A close look at current γδ T-cell immunotherapy

Abstract

Owing to their antitumor and major histocompatibility complex (MHC)-independent capacities, γδ T cells have gained popularity in adoptive T-cell immunotherapy in recent years. However, many unknowns still exist regarding γδ T cells, and few clinical data have been collected. Therefore, this review aims to describe all the main features of the applications of γδ T cells and provide a systematic view of current γδ T-cell immunotherapy. Specifically, this review will focus on how γδ T cells performed in treating cancers in clinics, on the γδ T-cell clinical trials that have been conducted to date, and the role of γδ T cells in the pharmaceutical industry.

Keywords: adoptive cell transfer (ACT); cancer immunotherapy; clinical trial; immunotherapy; γδ T cells.

Figure 1

Overview of cohorts from completed γδ T-cell immunotherapy trials. (A) Timeline of completed γδ T-cell immunotherapy trials in clinics by cohort; colors indicate treatment type (n = 37). (B) Detailed treatment methods applied in the cohorts treated with adoptive cell transfer (ACT) combined with other treatments except for IL-2 treatment (ACT+) (n = 13). Chemo: conventional therapies, mostly chemotherapy. In vivo: in vivo stimulation of Vγ9Vδ2 T cells using zoledronate. IRE: irreversible electroporation. ACTeg: engineered T cells. LD chemo: lymphodepletion chemotherapy. (C) Tumor types (pie chart) and detailed diseases (bar chart) of γδ T-cell immunotherapy cohorts (n = 37); colors indicate treated tumor types. (D) Average, maximum, and minimum γδ T-cell total infusion doses of cohorts with dosage information (ACT, n = 12, ACT+, n = 4). The lower and upper hinges of the boxplot show the 25th and 75th percentile, respectively. The medians are indicated inside the box, and p-values (Wilcoxon rank-sum test) are also indicated.

Figure 2

Forest plot of objective response (OR) rate (n = 27). The OR indicates the number of patients in each cohort who achieved an objective response. The total indicates the total number of measurable patients in each cohort. The OR rate, 95% confidence interval (CI), and weights of fixed- and random-effects models are indicated for each cohort. Blue squares show the mean OR rate of each cohort, and the size indicates the weight of the cohort; gray lines show the 95% CI, and the diamond shapes show the pooled weighted means of the OR rate using fixed- and random-effects models.

Figure 3

Overview of patients treated with γδ T-cell immunotherapy (n = 307). (A) Proportions of treatment outcomes in total measurable patients and different treatment types [in vivo stimulation, n = 164; adoptive cell transfer (ACT), n = 88; ACT combined with other treatments except for IL-2 treatment (ACT+), n = 55]. Pie charts show the proportions of complete response (CR) and partial response (PR) within objective response (OR) patients for each treatment method (in vivo stimulation, n = 32; ACT, n = 2; ACT+, n = 20). (B) Proportions of treatment outcomes in different types of tumors (solid, n = 258; hematological, n = 49). Pie charts show the proportions of CR and PR within OR patients for each tumor type (solid, n = 36; hematological, n = 18). (C) Proportions of treatment types applied in different types of tumors (solid, n = 258; hematological, n = 49). p-values (Pearson’s chi-squared test) are indicated in (A–C). PD, progressive disease; SD, stable disease; OR, objective response; CR, complete response; PR, partial response.

Figure 4

Overview of cancer types of patients treated with γδ T-cell immunotherapy (n = 138). (A) Diseases (left) and chosen treatment strategies (right) of hematological cancer patients (n = 49). Pie charts show the proportions of patients who achieved a complete response (CR) or a partial response (PR) after treatment (CR, n = 9; PR, n = 9). (B) Diseases (upper) and chosen treatment strategies (lower) of female (left) and male (right) solid tumor patients (female, n = 38; male, n = 51). Pie charts show the proportions of patients who achieved a CR or PR after treatment (female CR, n = 1; female PR, n = 2; male CR, n = 2). MM, multiple myeloma; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; FCL, follicle center lymphoma; MZL, mantle zone lymphoma; IC, immunocytoma; SPL, secondary plasma cell leukemia; T-NHL, T-cell non-Hodgkin lymphoma; RCC, renal cell carcinoma.

Figure 5

Relationships between γδ T cell reinfusion doses and treatment outcome, strategy, tumor type, age, and sex (n = 46). (A) Relationship between treatment outcome and dosage. γδ T-cell total infusion cell numbers (10 (9) cells) were divided into five groups and are presented on the x-axis; the y-axis indicates total infusion times. The bubble color indicates the treatment outcome, and the bubble size indicates the number of patients. (B) Relationship between treatment strategy and dosage. (C) Relationship between tumor type and dosage. (D) Relationship between age and dosage. (E) Relationship between sex and dosage.

Figure 6

Overview of currently registered γδ T-cell immunotherapy clinical trials (n = 48). (A) Proportions of currently registered γδ T-cell immunotherapy clinical trials according to status, phase, and location. (B) Timeline of registered clinical trials by treatment strategy. The pie chart shows the proportion of trials for each strategy. (C) Timeline of registered clinical trials by infusion cell origin. (D) Timeline of registered clinical trials by tumor type (left) and detailed malignancies involved in registered trials (right). The pie chart indicates the proportions of different tumor types across all registered trials. (E) Planned infusion dosage of registered trials. Left: treatment strategies are indicated on the x-axis, and planned γδ T-cell infusion cell numbers are indicated on the y-axis. The round yellow dot shows the planned maximum infusion dose, and the gray triangle dot shows the planned minimum infusion dose. The bar connects the maximum and minimum number for each trial. Right: the proportions of different planned minimum (upper) and maximum (lower) infusion doses. (F) Upper age limit of registered γδ T-cell immunotherapy clinical trials. Left: proportions of different upper age limits. Right: the relationship between upper age limits, treatment strategy usages, and tumor types. The bubble color shows the tumor type of the trial, and the bubble size indicates the number of trials. (C–F) Not applicable: strategies not involving cell infusion; not defined: infusion cell origin not defined.