CAR-T Alternative
CAR-T-cell therapy methods have been approved for the treatment of blood cancers, and T-therapy for other tumors is in the process of development. This treatment is based on reprogramming the patient's own lymphocytes to express the chimeric antigen receptor (CAR), which targets tumor cells. The process of reprogramming a patient's own T cells is expensive and time-consuming.
High affinity natural killer cells (haNK) are potential "ready-made" cellular therapies that do not require reprogramming of the patient's own immune cells. They can be mass-produced and potentially used in any cancer patient. But the presence of immunosuppressive myeloid cells in the tumor microenvironment remains an obstacle to effective immunotherapy with haNK.
To overcome this barrier, researchers from the National Institute of Deafness and Other Communication Disorders (NIDCD) and the National Cancer Institute have created haNK cells expressing CAR, which targets the ligand of programmed death (programmed death ligand 1, PD-L1). PD-L1 is known to be the cause of cancer resistance to immunotherapy; myeloid cells produce it in large quantities to weaken the immune system.
The Clint Allen-led group tested haNK with anti-PD-L1 CAR on mouse models of head and neck cancer, as well as on cell lines and compared them with conventional haNK. They found that hanks with anti-PD-L1 CAR kill mouse and human tumor cells more effectively than hanks without CAR, and that this ability persists even if they have previously been in contact with PD-L1-carrying cells. This is important because natural killer cells usually "deplete" after killing target cells.
haNK-based therapy with anti-PD-L1 CAR cured mice in 30% of cases and slowed down tumor growth in the remaining cases without causing toxicity. The treatment also reduced the number of immunosuppressive myeloid cells that produce PD-L1 in the tumor, but did not affect immunostimulating leukocytes.
To find out if this effect was observed on human immune cells, the group incubated leukocytes taken from patients with head and neck cancer with haNK cells carrying anti-PD-L1 CAR. Just like in mouse models, the number of immunosuppressive myeloid cells that carry PD-L1 was significantly reduced after treatment with haNK cells with anti-PD-L1 CAR. This suggests that such treatment can directly kill tumor cells and remove immunosuppressive myeloid cells that interfere with conventional immunotherapy.
Natural killers producing anti-PD-L1 CAR have overcome some limitations of the immunotherapy used today, which is based on the activation of T-cells, and can potentially be used in patients who have not been helped by classical immunotherapy.
The authors intend to obtain permission to conduct clinical trials to assess the safety of haNK with anti-PD-L1 CAR in patients with advanced or recurrent cancer and to check whether the combination of haNK cell therapy with other immunotherapy methods can improve the effectiveness of treatment.
Article by Y.Robbins et al. Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells is published in the journal eLife.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of eLife Sciences: Engineered killer immune cells target tumours and their immunosuppressive allies.