What Are the Pros and Cons of Adoptive Cell Therapy?

Adoptive Cell Therapy (ACT) is a cutting-edge immunotherapy that uses modified immune cells to target and destroy cancer cells. ACT has demonstrated remarkable success in hematological malignancies and is showing progress in solid tumor treatment. Below is an overview of recent breakthroughs, key advantages, and challenges for clinical application.

Applications of Adoptive Cell Therapy

Adoptive cell therapy has been extensively applied in the treatment of various types of cancers, especially hematological malignancies. The following examples illustrate recent progress in ACT treatment methods for different cancer types.

1. Hematological malignancies

Acute Lymphoblastic Leukemia (ALL)

In recent years, CAR-T cell therapy has achieved remarkable breakthroughs in the treatment of ALL. For example, Kymriah (tisagenlecleucel) was the first CAR-T cell therapy approved by the FDA for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia. In clinical trials, Kymriah achieved a complete remission rate of up to 83%, providing new hope for the treatment of ALL.

Non-Hodgkin Lymphoma (NHL)

CAR-T cell therapy has also been used to treat non-Hodgkin lymphoma (NHL) with good efficacy. Yescarta (axicabtagene ciloleucel) is another CAR-T cell therapy approved by the FDA for the treatment of relapsed or refractory large B-cell lymphoma. In clinical trials, Yescarta achieved an objective response rate of 72% and a complete remission rate of 51%, significantly prolonging the survival of NHL patients.

Multiple Myeloma

In 2021, BCMA-targeted CAR-T therapy Abecma was approved by the FDA, and the overall survival of patients was prolonged to 24.8 months.

2. Solid tumors

Although ACT has achieved significant success in hematological malignancies, its application in solid tumors still faces many challenges. However, there has been some progress in recent years:

Melanoma

Tumor-infiltrating lymphocyte (TIL) therapy has shown promise in the treatment of melanoma. TILs are immune cells that have already entered the tumor tissue and have natural anti-tumor effects. By extracting TILs from the patient's tumor tissue, expanding them ex vivo, and then reinfusing them into the patient, TIL therapy has achieved impressive results in some melanoma patients. In 2024, the FDA approved the first TIL therapy, Lifileucel, for treating advanced melanoma resistant to PD-1 antibodies, achieving an objective response rate of 31.4%.

Lung Cancer

The tumor microenvironment of lung cancer is complex, and it has been difficult to achieve ideal results. However, some studies have shown encouraging initial results. For example, CAR-T cell therapy targeting lung cancer-related antigens achieved tumor shrinkage or stabilization in some patients during clinical trials.

Advantages of Adoptive Cell Therapy

Precision targeting of cancer cells

ACT's key advantage is its precise targeting of cancer cells. Traditional chemotherapy and radiotherapy are not selective and can also kill normal cells, while ACT first identifies the patient's cancer cells and then designs corresponding methods to selectively kill them. For example, in CAR-T cell therapy, the chimeric antigen receptor (CAR) can be designed to precisely recognize the antigen on the surface of the target cancer cells, such as CD19 in acute lymphoblastic leukemia (ALL) or BCMA in multiple myeloma. This high degree of precision can reduce treatment side effects, thereby improving the quality of life of patients.

Activation of the patient's immune system

In addition to directly killing cancer cells, ACT can also activate other immune cells in the patient's body, thereby forming a comprehensive anti-tumor effect. For example, when CAR-T cells recognize and kill cancer cells, they can release cytokines that can further activate other immune cells, such as natural killer (NK) cells and macrophages. Additionally, ACT can induce the formation of memory immune cells that persist in the patient's body for an extended period, preventing tumor relapse.

Personalized treatment plans

ACT is a highly personalized therapy. In addition to directly killing cancer cells, ACT can also activate other immune cells in the patient's body, thereby forming a comprehensive anti-tumor effect. For example, when CAR-T cells recognize and kill cancer cells, they can release cytokines that can further activate other immune cells, such as natural killer (NK) cells and macrophages.

Long-term efficacy

ACT has shown long-term efficacy in some cancers. For example, CAR-T cell therapy for the treatment of acute lymphoblastic leukemia (ALL) has enabled some patients to achieve complete remission and long-term disease-free survival after treatment.

Combination therapies to overcome limitations

ACT can be combined with chemotherapy, radiation, immune checkpoint inhibitors, and other treatments to achieve a synergistic effect. For example, CAR-T cells can be combined with PD-1 inhibitors to alleviate immune suppression in the tumor microenvironment, thus enhancing CAR-T cell function. In addition, combining tumor-infiltrating lymphocytes (TILs) with oncolytic viruses can destroy the tumor vasculature, thus improving the infiltration of TILs into solid tumors.

Challenges in Adoptive Cell Therapy

1. Technical challenges

Complexity of Cell Collection and Preparation: ACT involves collecting immune cells from patients, modifying and expanding them ex vivo, and then reinfusing them. This complex process requires high technical expertise and can involve multiple procedures, causing discomfort and anxiety for patients. Additionally, failures during manufacturing can lead to insufficient therapeutic cells.

Challenges in Treating Solid Tumors: ACT struggles to treat solid tumors due to the immunosuppressive tumor microenvironment and the high heterogeneity of antigens, which complicate the ability of CAR-T cells to effectively target all cancer cells.

2. Safety concerns

Cytokine Release Syndrome (CRS): CRS is a severe side effect of ACT, causing symptoms like high fever and low blood pressure that can be life-threatening. It arises from the excessive activation of immune cells releasing cytokines.

Neurotoxicity: This side effect includes headaches, confusion, and seizures, potentially related to cytokine release and immune cell infiltration into the central nervous system.

Off-Target Toxicity: Off-target toxicity occurs when CAR-T cells mistakenly attack normal tissues, leading to severe reactions due to non-specific binding or target antigen expression in healthy tissues.

3. Clinical application challenges

Patient Variability: Differences in tumor characteristics, immune status, and health among patients can lead to varied treatment responses, with some responding well while others may not or experience relapses.

Treatment Window: The lengthy manufacturing process may cause delays that result in patients missing optimal treatment opportunities. Their conditions could worsen while waiting for cell production.

Long-Term Efficacy and Monitoring: Although some patients achieve long-term remission, the sustained efficacy and safety of ACT need further research, and ongoing monitoring for side effects and immune status remains complex.

4. Economic and accessibility issues

High Treatment Costs: The costs associated with developing and preparing ACT are very high, often reaching hundreds of thousands of dollars, which limits its accessibility.

Resource Allocation and Accessibility: The complexity and cost of ACT restrict access to this therapy globally, as many regions lack the necessary resources and technical expertise.

5. Regulatory and ethical concerns

Regulatory Complexity: ACT, as a live cell therapy, is subject to stringent regulatory requirements that increase costs and complexity across all phases of treatment.

Ethical Issues: The use of advanced technologies such as gene editing raises ethical concerns, including long-term safety, hereditary risks, and the need for informed patient consent.

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Reference

1. Dogra A, Yadav RK, et al. Emerging frontiers in adoptive cell therapies: innovations, challenges, and future perspectives. Med Oncol. 2025. 42(7):261.