Breakthroughs continue to emerge in cancer treatment, and one promising new therapy, anti-CD19 CAR T-cell therapy, has brought new hope to patients with relapsed or refractory large B-cell lymphoma. However, why does this therapy fail in some patients? A recent study published in Nature Medicine has revealed a key factor: the tumor microenvironment.
What is the tumor microenvironment?
The tumor microenvironment (TME) is the “ecosystem” for tumor growth and development, consisting of tumor cells and their surrounding immune cells, stromal cells, and blood vessels. It not only provides support for tumors, but may also inhibit anti-tumor treatment.
Advantages of CAR T-cell therapy
The researchers compared the effects of CAR T-cell therapy with standard of care (SOC, including chemotherapy and autologous stem cell transplantation). The results showed that CAR-T cell therapy showed significant efficacy advantages in a variety of patient groups, especially when tumor gene expression characteristics were greatly different.
CAR T-cell therapy directly recognizes the CD19 protein on the surface of tumor cells without relying on complex gene expression patterns. This means that even if the tumor’s B cell gene expression signature is weak (such as low CD19 expression), CAR-T cells can still effectively locate and attack tumor cells. This feature makes CAR T-cell therapy effective for a wider range of patients.
The effectiveness of conventional therapies often decreases significantly with increasing tumor burden (volume) or lactate dehydrogenase (LDH) levels. This is because chemotherapy drugs enter the tumor through the blood circulation, but large tumors often lack sufficient blood supply, making it difficult for the drugs to penetrate deeply. At the same time, a “barrier” – such as stromal cells and myeloid immune cells – will form around the tumor, which will resist the effects of the drug and make it more difficult for treatment to be effective. Studies have found that CAR T-cell therapy does not rely on drug diffusion, but directly attacks tumor cells through customized immune cells. Regardless of whether the tumor is large or small, CAR T-cells can find the target and launch a “precise attack.” Therefore, CAR-T therapy can still provide excellent efficacy even in patients with larger tumors or metabolically active tumors.
The core advantage of CAR T-cell therapy lies in its precise recognition of CD19 protein. Even in situations where the tumor microenvironment is complex and immunosuppression is strong, CAR-T cells can still avoid obstacles and directly attack target tumor cells. This ability allows CAR-T therapy to bypass the microenvironmental barriers commonly encountered by traditional chemotherapy drugs, providing patients with higher treatment success rates and longer event-free survival.
Mechanism
The expression level of CD19 on tumor cells has a certain impact on the efficacy – the higher the expression level, the easier it is for CAR-T cells to accurately locate and kill tumors. However, even if CD19 expression is low, CAR-T therapy still shows good efficacy because it can partially overcome the treatment challenges brought about by it.
The tumor microenvironment is a “shelter” for tumor cell growth, composed of immune cells, stromal cells, and secreted factors. It may support or hinder the treatment. There are many factors in the TME that inhibit the activity of CAR-T cells, such as regulatory T cells (Tregs), myeloid suppressor cells (MDSCs), macrophages, and some inhibitory molecules (such as B7-H3, TGFβ, etc.). These factors can interfere with the attack of CAR-T cells on tumors, making the treatment effect discounted. In addition, there is often low oxygen and high lactate concentrations in the tumor microenvironment, which can cause CAR-T cell fatigue and weakened function.
The core of CAR-T therapy is the patient’s own T cells, and the treatment effect is closely related to the quality and quantity of these cells. If the patient’s T cells are in a more “young” or “primitive” state (such as CCR7+CD45RA+ phenotype), their killing power and duration will be significantly enhanced.
onversely, if the patient’s T cells are small or have been weakened by the disease, the treatment effect may be limited. As the number of treatment lines increases (from first-line to third-line treatment), the function of immune cells in the patient’s body gradually decreases. Therefore, early intervention can significantly improve the success rate of CAR-T therapy.
In general, the efficacy of CAR-T therapy is the result of the interaction between target protein expression and tumor microenvironment. For patients with low CD19 expression and dominant immunosuppressive TME, the treatment effect may be suppressed. However, the efficacy can be further improved by improving CAR-T cell products (such as increasing the proportion of “young” T cells) and combining targeted immunosuppressive factors.
