Chimeric Antigen Receptor-Engineered Human Gamma Delta T Cells: Enhanced Cytotoxicity with Retention of Cross Presentation.

Gamma delta T (γδT) lymphocytes are primed for rapid function, including cytotoxicity toward cancer cells, and are a component of the immediate stress response. Following activation, they can function as professional antigen-presenting cells. Chimeric antigen receptors (CARs) work by focusing T cell function on defined cell surface tumor antigens and provide essential costimulation for robust activation. Given the natural tropism of γδT cells for the tumor microenvironment, we hypothesized that their transduction with CARs might enhance cytotoxicity while retaining their ability to migrate to tumor and act as antigen-presenting cells to prolong the intratumoral immune response. Using a GD2-targeting CAR as a model system, we showed that γδT cells of both Vδ1 and Vδ2 subsets could be expanded and transduced to sufficient numbers for clinical studies. The CAR added to the cells' innate cytotoxicity by enhancing GD2-specific killing of GD2-expressing cancer cell lines. Migration toward tumor cells in vitro was not impaired by the presence of the CAR. Expanded CAR-transduced Vδ2 cells retained the ability to take up tumor antigens and cross presented the processed peptide to responder alpha beta T (αßT) lymphocytes. γδ CAR-T cell products show promise for evaluation in clinical studies of solid tumors.

Botulinum toxin injections after surgery for Hirschsprung disease: Systematic review and meta-analysis.

BACKGROUND: A large proportion of patients with Hirschsprung disease experience persistent obstructive symptoms after corrective surgery. Persistent obstructive symptoms may result in faecal stasis that can develop into Hirschsprung-associated enterocolitis, a potential life-threatening condition. Important treatment to improve faecal passage is internal anal sphincter relaxation using botulinum toxin injections. AIM: To give an overview of all empirical evidence on the effectiveness of botulinum toxin injections in patients with Hirschsprung disease. METHODS: A systematic review and meta-analysis was done by searching PubMed, EMBASE and the Cochrane Library, using entry terms related to: (1) Hirschsprung disease; and (2) Botulinum toxin injections. 14 studies representing 278 patients met eligibility criteria. Data that were extracted were proportion of patients with improvement of obstructive symptoms or less enterocolitis after injection, proportion of patients with adverse effects and data on type botulinum toxin, mean dose, average age at first injection and patients with associated syndromes. Random-effects meta-analysis was used to aggregate effects and random-effects meta-regression was used to test for possible confounding factors. RESULTS: Botulinum toxin injections are effective in treating obstructive symptoms in on average 66% of patients [event rate (ER) = 0.66, P = 0.004, I 2 = 49.5, n = 278 patients]. Type of botulinum toxin, average dose, average age at first injections and proportion of patients with associated syndromes were not predictive for this effect. Mean 7 duration of improvement after one botulinum toxin injections was 6.4 mo and patients needed on average 2.6 procedures. There was a significant higher response rate within one month after botulinum toxin injections compared to more than one month after Botulinum toxin injections (ER = 0.79, vs ER = 0.46, Q = 19.37, P < 0.001). Botulinum toxin injections were not effective in treating enterocolitis (ER 0.58, P = 0.65, I 2 = 71.0, n = 52 patients). There were adverse effects in on average 17% of patients (ER = 0.17, P < 0.001, I 2 = 52.1, n = 187 patients), varying from temporary incontinence to mild anal pain. CONCLUSION: Findings from this systematic review and meta-analysis indicate that botulinum toxin injections are effective in treating obstructive symptoms and that adverse effects were present, but mild and temporary.