Autoimmune cell therapy, currently not the best option for lung cancer

Since the “Weizexi case” in 2016, autoimmune cell therapy has been in the limelight, and does it work or not? There are many different opinions. This article provides a brief overview of this therapy and whether it can be used for lung cancer patients.

Autologous immune cell therapy, also known as transitional immune cell therapy, involves taking the patient’s blood, isolating immunocompetent cells, modifying, activating, and amplifying them in vitro, and then feeding the activated immune cells back into the patient to kill tumor cells.

There are many different types of secondary immune cell therapy, including lymphokine-activated killer cells (LAK), cytokine-induced killer cells (CIK), tumor-infiltrating lymphocytes (TIL), anti-CD3 monoclonal antibody-activated killer cells (CD3AK), donor lymphocytes (DLI), dendritic cell-stimulated CIK cells (DC-CIK), natural killer cells (NK), tumor antigen-specific TCR transgenic cells (TCR-T), and chimeric antigen receptor T cells (CAR-T). Two of these CAR-T cell therapies have been approved for marketing in the United States.

What is CAR-T?

CAR-T stands for Chimeric Antigen Receptor T-Cell Immunotherapy, a technology that involves taking T lymphocytes from a patient’s blood and, in the lab, combining the receptor for a protein that is specific to the surface of the tumor cells. This technique involves extracting T lymphocytes from the patient’s blood and “implanting” the receptor gene for a protein specific to the surface of the tumor cells in the laboratory, so that the T cells eventually express the chimeric antigen receptor (CAR), which gives the modified T cells the ability to accurately identify tumor cells. The obtained CAR-T cells are expanded in vitro and then infused back into the patient, and these super-trained special forces soldiers begin the process of fighting the tumor.

CAR-T: New hope for treating lymphohematologic tumors

In 2012, Emily Whitehead, a six-year-old American child with acute lymphoblastic leukemia, became the first child in the world to receive cellular therapy when she received experimental CAR-T therapy at the end of her life.

She woke up the next day and doctors miraculously found that the cancer cells in her body had completely disappeared. Emily, the first crab, is now 12 years old, and her experience has rekindled scientists’ enthusiasm for cell therapy.

On August 31, 2017, the U.S. Food and Drug Administration (FDA) approved the first CAR-T immunotherapy, Kymriah, for the treatment of refractory or relapsed acute lymphoblastic leukemia under age 25; on October 19 of the same year, the FDA approved a second CAR-T immunotherapy, Yescarta, for the treatment of relapsed acute lymphoblastic leukemia. – Yescarta, for relapsed or refractory aggressive non-Hodgkin’s lymphoma.

Both drugs have shown excellent results in clinical trials. In one clinical trial with Kymriah in patients with advanced leukemia, 83% of patients achieved complete remission over a three-month treatment period, and in a clinical trial with Yescarta in patients with non-Hodgkin’s lymphoma, complete remission was achieved at 51%.

CAR-T is not yet the best option for lung cancer patients

At present, the efficacy of CAR-T therapy in lung cancer has not been proven. CAR-T kills tumor cells by recognizing a specific protein molecule on the tumor cells. To achieve this, molecules must first be found that are expressed only on tumor cells and not on normal cells.

Both of the CAR-T cell therapies currently on the market are designed to target the CD19 molecule on the surface of B lymphocytes, which meets this requirement: it is expressed only on the surface of B lymphocytes and is not present in any other healthy tissue cells. So these two therapies work well for malignancies derived from B lymphocytes.

But in lung cancer, on the one hand, it is difficult to find specific molecules that are present only on the surface of lung cancer cells and not in healthy tissue cells, and proteins from solid tumor cells such as lung cancer are present in almost all normal cells. On the other hand, even if a molecule specific to the surface of lung cancer cells is found, it is not expressed on the surface of all lung cancer cells, so it “leads the way” to kill only some of the cancer cells.

CAR-T: side effects that cannot be ignored

Despite initial successes in lymphohematologic tumors, there is no way to mask the toxicity of CAR-T therapy. CAR-T cells that are genetically modified and heavily amplified are a double-edged sword, killing tumors while also causing immune stimulation and inflammatory responses with some serious adverse effects.

Toxic side effects of CAR-T therapy may include:

Cytokine storm, also called cytokine release syndrome, in which patients develop fever, hypotension, hypoxia, and significantly elevated levels of certain cytokines in the blood; in severe cases, this can cause organ failure (liver failure, hyperbilirubinemia, and respiratory failure, etc.) and hemodynamic instability (tachycardia, hypotension, etc.);

Neurotoxicity, including intracranial vascular injury, disruption of the blood-brain barrier, and in severe cases, delirium, aphasia, mania, cerebral edema, and intracranial hemorrhage.

In summary, there are still many obstacles to percutaneous immune cell therapy, but due to continued technological advances, future breakthroughs in immune cell-based therapies are possible in lung cancer.