CAR-T therapy challenges colorectal cancer

CAR-T therapy challenges colorectal cancer. The new CAR-T therapy is upgraded! Double the anti-cancer effect! A variety of new targets challenge colorectal cancer!

In recent years, scientists have made considerable efforts to develop new methods to overcome the obstacles of colorectal cancer and other solid tumors.

The trend of population aging in many countries continues to expand, coupled with changes in dietary structure, the incidence and mortality of colorectal cancer have been high. 

Unfortunately, most patients are already in the middle and advanced stages at the time of diagnosis. Surgery is only used as a palliative treatment method for patients, or is only used to eliminate symptoms that have a greater impact on patients, and adjuvant treatment is the mainstay. The prognosis of general treatment is not ideal.

Since tumor immunotherapy became the fourth cancer treatment method, researchers have gradually focus on the popular therapy in recent years-Chimeric Antigen Receptor T Cell Immunity (CAR-T) therapy.

Install different “radars” for CAR to accurately target cancer cells

As we all know, the achievements of CAR-T in the treatment of malignant hematological tumors are obvious to all. This is all due to the ancestral target of hematological tumors-CD19, which only exists in tumor cells and not in normal In the cell. Therefore, in the treatment of tumors, this target can be used to lead CAR-T cells to find and eliminate cancer cells, but the achievements of CAR-T in solid tumors are lackluster.

Therefore, CAR-T treatment needs to collect the patient’s own T cells first, and then add a foreign gene to them to express CAR receptors on their surface. The CAR receptors can be equipped with “radars” for different ligands, so that The patient’s own immune cells can recognize different tumors and destroy them.

CAR-T cell therapy flow chart

Especially advanced colorectal cancer has a high mortality rate, and there is almost no more effective treatment. Fortunately, the CAR-T research results in recent years have brought new hope to patients with advanced colorectal cancer!

The editor sorted out the potential targets of CAR-T cell therapy in colorectal cancer based on numerous clinical studies, including anti-4-1BB (ANTI-4-1BB), carcinoembryonic antigen (CEA), GUCY2C, TAG-72, EpCAM , Epiglycoprotein 40 (EGP40), NKG2D, HER-2, recombinant human interferon α/β receptor 1 (IFNAR1), prominin-1 (CD133), epiglin 2 (EGP-2).

CYAD-01 alone or in combination with standard chemotherapy is better

Target: NKG2D

Today the editor introduced the first “high light” CAR-T that can kill colorectal cancer called CYAD-01, Its “radar” can detect the target NKG2D is not simple, this target is not expressed or expressed less in normal cells, but when the cell is infected or cancerous, the expression of these ligands will Increase rapidly. in short, With NKG2D as the target, it can precisely target and target cancer cells without accidentally injuring normal cells.

1. Single drug has good effect

The THINK trial is evaluating the therapeutic effect of CYAD-01 alone on 7 types of refractory cancer patients, including 5 solid tumors (colorectal cancer, ovarian cancer, bladder cancer, triple negative breast cancer and pancreatic cancer) and 2 Kind of blood cancer (acute myeloid leukemia and multiple myeloma).

This study currently enrolls only 14 patients, including 11 cases of metastatic colorectal cancer, 2 cases of ovarian cancer, and 1 case of pancreatic cancer. The results show that,
4 patients (29%) reached stable disease, 3 patients with metastatic colorectal cancer and 1 patient with ovarian cancer.

In addition, patients with different treatment doses were observed to have stable disease, and the duration of stable disease in the 2 patients with metastatic colorectal cancer assigned to the highest dose group was not less than 4 months.

2. Strong combination with chemotherapy

The SHRINK trial directly studied the therapeutic effect of CYAD-01 combined with standard chemotherapy (called FOLFOX) in the treatment of patients with liver metastases from colorectal cancer.

This trial recruited 3 patients with colorectal cancer who had not been treated for metastases, and all patients benefited from the combined treatment plan.
One patient achieved complete tumor remission, and the other two patients had tumor partial remission.
Moreover, the combination therapy is well tolerated, safe, and has no serious adverse events.

For CEA-positive CRC patients, CAR-T therapy is safe and effective

Target: CEA

Carcinoembryonic Antigen (CEA) is an acid glycoprotein with the characteristics of human embryonic antigen and a broad-spectrum tumor marker.

This study mainly used 5 increasing doses of CAR-T cells to treat 10 patients with CEA-positive metastatic colorectal cancer, and the results did not show serious adverse events related to CAR-T treatment.   7 patients were in stable condition after treatment, of which 2 patients were in stable condition for more than 30 weeks, and the other 2 patients had tumor lesions shrinking. Serum CEA levels in most patients decreased significantly and even proliferation of CAR-T cells was observed. And for CEA-positive patients, high-dose CAR-T cell therapy can be tolerated.

The study showed that the effectiveness and safety of CAR-T cells in the treatment of CEA-positive colorectal cancer is extremely impressive.
Schematic diagram of typical cases

PET/CT of patient P9 showed that tumor activity was significantly weakened

It was observed by MRI that a liver lesion of the patient’s P10 was atrophy

The killing effect of CAR-T targeting EpCAM antigen cannot be underestimated

Target EpCAM

Epithelial cell adhesion molecule (EpCAM), also known as CD326, is a transmembrane glycoprotein that plays an important role in the occurrence and development of colorectal cancer and has been used in the treatment of colorectal cancer.

In a research paper of Shanxi Medical University, researchers used transfected T cells to construct CAR-T cells targeting EpCAM antigen (anti-EpCAM-CAR-T), and divided nude mice into CAR-T groups (injection transfection EpCAM-CAR T cells), empty vector group (injection of T cells transfected with empty vector), T cells (injection of ordinary T cells) and blank group (injection of medium), each group has 6 cells.

Results The nude mice were dissected, the tumor was stripped, and the tumor was observed by naked eyes. The volume of the tumor was measured by volumetric method. The results showed that the EpCAM-CAR-T group had the lightest tumor (2.31g) and the smallest average volume (281.01mm3), as shown in the figure below.

This result indicates that EpCAM-CAR-T cells have a killing effect on EpCAM-positive colorectal cancer cells.

The lifetime is 5 times! New CAR-T therapy will carry out human trials

Target GUCY2C

Researchers from the Sidney Kimmel Cancer Center (SKCC) of Jefferson Health said,
CAR-T cell therapy can successfully kill tumors (colorectal cancer) and prevent tumor metastatic growth in mouse disease models.
Related research results are published in the journal Cancer Immunology Research. It is worth mentioning that the research published in this journal is the last step before entering human clinical trials.

This tumor antigen of colorectal cancer is called GUCY2C.
Director of the Jefferson Department of Pharmacology and Experimental Therapy, Dr. Scott Waldman identified the antigen as
Potential biomarkers and therapeutic targets for colorectal cancer.

In order to more accurately simulate advanced human diseases, in further experiments, Dr. Snook and his colleagues also studied a mouse model of colorectal cancer with lung metastasis, which is a common site of metastasis in colorectal cancer patients. The results show that:

The mice receiving CAR-T treatment survived within 100 days without metastasis, while the average survival time of the control group was only 20 days, which means that the survival time of the mice receiving CAR-T treatment was 5 times that of the control group!

Clinical research on CAR-T cell therapy for solid tumors is in progress

In addition to the prominent studies mentioned above, the main targets of CAR-T for colorectal cancer include CD133, EGFR, HER2, etc.

In recent years, scientists have made considerable efforts to develop new methods to overcome the obstacles of solid tumors such as colorectal cancer, and adopt optimized strategies for CAR-T therapy for these specific indications.

We look forward to the fact that more and more preclinical/clinical trial data can piece together a complete puzzle, fully demonstrating the true strength of CAR-T cell therapy in the treatment of colorectal cancer and other solid tumors.

(source:internet, reference only)

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