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Recently approved by the FDA and European Medicines Agency, CAR-T cell therapy is a new treatment option for B-cell malignancies. Currently, CAR-T cells are manufactured in centralized facilities and face bottlenecks like complex scaling up, high costs, and logistic operations. These difficulties are mainly related to the use of viral vectors and the requirement to expand CAR-T cells to reach the therapeutic dose. In this paper, by using Sleeping Beauty-mediated genetic modification delivered by electroporation, we show that CAR-T cells can be generated and used without the need for ex vivo activation and expansion, consistent with a point-of-care (POC) approach. Our results show that minimally manipulated CAR-T cells are effective in vivo against RS4;11 leukemia cells engrafted in NSG mice even when inoculated after only 4 h of gene transfer. In an effort to better characterize the infused CAR-T cells, we show that 19BBz T lymphocytes infused after 24 h of electroporation (where CAR expression is already detectable) can improve the overall survival and reduce tumor burden in organs of mice engrafted with RS4;11 or Nalm-6 B cell leukemia. A side-by-side comparison of POC approach with a conventional 8-day expansion protocol using Transact beads demonstrated that both approaches have equivalent antitumor activity in vivo. Our data suggest that POC approach is a viable alternative for the generation and use of CAR-T cells, overcoming the limitations of current manufacturing protocols. Its use has the potential to expand CAR immunotherapy to a higher number of patients, especially in the context of low-income countries. [ABSTRACT FROM AUTHOR]

We consider the design of dose-finding trials for patients with malignancies when only a limited sample size is available. The small sample size may be necessary because (1) the modality of treatment is very expensive, and/or (2) the disease under investigation is rare, requiring a lengthy period to enroll a target patient population. Both of these are common in the field of adoptive immunotherapy, in which T cells are infused to prevent and treat infections and malignancies. The clinical trial described in this paper investigates a novel therapy to adoptively transfer genetically modified T cells in small pilot protocols enrolling patients with B-lineage malignancies. Due to the constraints of cost and infrastructure, the maximum sample size for this trial is fixed at 12 patients distributed among four doses of T cells. Given these limitations, an innovative statistical design has been developed to efficiently evaluate the safety, feasibility, persistence, and toxicity profiles of the trial doses. The proposed statistical design is specifically tailored for trials with small sample sizes in that it uses the toxicity outcomes from patients treated at different doses to make dose-finding decisions. Supplementary materials including an R function and a movie demo can be downloaded in the websites mentioned in the paper. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many hematologic malignancies and inherited disorders of the hematopoietic system. Ex vivo T-cell depletion (TCD) of the graft and post-transplantation immunosuppression efficiently prevents the development of GvHD in no- MHC-identical settings. However, the consequence of these non-specific strategies is a long-lasting immunodeficiency associated with increased incidence of disease relapse, graft rejection and reactivation of viral infections. Donor lymphocyte infusion, which is used for treating leukemic relapse after allogeneic HSCT, can result in severe GvHD. Several strategies are being optimized specifically to inactivate anti-host T cells while preserving anti-leukemic or anti-microbial immunocompetence. Based on the ex vivo or in vivo elimination of anti-host T cells, or on the modulation of their anti-host activity, these approaches, which have been explored extensively in pre-clinical studies and tested in some preliminary clinical trials, are discussed in this paper. [ABSTRACT FROM AUTHOR]

IL-15 is a pleiotropic cytokine that plays an important role in both the innate and adaptive immune system. IL-15 promotes the activation of neutrophils and macrophages, and is critical to DC function. In addition, IL-15 is essential to the development, homeostasis, function and survival of natural killer (NK) cells, NK T (NKT) cells and CD8 + T cells. Based on these properties, IL-15 has been proposed as a useful cytokine for immunotherapy. It is currently being investigated in settings of immune deficiency, for the in vitro expansion of T and NK cells, as well as an adjuvant for vaccines. In this paper, we will review the targeting of IL-15 for immunotherapy, with a particular emphasis on its effects on CD8 + T cells. [ABSTRACT FROM AUTHOR]

Background Priming with autologous tumor vaccine followed by ex vivo expansion of activated T cells is a feasible experimental strategy. This paper describes the application of this cellular therapy to treat patients with late-stage non-small-cell lung cancr (NSCLC). Methods Twenty-one patients with Stages III and IV NSCLC were treated. Tumor samples were obtained surgically (five patients) or by using a co-axial biopsy needle (16 patients). Each course of vaccination consisted of irradiated tumor cells, mixed with GM-CSF and injected intradermally on Day 1, followed by GM-CSF only on Days 2–5. The course was repeated 10–14 days later. Lymphocytes were collected 10–14 days after the second course and ex vivo expanded using IL-2 and anti-CD3 Ab. The expansion products were then re-infused into the patients. Results Twelve out of 16 biopsies resulted in optimal cell numbers for vaccine preparation. Nineteen out of 21 patients achieved a delayed type hypersensitivity (DTH) response after two courses of vaccination. In 18/21 patients, the ex vivo expansion products contained >1.6×10 10 cells. Subset analysis showed 77.0–97.2% T cells with a CD4:CD8 ratio of 0.65–4.0; natural killer cells were 2.0–18.6%. There were no significant toxicities. The median survival of all 21 patients was 18.6 months, with a 1-year survival of 51.6%. Conclusion Autologous tumor cell-vaccination may be combined with ex vivo expansion of lymphocytes as adoptive cellular immunotherapy for advanced NSCLC. Overall survival in this cohort of poor prognosis patients compared favorably with results reported in the literature. [ABSTRACT FROM AUTHOR]

Allergic hypersensitivity of type I for hymenoptera venoms is the most frequent reason for acute IgE-mediated anaphylactic reactions. The subcutaneous injection of increasing doses of purified allergen followed by long-term administration of an adequate maintenance dose over a period of 3-5 years called venom immunotherapy (VIT) has been proven to be a very effective treatment achieving protection in about 96% of allergic patients. Even though the principle of hyposensitisation has been introduced already 90 years ago, the underlying immunoregulatory mechanisms of VIT remain poorly understood. Recent studies suggest a shift in cytokine production from a Th2 to a Th1 cytokine profile during therapy. In this paper, a mathematical model for T-cell regulation and a model for mast cell/basophil desensitisation are presented and analysed to explain the mechanism of conventional rush and ultra-rush VIT. [ABSTRACT FROM AUTHOR]