CAR T-Cell Therapy Advances Target Solid Tumors and Selective Cancer Killing

Researchers at LMU University Hospital have genetically engineered therapeutic CAR T cells that are no longer able to produce receptors for prostaglandin E2, allowing the cells to destroy solid tumor sites. The modified cells can no longer be blocked by the metabolite prostaglandin E2, which suppresses T cell function in the tumor microenvironment by binding to special receptors on the surface of T cells. The study is published in the journal Nature Biomedical Engineering.

In 2024, the research group had already shown that the metabolite prostaglandin E2 can block T cells—the killer cells of the immune system—in the vicinity of a tumor, such that they do not attack cancer cells. This is one of the reasons why therapeutic CAR T cells have lacked success against solid tumors such as bowel or pancreatic cancer.

The immunopharmacology team at the Institute of Clinical Pharmacology, working in close cooperation with the University of Tübingen, demonstrated the effectiveness of the modified CAR T cells in models of breast or pancreatic cancer, where the CAR T cells kept the tumors in check. Moreover, these CAR T cells proved to be highly effective in tumor samples from human patients with pancreatic or bowel cancer or neuroendocrine tumors.

Soon it will be possible to test the approach in clinical studies. Initially, this will not involve people with solid tumors, but with lymphomas. Barely half of lymphoma patients have been able to benefit from CAR T therapy to date. According to the findings, there is a good chance that therapy with silenced PGE2 will be considerably more successful. Should this prove to be the case, a study on patients with solid tumors could follow if suitable funding is found.

In a separate development, a research team led by the University of Pennsylvania has developed a CAR-T cell, CART4-34, that selectively attacks a specific surface protein common in cancer cells but rare in normal cells. The therapy was reported in the international journal Science Translational Medicine.

The current CD19 CAR-T therapy, approved by the U.S. Food and Drug Administration (FDA), works by targeting a molecule called CD19 on the surface of B cells to destroy them. The problem is that CD19 is present not only on cancer cells but also on normal B cells. B cells are immune cells that naturally produce antibodies to fight infections. With CD19 CAR-T therapy, normal B cells are also eliminated, leaving the patient in a long-term state of immunosuppression. Furthermore, in cases of relapse, antigen-negative escape, where cancer cells lose CD19 expression and become invisible to the CAR-T cells, is reported in a significant number of cases.

The research team focused on finding a target that is abundant on cancer cells but rare on normal cells. The IGHV4-34 gene is present in only about 5% of normal B cells. It is found at a much higher frequency in lymphomas and leukemias, which arise from B cells turning cancerous.

The team's analysis of 74,930 cases of such blood cancers revealed that this gene was present in 63.6% of patients with primary vitreoretinal lymphoma (PVRL), 34.7% with primary central nervous system lymphoma (PCNSL), and 30.2% with a subtype of diffuse large B-cell lymphoma (ABC-DLBCL).

The initial version selectively destroyed cancer cells in in-vitro experiments at the cellular level. However, when tested in mice transplanted with cancer cells, its effectiveness was lower than that of existing CD19 CAR-T therapy. The cause was a structural issue. The target B-cell receptor (BCR) was found to protrude further from the cell membrane than CD19, making it difficult for the CAR-T cells to get close to the cancer cells. The team significantly shortened the linker region of the CAR that extends outside the cell, allowing the CAR-T cells to bind more closely to the cancer cells.

The improved CART4-34 demonstrated tumor suppression effects and survival rate improvements equivalent to a conventional CD19 CAR-T in mice transplanted with diffuse large B-cell lymphoma. Genetic analysis after co-culturing with B cells from healthy donors showed that CART4-34 only reduced cells carrying IGHV4-34, leaving the other normal B cells unaffected. In effect, it selectively eliminated cancer cells while preserving immune function.

The therapy also showed potential for application in lupus, an autoimmune disease. In a significant number of lupus patients, IGHV4-34 antibodies are found at high levels and are associated with disease severity. Experiments with cells from lupus patients showed that CART4-34 eliminated only the problematic cells carrying IGHV4-34 and their autoantibodies, while preserving normal B cells.

The team is planning the first clinical trial for patients with blood cancers or severe lupus who carry IGHV4-34.

Using CAR T cells to direct the immune system of a cancer patient against tumor cells, and thus combat the life-threatening disease, often works very well in patients with certain leukemias (blood cancer) and lymphomas (lymph node cancer). CAR-T stands for chimeric antigen receptor modified T cell. Cancer cells employ various molecular tricks to elude the normal lines of attack of these immune system cells. As a result, the immune cells do not recognize their enemies, the cancer cells, anymore. In modern therapies, T cells can be taken from patients and genetically engineered to produce a certain protein (CD19) on their surface. When these modified CAR T cells are reintroduced into the body, CD19 ensures that the CAR T cells recognize the cancer cells and bind to them with precision. This causes the cancer cells to die.

Unfortunately, solid tumors like bowel, pancreatic, prostate, and lung cancer have developed mechanisms for rendering CAR T cells ineffective. Solid tumors have long posed a challenge for CAR-T developers due to antigen heterogeneity, limited T-cell infiltration, and suppressive tumor microenvironments.

Despite the effectiveness of CAR T-cell therapy, a significant delivery gap exists. Only 25% to 30% of eligible patients actually receive the CAR T therapy they need. Simply optimizing patient access to existing treatments could triple the cure rate for large cell lymphoma.

In a small pilot study that began in the summer of 2010, some leukaemia patients who had exhausted other treatment options have no trace of the disease more than four years after being given an experimental type of therapy called CAR T cells. The 14-patient study enrolled patients who had failed to benefit from standard treatments for chronic lymphocytic leukaemia (CLL), a cancer of white blood cells that most commonly affects adults. The first patient to receive the therapy is cancer-free after five years and another of the first three enrolled patients also remains in remission. All signs of cancer disappeared in four patients, or 29 per cent, but one of them died almost two years after therapy due to an unrelated infection. Another four patients achieved some reduction in tumours, with responses lasting an average of about seven months. Six patients, or 43 per cent, failed to respond to therapy, and their leukaemia progressed within one to nine months.