December 4, 2022

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CAR-T therapy treats solid tumors: 10 New breakthroughs are expected in 2022

CAR-T therapy treats solid tumors: 10 New breakthroughs are expected in 2022



 

CAR-T therapy treats solid tumors: 10 New breakthroughs are expected in 2022.

CAR-T therapy treats solid tumors! These 10 major targets involved in more than 10 types of cancer, and new breakthroughs are expected in 2022.

 

As a “living” drug, CAR-T therapy is very different from traditional drugs. It is a novel precision targeted therapy for the treatment of tumors.

Through genetic engineering technology, T cells are activated, and the positioning and navigation device CAR (Tumor Chimeric Antigen Receptor) is installed to transform the ordinary “fighters” of T cells into “super soldiers”, namely CAR-T cells, which specifically recognize tumors in the body cells, and efficiently kill tumor cells, so as to achieve the purpose of treating malignant tumors.

 

Compared with traditional chemotherapy and hematopoietic stem cell transplantation, it kills tumor cells more accurately, and greatly reduces the side effects while improving the curative effect.

 

The world’s first girl to receive CAR-T cell therapy has now been cancer-free for 10 years.

 

At the same time, in the past 10 years, CAR-T cell therapy has also been developing continuously. In addition to the treatment of blood tumors, the treatment of solid tumors is also progressing. Let us take a look at the representative targets of CAR-T cell therapy in the treatment of solid tumors. point progress.

 

CAR-T therapy treats solid tumors: 10 New breakthroughs are expected in 2022.

 

 

Ganglioside 2 (GD2): Brain tumor, sarcoma, melanoma, etc.

GD2 is a surface glycolipid antigen, which is highly expressed in neuroblastoma, astrocytoma, retinoblastoma, sarcoma, melanoma and other tumor cells, while its expression is limited in normal tissues, mainly in neurons. It is expressed at low levels on cell bodies and mesenchymal stem cells, making it an ideal target for CAR-T.

 

GD2-targeted GD2-targeted CAR-T cells for the treatment of neuroblastoma. The results of a phase I clinical trial showed that 3 out of 19 patients were completely relieved, with no obvious discomfort except mild pain .

 

In 2016, in the results of a GD2 CAR-T cell clinical trial published by Baylor College of Medicine, 5 of 11 neuroblastoma patients achieved stable disease, and 2 patients achieved complete remission after follow-up supplemental therapy .

 

At present, GD2 CAR-T cells have the most significant efficacy in solid tumors, and are expected to successfully enter Phase III clinical trials, becoming the first solid tumor CAR-T cell target to enter Phase III clinical trials.

 

 

 

EGFR:Glioblastoma, lung cancer, liver cancer, gastric cancer, etc.

Epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor that is present in approximately 50% of adult primary glioblastomas, and also acts as a Targets of cancers such as rectal cancer.

 

301 Hospital took the lead in developing CAR-T therapy in China, and achieved remarkable results. EGFR-targeted CAR-T is used to treat patients with advanced and refractory non-small cell lung cancer with strong EGFR expression (more than 50% EGFR expression). The results of the study showed that the efficacy of 11 patients was evaluable: 2 patients had significantly reduced tumors, and 5 patients had stable disease .

 

 

HER2:Breast cancer, bladder cancer, ovarian cancer, etc.

Human epidermal growth factor receptor-2 (HER2) is a macromolecular type I transmembrane protein, also known as ErbB2, a member of the ErbB receptor family.

HER2 first appeared in breast cancer research, breast cancer red gene mutation easily leads to HER2 positivity, and high HER2 expression is associated with low tumor prognosis and low disease-free survival.

HER2 is also highly expressed in some bladder cancer, ovarian cancer, and uterine cancer. membranous carcinoma, pancreatic carcinoma and non-small cell lung carcinoma.

 

HER2 is overexpressed in about 10% of gastric cancers, and Herceptin, a monoclonal antibody directed against Her2, has also been approved for use in gastric cancers overexpressing Her2.

Recent preclinical studies have shown that CAR-T-HER2 cells have a specific killing effect on HER2+ gastric cancer cells .

 

Mesothelin: Triple negative breast cancer, pancreatic cancer, ovarian cancer, etc.

Mesothelin (MSLN) is widely expressed in tumors, with about 95% of malignant mesothelioma, 80% to 85% of pancreatic cancer, 68.8% of ovarian cancer and 53% of lung cancer expressing mesothelin .

The high expression of MSLN regulates a variety of cell signaling pathways and is closely related to tumor proliferation, invasion and poor prognosis.

 

MSLN is also a characteristic marker of triple-negative breast cancer, and triple-negative breast cancer is almost insensitive to monoclonal antibody drugs.

MSLN CAR-T cells are expected to become the only immunotherapy drug for triple-negative breast cancer.

 

The internationally renowned journal “Journal of Hematology & Oncology” published a clinical study of Chinese medical researchers successfully transforming CAR-T technology, that is, selecting the target mesothelin.

One of the patients with advanced pancreatic cancer received intravenous CAR-T therapy. After treatment, the lesions in the whole body basically completely disappeared .

 

GPC3: Liver cancer, ovarian cancer, etc.

Glypican 3 (GPC3) plays an important role in regulating cell growth and differentiation, and is closely related to the occurrence and development of liver cancer.

 

GPC3 is expressed in hepatocellular carcinoma, ovarian clear cell carcinoma, yolk sac carcinoma and other reproductive system tumors, and its expression rate in hepatocellular carcinoma reaches 74.8%, but almost no expression in normal liver tissue, which is called liver cancer CAR-T New ideal targets for treatment .

 

The breakthrough research results completed by Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine were published in the international authoritative journal “Clinical Cancer Research” on May 5, 2020.

 

As of July 24, 2019 , a total of 13 patients had received a median of 19.9×108 CAR-GPC3 T cells. All patients were GPC3 positive, had received surgical treatment, local treatment or systemic systemic treatment, and all carried hepatitis B virus (HBV) .

 

Among them, 2 patients achieved partial response (PR), the 6-month, 1-year and 3-year survival rates of all patients were 50.3%, 42.0% and 10.5%, respectively, and the median survival time (OS) was 278 days (39.7 weeks). ).

 

At the 2021 ASCO annual meeting, Chinese medical researchers announced for the first time the latest clinical research data on GPC3-targeting CAR-T drug (Ori-CAR-001) in the treatment of relapsed/refractory hepatocellular carcinoma.

 

As of March 10, 2021, a total of 11 relapsed subjects who received cell infusions were enrolled. All subjects had advanced hepatocellular carcinoma and were ineffective after chemotherapy, TACE (transarterial chemoembolization) and targeted therapy.

Of the 9 evaluable subjects, 4 achieved partial response (PR), 3 achieved stable disease (SD), and 2 experienced progressive disease (PD), resulting in an objective response rate of 44% and a disease control rate of 78% .

 

 

 

Mucin 1 (MUC1): Gastric cancer, liver cancer, pancreatic cancer, etc.

MUC1 is a transmembrane mucin, which is widely overexpressed in gastric cancer, liver cancer, and pancreatic cancer.

At present, clinical trials of anti-MUC1 CAR-T therapy have been widely carried out.

 

In 2016, animal experiments verified that MUC1 CAR-T can recognize and kill various cancer cells such as pancreatic cancer, breast cancer, non-small cell lung cancer, and leukemia cells.

 

A domestic team has reported a clinical trial of MUC1 CAR-T cells in the treatment of spermatic cord cell carcinoma.

The patient experienced tumor shrinkage and intra-tumor necrosis, and no adverse reactions occurred in the trial.

 

CAR-T therapy treats solid tumors: 10 New breakthroughs are expected in 2022

Image source: The official website of Pixabay

 

 

 

Carcinoembryonic Antigen (CEA): Gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, etc.

Carcinoembryonic antigen (CEA) was initially found in colon cancer and fetal intestinal tissue, and was later confirmed to be widely present in digestive system tumors of endodermal origin, such as gastric cancer, liver cancer, pancreatic cancer (over 75%), and colorectal cancer (60%). %).

A preclinical study showed that CAR-T cells targeting CEA could induce apoptosis in gastric cancer cells.

 

For example, the research team of the Third Military Medical University has reported the clinical effect of CEA CAR-T cells in 10 patients with advanced colorectal cancer, of which 7 patients had stable disease, 2 patients had obvious tumor shrinkage, and serum CEA was observed in all patients. decreased to varying degrees.

 

 

 

Claudin 18.2: Gastric cancer, pancreatic cancer, etc.

Claudin18.2 (CLDN18.2) is a member of the Claudin protein family and is located on the surface of the cell membrane.

Normally, it is only expressed at low levels in differentiated epithelial cells of the gastric mucosa. However, under pathological conditions, Claudin18.2 is present in a variety of tumors.

Expression was significantly up-regulated, including 80% of gastrointestinal adenomas and 60% of pancreatic tumors.

In addition, CLDN 18.2 activation is also seen in esophageal, ovarian, and lung adenocarcinomas, making it a promising target for potential cancer therapy .

 

Due to the highly specific expression of this target in normal tissues, coupled with its activated expression in various cancers, the Claudin18.2 protein has become an ideal target for researchers to develop immunotherapy for solid tumors such as gastric cancer and pancreatic cancer.

At the same time, since gastric cancer is a major tumor type in China, the Claudin 18.2 target is expected to achieve a breakthrough in the bottleneck of new gastric cancer target drugs.

 

As the first CAR-T cell targeting Claudin18.2 in the world, CT041 emerged as early as the 2019 ASCO annual meeting.

At that time, the total objective response rate of 33.3% was already amazing to the world, and then it was recently published in the journal “Nature Medicine” The research data above is particularly eye-catching!

 

The objective response rate of all patients was 48.6%, and the disease control rate was 73%; the overall objective response rate of all gastric cancer patients was 57.1%.

  • Gastric cancer patients who had failed at least 2 lines of therapy: the objective response rate was 61.1%, and the disease control rate was 83.3%.
  • Well tolerated overall!

 

As of March 3, 2022, CT041 has become the world’s first and only CAR-T cell product candidate for the treatment of solid tumors that has entered a confirmatory phase II clinical trial.

This is also a major progress of the National Research Institute CAR-T cell therapy.

 

 

 

Epithelial cell adhesion molecule (EpCAM): stomach cancer, etc.

EpCAM is a transmembrane glycoprotein overexpressed in a variety of tumors and is considered to be a potential tumor stem cell marker.

More than 90% of gastric cancers overexpress EpCAM, but EpCAM is also expressed in tissues such as the pancreas.

Monoclonal antibodies can cause pancreatitis in the clinic, so CAR-T targeting EpCAM must pay attention to such risks.

 

 

 

 

Prostate-specific membrane antigen (PSMA): prostate cancer

Prostate Specific Membrane Antigen (PSMA) – Prostate Cancer

 

PSMA is a type II transmembrane protein that is normally expressed in renal tubules and duodenum, and is specifically expressed in prostate cancer epithelial cells. In prostate cancer tissues, the expression of PSMA was significantly up-regulated.

 

Studies have shown that PSMA is overexpressed on the surface of more than 90% of prostate cancer cells (100-1000 times higher than normal prostate cells), and the expression level is higher in cancer cells of advanced and castration-resistant prostate cancer patients.

Therefore, PSMA is regarded as an important target for the diagnosis and treatment of prostate cancer.

 

CAR-T cell therapy P-PSMA-101 in patients with metastatic castration-resistant prostate cancer (mCRPC) at the 2022 American Society of Clinical Oncology Symposium on Genitourinary Cancers (ASCO GU) on February 17, 2022 Interim results of a Phase 1 clinical trial.

 

As of December 31, 2021, a total of 17 patients with metastatic castration-resistant prostate cancer (mCRPC) were enrolled, of whom 14 were evaluable.

Notably, these patients received an average of seven lines of therapy, and the median time since diagnosis was 6.4 years. Key findings from the trial include:

  • 71% (10/14) of patients had significantly decreased levels of the tumor marker prostate-specific antigen (PSA);
  • 36% (5/14) of patients had a >50% decrease in PSA level;
  • 1 patient showed complete tumor eradication with durable remission over 10 months.


Biopsies from some patients have confirmed that the properties of stem cell memory T cells (Tscm), a product that enables targeted transport of CAR-T cells into bone, are important in diseases that are prone to bone metastases, such as prostate cancer. P-PSMA-101 showed good safety and tolerability.

 

CAR-T therapy treats solid tumors: 10 New breakthroughs are expected in 2022
Image source: The official website of Pixabay

 

 

In addition to the popular targets mentioned by the editor above, there are many therapeutic targets.

These CAR-T cell therapy targets are also constantly advancing, and I believe they will bring us more therapeutic surprises.

 

In 2021, some countries will usher in the first year of cellular immunotherapy. As a pioneer, CAR-T therapy is one of the future development directions.

 

It is hoped that in the near future, with the efforts of domestic and foreign medical researchers, the toxic and side effects of CAR-T cell therapy will be reduced, the price will be reduced, and the bottleneck of solid tumors will be broken, so that more and more advanced cancer patients can benefit from it!

 

 

 

 

 

 

 

 


References:

1. https://stemcellres.biomedcentral.com/articles/10.1186/s13287-020-02128-1

2. https://www.sciencedirect.com/science/article/pii/S0024320520310523

CAR-T therapy treats solid tumors: 10 New breakthroughs are expected in 2022

(source:internet, reference only)


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