CAR-T Cells and Beyond: Breakthroughs and Challenges Ahead

Chimeric antigen receptor (CAR)-T cells and T-cell therapies have been used in the treatment of various cancers for several years. In a review published in JAMA, a research team led by Christian Hinrichs, MD, of the Rutgers Cancer Institute of New Brunswick, New Jersey, summarizes the current understanding of cellular immunotherapies in cancer treatment.

CAR-T cells are genetically modified T cells that express a synthetic receptor designed to recognize a surface protein found on tumor cells. Tumor-infiltrating lymphocytes (TILs) are natural T cells that are cultured ex vivo from resected tumor tissue. T-cell receptor (TCR)-T cells are genetically altered T cells that express a natural T-cell receptor targeting a cellular protein.

Hinrichs is one of the developers of TIL therapy and TCR treatment for human papillomavirus-associated cancers.

CAR-T-Cell Therapies

At present, six CAR-T-cell therapies have been approved by the European Commission and the US Food and Drug Administration (FDA). The CAR-T-cell products targeting CD19 are axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, and tisagenlecleucel. They are used for:

• B-cell non-Hodgkin lymphoma 
• Acute lymphoblastic B-cell leukemia 
• Chronic lymphocytic leukemia 

Tisagenlecleucel is also approved for use in children and young adults with acute lymphoblastic B-cell leukemia.

The CAR-T-cell therapies targeting B-cell maturation antigen — ciltacabtagene autoleucel and idecabtagene vicleucel — are indicated for multiple myeloma.

Challenges in treating hematologic diseases with CAR-T cells include acute and long-term side effects, limited effectiveness and duration of effect, the lack of effective salvage therapies, long wait times, and often restricted access to these therapies.

Side Effects

Anti-CD19 CAR-T cells can expand rapidly in the recipient, causing significant increases in proinflammatory cytokines such as interleukin-6 or interferon-gamma. This can trigger a cytokine release syndrome with fever, hypotension, and coagulopathies, which can be life-threatening. The syndrome can be treated with the interleukin-6 receptor blocker tocilizumab. In second-line treatment, high-dose corticosteroids can be used.

Because CAR-T cells can pass through the blood-brain barrier, they may cause reversible neurological syndromes, including encephalopathy, dysphasia, reduced attention, tremors, and in more severe cases, focal motor defects, seizures, and brain edema. These syndromes are referred to collectively as immune effector cell-associated neurotoxicity syndrome. First-line treatment is with corticosteroids. However, it is important to note that high-dose corticosteroids may impair the efficacy of CAR-T cell therapy.

Long-term side effects include prolonged myelosuppression lasting more than 28-30 days and immune suppression, which increases the patient’s susceptibility to infections. Bacterial infections are most common in the first month after CD19 CAR-T-cell infusion. Viral infections, particularly of the respiratory tract, can occur more than a year after therapy. Candida infections are most common in the first month posttreatment, while Aspergillus and other fungal infections typically occur within the first 90 days.

Secondary myeloid malignancies, such as acute myeloid leukemia and myelodysplastic syndromes, are observed in about 2%-10% of patients within 5 years of CAR-T-cell infusion. Patients may already be at risk for secondary malignancies due to the mutagenic effects of previous chemotherapy.

The role of CAR-T-cell therapy in triggering T-cell malignancies is currently under investigation. The prevailing opinion is that the benefits of the therapy outweigh the risks.

Effectiveness

Many patients, even those with potentially curable malignancies such as large B-cell lymphoma and acute lymphoblastic B-cell leukemia, do not achieve durable remission with CAR-T-cell therapy. One mechanism proposed for this is antigen escape, where the patients no longer express the target antigen, express it less strongly, or express it in a modified form.

Another mechanism is the poor quality of the autologous T-cells obtained through leukapheresis, which can lead to lower quality CAR-T cells. Previous treatments may affect the quality of the harvested T-cells.

The effectiveness of CAR-T-cell therapies in solid tumors is limited, and the underlying mechanisms of their lack of effectiveness remain unclear.

Wait Times and Costs

The wait time between leukapheresis of the patient’s cells and the infusion of CAR-T cells, known as vein-to-vein time, ranged from approximately 13-54 days for FDA-approved CAR-T cell products. In clinical trials and with approved CAR-T-cell therapies, 0%-31% of patients did not receive CAR-T-cell infusions, either due to manufacturing errors or more frequently due to disease progression with worsening clinical conditions during the wait.

CAR-T-cell therapies are costly, with prices ranging from €200,000 to €250,000, which can be a barrier to treatment.

TIL Therapy for Solid Tumors

TILs are primarily used for solid tumors. Lifileucel, which has received accelerated US FDA approval, can be used for pretreated patients with unresectable or metastatic melanoma. It has also been designated a “breakthrough therapy” for cervical cancer, which allows for accelerated approval.

TCR-T-Cell Therapy

The TCR-T-cell therapy afamitresgen autoleucel was accelerated by the US FDA in early August 2024 for the treatment of synovial cell sarcomas following prior chemotherapy. It targets the melanoma-associated antigen A4, a cancer germline antigen expressed by certain carcinomas, during embryonic development, and in germ cells, but not by healthy cells.

Other TCR-T-cell therapies are in early stages of clinical development.

This story was translated fromMedscape’s German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.