CAR T-Cell Therapy for gastric cancer

CAR T cell therapy is an innovative cancer therapy that holds promises of a renewed hope for those suffering from gastric cancer. Targeting cancerous cells by deploying the immune system of the human body, it is revolutionizing the field of oncology. HER2, Claudin 18.2, MUC1, EpCAM, Mesothelin, CEA, NKG2D legend, PD-L1, GPC3 are the targets are used in gastric cancer CAR T Cell therapy.

Gastric cancer

Gastric cancer, or stomach cancer, is a global health threat and is among the major killers of cancer worldwide. It arises from the lining cells of the stomach and usually starts as a localized growth that can later become an invasive tumor. Although early gastric cancer can be symptomless, the disease is often diagnosed in an advanced stage because the disease has no apparent symptoms in its initial stages. Indigestion, abdominal pain, unintentional weight loss, nausea, and vomiting are some typical symptoms. The main risk factors for gastric cancer are infection with Helicobacter pylori, chronic gastritis, smoking, obesity, a high salt and smoked food diet, and a history of the disease in the family. The diagnosis is usually made with endoscopy, biopsy, imaging, and staging tests to assess the spread of the cancer.

Treatment of gastric cancer is based on the stage and can involve surgery, chemotherapy, radiation therapy, and targeted treatments. Although the traditional treatments have improved, results for metastatic or resistant gastric cancer patients continue to be unfavorable. More recently, immunotherapy has become an exciting development in which the patient’s immune system is used to combat cancer.

One of the most revolutionary developments in cancer immunotherapy is chimeric antigen receptor (CAR) T cell therapy. Although CAR T cell therapy has been highly successful in hematologic malignancies, its use in solid tumors, such as gastric cancer, is faced with special challenges. Nevertheless, research and clinical trials are ongoing to develop new strategies to overcome these challenges, and there is hope for enhanced survival and quality of life for patients.

This piece explores the future of CAR T cell therapy in gastric cancer, discussing its mechanisms, clinical advancements so far, challenges, and future prospects in the pursuit of better therapeutic options.

CAR T Cell therapy

It is one of the groundbreaking forms of immunotherapy that puts to bear the power of a person’s own immune system against cancer. This treatment involves making T cells carry a synthetic receptor known as CAR that specifically makes them recognize tumor-specific antigens expressed by cancer cells, and on infusing them back into the body, these engineered T cells can recognize and destroy cancer cells with remarkable precision.

CAR T-cell therapy has greatly succeeded in hematologic malignancies, including leukemia and lymphoma. The same cannot be said for its use in solid malignancies such as breast and lung cancer. Such is mainly attributed to heterogeneity of tumors, the immunosuppressive nature of the tumor microenvironment, and lack of targetable antigens. Many researchers are pursuing CAR T-cell therapy in the treatment of breast cancer with attention to HER2, MUC1, and FRα for specificity and potency.

Though promising, CAR T-cell therapy comes with potential side effects, including cytokine release syndrome (CRS) and neurotoxicity. Studies are underway to improve safety and efficacy, including the development of bispecific CARs and armored CAR T cells. As the clinical trials advance, CAR T-cell therapy promises to revolutionize cancer treatment and provide hope to patients with aggressive or treatment-resistant cancers.

Pic: Working of CAR T Cell therapy

CAR T Target Markers in Gastric Cancer

In gastric cancer, CAR T cell therapy is an emerging treatment strategy that involves engineering T cells to target specific tumor-associated antigens (TAAs) or cancer-specific markers. While CAR T cell therapy has shown remarkable success in hematologic malignancies, its application in solid tumors like gastric cancer remains challenging due to factors like the immunosuppressive tumor microenvironment and tumor heterogeneity.

Here are some key target markers explored in gastric cancer CAR T cell therapy:

1. HER2 (Human Epidermal Growth Factor Receptor 2)

Rationale: HER2 is overexpressed in approximately 15-20% of gastric cancers, especially in gastroesophageal junction cancers.
Status: HER2-specific CAR T cells are actively being tested in clinical trials, with modifications like armored CARs or combined therapies to overcome the immunosuppressive microenvironment.
Example: HER2-CAR T cells have demonstrated promising preclinical efficacy and early-stage clinical responses.

2. CLDN18.2 (Claudin 18.2)

Rationale: CLDN18.2 is a tight junction protein highly expressed in gastric cancer cells, while its expression in normal tissues is restricted to the gastric mucosa.
Status: CLDN18.2 CAR T cell therapy is under investigation in multiple clinical trials in China, showing encouraging results.
Example: Clinical trials using CLDN18.2-CAR T cells are demonstrating manageable toxicities and promising efficacy.

3. MUC1 (Mucin 1)

Rationale: MUC1 is a transmembrane glycoprotein overexpressed in gastric cancer and other adenocarcinomas.
Status: MUC1-CAR T cells are being studied for their potential to target tumors with high MUC1 expression.
Example: Trials are exploring MUC1-targeted CAR T cells, sometimes combined with checkpoint inhibitors.

4. EpCAM (Epithelial Cell Adhesion Molecule)

Rationale: EpCAM is commonly overexpressed in gastric and other epithelial cancers.
Status: EpCAM-CAR T cells are currently in preclinical and early-phase clinical trials.
Example: Researchers are investigating bispecific or dual-target CARs targeting both EpCAM and other gastric cancer antigens.

5. Mesothelin (MSLN)

Rationale: Mesothelin is overexpressed in various solid tumors, including gastric cancer.
Status: MSLN-CAR T cells are in development to evaluate their efficacy in patients with mesothelin-positive gastric cancer.
Example: Combination therapies with MSLN-CAR T cells and immune checkpoint inhibitors are being explored.

6. CEA (Carcinoembryonic Antigen)

Rationale: CEA is a well-established tumor marker highly expressed in gastric cancer.
Status: CEA-CAR T cells are being tested in clinical trials, particularly in metastatic or refractory gastric cancer.
Example: Clinical trials are assessing safety and efficacy in combination with other therapies like immune checkpoint inhibitors.

7. NKG2D Ligands

Rationale: NKG2D ligands (e.g., MICA, MICB) are stress-induced molecules expressed on gastric cancer cells.
Status: NKG2D-CAR T cells leverage the immune recognition system to enhance tumor targeting.
Example: Trials are underway to evaluate their potential in gastric and other solid tumors.

8. PD-L1 (Programmed Death-Ligand 1)

Rationale: PD-L1 is commonly expressed in gastric cancer cells and contributes to immune evasion.
Status: PD-L1-targeted CAR T cells or armored CAR T cells with PD-1/PD-L1 blockade mechanisms are in early trials.
Example: Combining PD-L1-CAR T cells with immune checkpoint inhibitors is a potential strategy.

9. GPC3 (Glypican-3)

Rationale: GPC3 is an oncofetal protein overexpressed in some gastric cancers.
Status: GPC3-CAR T cells are being explored for their role in targeting GPC3-positive gastric cancer.
Example: Ongoing trials are investigating their safety and antitumor effects.

Gastric cancer CAR T cell therapy is a rapidly evolving field with numerous promising targets. Researchers are also exploring dual-targeting CAR T cells, armored CAR T cells, and combination therapies to overcome resistance mechanisms and enhance efficacy. Key targets like HER2, CLDN18.2, and MUC1 remain at the forefront of ongoing clinical trials.

Potential Side Effects of CAR T Cell Therapy

While CAR T cell therapy is generally well-tolerated, it may lead to some side effects, including:

Cytokine Release Syndrome (CRS): A systemic inflammatory response caused by the rapid activation of immune cells.
Neurotoxicity: Symptoms such as confusion, headaches, or seizures may occur.
Hematological Toxicity: Low blood cell counts and increased risk of infection.

Patients undergoing CAR T therapy are closely monitored to manage these effects effectively.

Who is Eligible for CAR T Cell Therapy?

Eligibility criteria for CAR T cell therapy in gastric cancer patients include:

Diagnosis of advanced or metastatic gastric cancer.
Failure of conventional therapies, including chemotherapy and targeted treatments.
Adequate organ function and overall health to undergo the therapy.

Oncologists assess each patient’s medical history to determine their suitability for CAR T cell therapy.

Challenges in CAR T Cell Therapy for Gastric Cancer

Despite its potential, several challenges remain in applying CAR T cell therapy for gastric cancer:

Tumor Microenvironment (TME): The solid tumor environment is often immunosuppressive, preventing CAR T cells from effectively attacking cancer cells.
Antigen Heterogeneity: Gastric cancers may exhibit heterogeneity in antigen expression, leading to treatment resistance.
Toxicity: On-target, off-tumor effects can damage healthy tissues expressing the same antigens.Challenges in CAR T Cell Therapy for Gastric Cancer
Limited Persistence: CAR T cells may face exhaustion and lose their effectiveness over time.

Strategies to Overcome Challenges

To enhance the efficacy and safety of CAR T cell therapy in gastric cancer, researchers are developing innovative strategies:

Dual-Targeting CAR T Cells: Engineering T cells to target multiple antigens reduces the likelihood of tumor escape.
Armored CAR T Cells: Modifying CAR T cells to secrete cytokines enhances their persistence and activity within the TME.
Gene-Editing Technologies: CRISPR and other gene-editing tools allow the removal of inhibitory receptors, improving CAR T cell functionality.
Combination Therapies: Combining CAR T therapy with immune checkpoint inhibitors or chemotherapy can improve overall efficacy.

Clinical Trials and Current Developments

Several ongoing clinical trials are exploring the use of CAR T cell therapy for gastric cancer. Early-phase trials targeting HER2 and Claudin 18.2 have shown encouraging results, demonstrating both safety and clinical benefit. Researchers are also evaluating different CAR constructs, dosing regimens, and combination therapies to optimize patient outcomes.

Future Directions

The future of CAR T cell therapy for gastric cancer lies in personalized approaches. By tailoring the therapy based on the patient’s tumor profile and immune response, oncologists can maximize therapeutic efficacy. Additionally, advancements in biomarker identification and real-time monitoring will further refine treatment strategies.

Future of CAR T Cell Therapy in Gastric Cancer

With continued research, new-generation CAR T cells are being designed with greater targeting efficiency and less toxicity. Also, using CAR T cells along with gene editing technologies such as CRISPR is unveiling new possibilities for individualized therapy.

Researchers are also investigating the possibility of using allogeneic (off-the-shelf) CAR T cells from healthy donors, which will offer quicker and more readily available treatment solutions.

Advancements in China

China has become the front-runner in CAR T cell therapy research, especially for gastric cancer. Chinese scientists have achieved great progress in creating CAR T cells that target Claudin 18.2, a potential antigen found in most gastric cancers. Chinese early-phase clinical trials have proven positive safety and efficacy outcomes. Moreover, Chinese biotech firms are investing heavily in CAR T innovations, such as dual-targeting CAR T cells and combination therapies. With robust government backing and streamlined regulatory routes, China is well placed to take a leading position in the future of CAR T cell therapy for gastric cancer.

A number of clinical trials are investigating the application of CAR T cell therapy for stomach cancer. Initial-phase trials in HER2 and Claudin 18.2 have proved to be promising, exhibiting both safety and clinical activity. Investigators are also comparing various CAR constructs, dosing schedules, and combination therapy to maximize patient benefit.

Contact CancerFax for CAR T Cell Therapy

If you or your loved one has been diagnosed with gastric cancer and are seeking advanced treatment options, CAR T cell therapy might be the solution. At CancerFax, we connect patients with leading cancer centers and specialists offering CAR T cell therapy for gastric cancer.

Our dedicated team will guide you through every step of the process, from medical evaluation to treatment coordination. Contact CancerFax today to learn more about your eligibility and explore this groundbreaking therapy.

Take the first step towards personalized cancer care. Reach out to CancerFax now and discover new hope in your cancer treatment journey.