunities. This article explores the evolving landscape of CAR T-cell therapy in gastric cancer, covering its mechanisms, clinical trials, key target antigens, potential side effects, and the future of this therapy, especially in countries like China, which are at the forefront of innovation.
What is Gastric Cancer?
Gastric cancer, also known as stomach cancer, originates from the lining of the stomach. It is one of the most prevalent and deadly cancers globally. Often asymptomatic in its early stages, it is usually diagnosed when already advanced, leading to a poor prognosis.
Common Symptoms:
Indigestion
Abdominal discomfort or pain
Unexplained weight loss
Nausea and vomiting
Major Risk Factors:
Helicobacter pylori infection
Chronic gastritis
Smoking and obesity
Diet high in salt and smoked foods
Family history of gastric cancer
Diagnosis typically involves endoscopy, biopsy, and imaging techniques, followed by staging to determine the extent of disease spread.
Traditional and Emerging Treatments
Treatment depends on the stage of the cancer and may involve:
Surgery
Chemotherapy
Radiation therapy
Targeted therapy
Although these methods can be effective, especially for localized tumors, patients with metastatic or drug-resistant gastric cancer often face poor outcomes. This has led to growing interest in immunotherapy, particularly CAR T-cell therapy, as a cutting-edge treatment option.
What is CAR T-Cell Therapy?
Chimeric Antigen Receptor (CAR) T-cell therapy is an advanced form of immunotherapy. It involves engineering a patient’s T cells to express synthetic receptors (CARs) that recognize specific antigens on cancer cells. Once infused back into the patient, these cells actively seek out and destroy tumor cells with remarkable precision.
Mechanism:
T cells are collected from the patient.
CARs are genetically added to these T cells to target tumor-associated antigens (TAAs).
The modified T cells are expanded in a lab.
They are infused back into the patient to attack cancer cells.
Key CAR T-Cell Targets in Gastric Cancer
1. HER2 (Human Epidermal Growth Factor Receptor 2)
Expression: 15–20% of gastric cancers
Clinical Status: HER2-CAR T cells show promising early trial results, especially when combined with other treatments.
2. CLDN18.2 (Claudin 18.2)
Highly expressed in gastric tumors, limited in normal tissues
China is leading in clinical trials, with early results showing safety and efficacy.
3. MUC1 (Mucin 1)
Overexpressed in gastric and other epithelial cancers
Trials are investigating MUC1-CAR T cells, sometimes in combination with checkpoint inhibitors.
4. EpCAM (Epithelial Cell Adhesion Molecule)
Widely expressed in gastric cancer
Dual-target CARs involving EpCAM are under development.
5. Mesothelin (MSLN)
Targeted in various solid tumors
Being studied in combination with immune checkpoint inhibitors.
6. CEA (Carcinoembryonic Antigen)
A well-known marker for gastric cancer
CEA-targeted CAR T trials are showing early-stage promise.
7. NKG2D Ligands
Include MICA and MICB, often upregulated in stressed tumor cells
NKG2D-CAR T cells may offer broader targeting capacity.
8. PD-L1 (Programmed Death-Ligand 1)
Plays a role in immune evasion
Armored CAR T cells with PD-1/PD-L1 blockade mechanisms are in early development.
9. GPC3 (Glypican-3)
An oncofetal antigen expressed in some gastric cancers
GPC3-targeted CAR T cells are under investigation in preclinical and early-phase trials.
Side Effects of CAR T-Cell Therapy
While often manageable, CAR T-cell therapy can cause:
Cytokine Release Syndrome (CRS): Fever, low blood pressure, and organ dysfunction.
Neurotoxicity: Confusion, seizures, or headaches.
Hematological Toxicity: Low blood cell counts, increasing infection risk.
Close monitoring and advanced supportive care are essential during treatment.
Who Is Eligible?
Patients may be candidates if they:
Have advanced or metastatic gastric cancer
Have not responded to conventional treatments
Are in adequate physical condition to undergo therapy
Eligibility is determined by oncologists based on the individual’s health status and cancer characteristics.
Challenges in Gastric Cancer CAR T Therapy
CAR T-cell therapy in solid tumors like gastric cancer faces several hurdles:
Immunosuppressive Tumor Microenvironment (TME)
Antigen Heterogeneity
On-target, off-tumor toxicity
Short CAR T-cell persistence and exhaustion
Strategies to Overcome Challenges
To enhance efficacy and safety, researchers are developing:
Dual-Targeting CARs: Attack multiple antigens to prevent tumor escape.
Armored CAR T Cells: Engineered to secrete immune-stimulating cytokines.
Gene-Editing (e.g., CRISPR): Removes inhibitory checkpoints in T cells.
Combination Therapies: Pairing CAR T with checkpoint inhibitors or chemotherapy.
Clinical Trials & Global Developments
Numerous early-phase trials are underway worldwide, particularly targeting HER2 and Claudin 18.2. These trials aim to evaluate:
Optimal CAR design
Dosing strategies
Combination approaches
The Role of China in CAR T Innovation
China is emerging as a global leader in CAR T-cell therapy for gastric cancer. Chinese researchers have led multiple successful clinical trials focusing on CLDN18.2, one of the most promising and selective targets for gastric tumors. Results have shown manageable toxicity and encouraging response rates.
The Future of CAR T Cell Therapy for Gastric Cancer
Advances are paving the way for:
Personalized CAR T therapies based on tumor profiling
Allogeneic CAR T cells from healthy donors (“off-the-shelf” products)
Smarter CARs with enhanced tumor-penetration and resistance to suppression
Real-time biomarker monitoring for treatment optimization
Conclusion
CAR T-cell therapy offers renewed hope to patients with advanced or treatment-resistant gastric cancer. While challenges remain, ongoing research, especially in countries like China, is rapidly accelerating progress. With innovations such as dual-targeting, armored CARs, and CRISPR gene-editing, this therapy is poised to become a cornerstone in the fight against gastric cancer.
