Extremely promising results of CAR-T therapy in the treatment of glioblastoma multiforme (2024)

A new immune cell-based treatment for glioblastoma multiforme, the most aggressive type of brain cancer, has shown extremely promising results, according to two studies. New therapies are still in their early stages of development and their effects are short-lived, but scientists believe there is reason for optimism.

Glioblastoma multiforme is one of the most malignant tumors. The median survival of patients is approximately 14 months. Treatment involves removing the tumor, radiotherapy and administering chemotherapy, but even this therapy extends survival by an average of 3 to 6 months. Therefore, gliomas are one of the most difficult tumors to treat and operate on.

Two new studies suggest that glioblastoma, the most aggressive brain cancer, can be defeated using next-generation engineered immune cells. Anticancer therapies that use immune system cells are classified as so-called immunotherapy. This method involves collecting lymphocytes produced in the bone marrow and maturing in the thymus from the patient. This therapy is called CAR-T therapy.

The description and results of the research of two different teams were published in Nature Medicine (DOI: 10.1038/s41591-024-02893-z) oraz „New England Journal of Medicine” (DOI: 10.1056/NEJMoa2314390).

CAR-T

CAR-T immunotherapy is a personalized therapy and involves the genetic modification of T lymphocytes - immune system cells - in a specific patient. Using a viral vector, a gene encoding a receptor that recognizes an antigen specific to the cancer the cell is supposed to fight is introduced into these cells. The modified cells are then reintroduced into the patient's body in the hope that they will detect and destroy tumors.

But CAR-T therapy has some limitations. It is expensive, technically demanding and only applies to a few types of cancer. It is also risky - some patients do not respond to treatment at all, and others may experience dangerous side effects. It also does not apply to solid tumors, which constitute the vast majority of cancers. At least that's how it was until now.

In new research, two teams saw promising signs of tumor shrinkage after using engineered T cells that target two proteins produced by glioblastoma cells. T cells are designed to focus on only one target, but the results presented show that T cells can be engineered to treat a wider range of cancers.

"This lends credence to the potential power of T cells to impact solid tumors, especially in the brain," says Bryan Choi, a neurosurgeon at Massachusetts General Hospital in Boston and lead author of the study published in the New England Journal of Medicine.

Gliomas

Gliomas pose a huge challenge. They grow quickly and can mix with healthy cells in the brain, creating widespread tumors that are difficult to remove surgically. Surgery, chemotherapy and radiation therapy are usually the only treatment options for these cancers and usually result in short-term, partial responses.

In CAR-T therapy, a person's own T cells are removed from the body and equipped with proteins that help the cells home to the tumor. The blended cells are then reintroduced into the body.

Over the past few years, researchers have been developing T cells that target specific molecules produced by certain gliomas. Both papers went a step further by designing T cells that attack not one type of molecule, but two.

Tests

In one approach, Choi and his colleagues engineered T cells to attach to a mutated form of a protein called epidermal growth factor receptor (EGFR), which is produced by some glioblastoma cells. The newly engineered cells also secreted antibodies that bind to both T cells and the unmutated form of EGFR, which is not typically produced by brain cells but often by glioblastoma cells. The result is CAR-T therapy, which primes the immune system to fight against cells expressing the mutated or unmutated form of EGFR.

Choi and his team administered the engineered cells to three adults with relapsed glioblastoma multiforme, meaning their cancer had returned after radiation and chemotherapy. The researchers observed that the tumors appeared to shrink in all three cases. Unfortunately, after a short period of reduction, the tumors returned to their former sizes. But in one man, the tumor shrinkage lasted for more than six months.

The second team, led by Stephen Bagley, a neuro-oncologist at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, developed T cells that target both EGFR and another protein found in gliomas called interleukin-13 alpha 2 receptor.

These studies were conducted on six people who also had recurrent glioma. After the modified T cells died, the tumors shrank in all participants. After a month, one patient's tumor began to grow again. In another, the tumor showed no signs of progression for seven months. One participant dropped out of the study, and in the remaining three people, the tumors did not return to their previous size during the six-month study period.

Measuring the size of a glioma is extremely difficult due to its diffuse shape, and visible changes in tumor size may be influenced by the inflammation that occurs when T cells are administered directly to the brain. However, tumor RNA measurements in Choi's study suggest that the tumors may have actually shrunk.

It turns out that engineering T cells with multiple targets could ultimately result in therapies with long-lasting effects by making it harder for cancer cells to develop ways to resist the therapy.

Promising results

Both studies found that CAR-T therapy was safe and reduced tumor size in all nine patients. In a study published in Nature Medicine, patients saw a reduction within one or two days of receiving the therapy. In a study published in the New England Journal of Medicine (NEJM), after one to five days. One patient's tumor in the study published in NEJM had almost completely regressed after five days, while another patient's tumor decreased in size by 60.7 percent. after 69 days.

But the effects of these therapies were not entirely permanent. In the study, which appeared in NEJM, tumors returned to size in two patients within a month and 72 days after the first injection. But one of the subjects showed no signs of cancer recurrence more than 150 days after treatment. This marked the end of the therapy's testing, and it is not known whether this occurred later. Some of the reductions seen in the Nature Medicine study also lasted for several months.

New CAR T-cell therapies are still in the early stages of development, and no data is yet available on the long-term survival rates of patients in which they have been tested. Nevertheless, scientists believe there are reasons for optimism.

More data is needed to assess the long-term effects of new therapies, and studies will need to be conducted in larger, more diverse groups of patients. - The results are exciting, but this is just the beginning. They tell us that we are on the right track in conducting therapy that can change the prospects of this incurable disease - emphasizes Dr. Marcela Maus, co-author of the study published in NEJM.

Source: Nature, Live Science, photo: Pexels

Extremely promising results of CAR-T therapy in the treatment of glioblastoma multiforme (2024)

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