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One day in 2010, Bruce Levine and Carl June, two immunologists at the University of Pennsylvania, were anxiously awaiting confirmation of the treatment outcomes of several patients.

They are conducting a clinical trial of a new type of anti-tumor therapy in which three leukemia patients who have no medically available medicine are involved.

When the treatment results were obtained, they found that the tumor cells in both patients were completely eliminated after a single treatment, and the third patient also had a partial response. This treatment makes them feel very excited.

This new treatment is CAR-T cell therapy: by extracting T cells from patients, they are edited in vitro to have the ability to kill tumor cells, and then return to the patient.

From left to right: Bruce Levine, patient Bill Ludwig and his wife, Carl June. Bill was one of the first three patients to receive Levine treatment.

At the moment, Levine couldn’t calm down. Over the past decade or so, he and June have been questioned by many scientists. Many people do not believe in the potential of CAR-T therapy. In the 1990s and early 2000s, CAR-T therapy has been a very unpopular area.

 

Despite the initial success of the clinical trial, Levine and June still did not have enough funds for follow-up clinical research, so they made a bold decision to publish the existing data.

After the Bruce Levine team published the article in the New England Journal of Medicine in 2011 [doi: 10.1056/NEJMoa1103849.], the CAR-T field also ushered in an outbreak.

In August 2017, the FDA approved the first CAR-T product, Kymriah, for the treatment of patients with B lymphoid precursor acute lymphoblastic leukemia under 25 years of age. Soon, in October 2017, the FDA approved another CAR-T product, Yescarta, for the treatment of adult diffuse large B-cell lymphoma.

 

Where is the next breakthrough for CAR-T?

 

With the approval of the product, the pioneers of CAR-T therapy have also ushered in a glorious moment of their career. For Levine, his relationship with CAR-T therapy originated from Levine’s research in the field of HIV many years ago.

In 1992, Levine was still a Ph.D. in immunology. He learned that Carl June was doing research in the field of T cells. Carl June had a great influence in the field of synthetic biology. Levine decided to go to June’s lab at the Institute of Naval Medicine for academic research.

His research topic at the time was to cultivate healthy human immune cells and then enter the body of AIDS patients in an attempt to rebuild the patient’s immune system. Levine finally found that this approach does improve the function of the patient’s immune system to some extent.

But because AIDS treatment was undergoing major changes at the time, this treatment was not as competitive as high-efficiency antiretroviral therapy.

However, June and Levine came up with another research idea: Can this treatment be used to treat cancer and enhance the anti-tumor immunity of cancer patients? In fact, there have been a lot of research on this issue.

Although the human immune system has the ability to recognize and kill tumor cells in theory, there are also many mechanisms for tumors to resist the identification and killing of the immune system. To address these issues, Levine and June teamed up with Genesys, a company that engineered T cells to express chimeric antigen receptors (CARs) that recognize tumor antigens, thereby altering the specificity of immune cells and enabling them to kill. Tumor cells expressing the relevant antigen.

 

For CAR-T therapy, CD19 is indeed an excellent antigen. In fact, CD19 has also achieved the early success of CAR-T therapy. But it is not easy to achieve such success in the field of solid tumors, because it is difficult to find an ideal antigen like CD19.

In addition to the problem of antigens, how efficient infiltration of CAR-T cells into tumors is also an important issue in the field of solid tumors. Furthermore, the microenvironment of the tumor may also inhibit the function of CAR-T cells.

 

Levine believes that the next breakthrough in the CAR-T field will be produced in the field of multiple myeloma, and the challenge of conquering solid tumors requires the joint efforts of researchers around the world.

At the same time, there are still many problems that need to be solved in the field of blood cancer. For example, although some patients have been relieved after treatment with CD19 CAR-T therapy, many patients are still likely to have disease recurrence, so Levine’s team is also looking for targets other than CD19 for the treatment of relapsed patients.

In addition to technically relevant issues, since CAR-T therapy is a highly individualized therapy, cost control of CAR-T products is also a very important factor affecting the development of this field.

 

Levine believes that by optimizing the preparation of CAR-T products, manufacturing costs can be reduced, potentially reducing the price of CAR-T products to benefit more patients, so Levine is also working with multiple research centers to optimize CAR- The preparation process of the T product.

 

There are many new technologies in the field of biomedicine, but there are many difficulties in turning these new technologies into new ones that can benefit patients. Levine has always been clear that his research path will not be smooth, but he still has not stopped exploring.

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