Allogeneic Vγ9Vδ2 T-Cell Therapy Promotes Pulmonary Lesion Repair: An Open-Label, Single-Arm Pilot Study in Patients With Multidrug-Resistant Tuberculosis

Abstract

The WHO’s “Global tuberculosis report 2020” lists tuberculosis (TB) as one of the leading causes of death globally. Existing anti-TB therapy strategies are far from adequate to meet the End TB Strategy goals set for 2035. Therefore, novel anti-TB therapy protocols are urgently needed. Here, we proposed an allogeneic Vγ9Vδ2 T-cell-based immunotherapy strategy and clinically evaluated its safety and efficacy in patients with multidrug-resistant TB (MDR-TB). Eight patients with MDR-TB were recruited in this open-label, single-arm pilot clinical study. Seven of these patients received allogeneic Vγ9Vδ2 T-cell therapy adjunct with anti-TB drugs in all therapy courses. Cells (1 × 108) were infused per treatment every 2 weeks, with 12 courses of cell therapy conducted for each patient, who were then followed up for 6 months to evaluate the safety and efficacy of cell therapy. The eighth patient initially received four courses of cell infusions, followed by eight courses of cell therapy plus anti-MDR-TB drugs. Clinical examinations, including clinical response, routine blood tests and biochemical indicators, chest CT imaging, immune cell surface markers, body weight, and sputum Mycobacterium tuberculosis testing, were conducted. Our study revealed that allogeneic Vγ9Vδ2 T cells are clinically safe for TB therapy. These cells exhibited clinical efficacy in multiple aspects, including promoting the repair of pulmonary lesions, partially improving host immunity, and alleviating M. tuberculosis load in vivo, regardless of their application in the presence or absence of anti-TB drugs. This pilot study opens a new avenue for anti-TB treatment and exhibits allogeneic Vγ9Vδ2 T cells as promising candidates for developing a novel cell drug for TB immunotherapy.Clinical Trial Registration(https://clinicaltrials.gov/ct2/results?cond=&term=NCT03575299&cntry=&state=&city=&dist=) ( NCT03575299).

The Changes in the Quantity of Lymphocyte Subpopulations during the Process of Sepsis

“…Treating this impairment is theoretically feasible, but progress has been slow [33]. It is only recently that some achievements in immunotherapy based on γ-δT cells have emerged [34][35][36]. Prior to this, Yuan, Fawei, and colleagues [37] proposed a different viewpoint, suggesting that γ-δ1T cells play an immune suppressive role in sepsis.…”

γδ T cells: origin and fate, subsets, diseases and immunotherapy

“…Studies from our group demonstrated the safety and efficacy of allogeneic Vδ2 T cells derived from healthy donors in the treatment of late-stage lung and liver cancer patients, 11,12 pointing towards the potential of off-the-shelf Vδ2 T cell products in cancer immunotherapy. Furthermore, the successful application of γδ T cells in treating MDR-TB 13 and their functional attenuation in COVID-19 patients [87][88][89] expanded our understanding of their therapeutic potential in combating challenging infectious diseases. Strikingly, the regulatory role of γδ T cells in the social behavior of mice 90 and the achievement of 100% complete remission in leukemia patients (NCT03533816) who received γδ T cell therapy have heightened our anticipation regarding the physiological functions of γδ T cells.…”

“…[5][6][7][8][9][10] Since 2016, we have been at the forefront of translating the application of allogeneic γδ T cells, specifically the Vγ9Vδ2 + γδ T subset, from the laboratory to clinical practice, with the aim of renormalizing the dysfunctional immune system in patients with advanced solid tumor 11,12 or multidrug-resistant tuberculosis (MDR-TB). 13 In a comprehensive study involving 132 patients diagnosed with various types of cancer (including liver, lung, pancreatic, breast, and others), we administered a total of 414 cell infusions. Through this investigation, we not only established the safety of transferring allogeneic Vγ9Vδ2 + γδ T cells (abbreviated as Vδ2 T cells below) generated from healthy donors' PBMCs after in vitro expansion but also demonstrated their clinical efficacy in extending patient survival and improving quality of life.…”

Chimeric antigen receptor–based therapies beyond cancer

“…The most feasible candidate are chronic infections, such as tuberculosis (Tbc). Feasible strategies in this regard would include engineered T cells displaying TCRαβ recognizing Tbc-specific pMHC-I or -II complexes expressed by infected cells, as well as unmodified Tγδ cells targeting nonpeptidic Tbc antigens [39,40].…”