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This review addresses T-cell engineering and synthetic immunity, with a focus on producing durable remissions in patients with treatment-refractory tumors. Toxic effects of chimeric antigen receptor therapies include cytokine release syndrome and neurologic dysfunction.

In this Perspective, June, Bluestone and Warshauer discuss potential cellular and molecular explanations for the autoimmunity often associated with immunotherapy, and propose additional research and changes to reporting practices to aid efforts to understand and minimize these toxic side effects. The emergence of immuno-oncology as the first broadly successful strategy for metastatic cancer will require clinicians to integrate this new pillar of medicine with chemotherapy, radiation, and targeted small-molecule compounds. Of equal importance is gaining an understanding of the limitations and toxicities of immunotherapy. Immunotherapy was initially perceived to be a relatively less toxic approach to cancer treatment than other available therapies—and surely it is, when compared to those. However, as the use of immunotherapy becomes more common, especially as first- and second-line treatments, immunotoxicity and autoimmunity are emerging as the Achilles' heel of immunotherapy. In this Perspective, we discuss evidence that the occurrence of immunotoxicity bodes well for the patient, and describe mechanisms that might be related to the induction of autoimmunity. We then explore approaches to limit immunotoxicity, and discuss the future directions of research and reporting that are needed to diminish it.

Background The primary aim of this pilot study was to determine the feasibility and safety of an adoptive transfer and in vivo expansion of human haploidentical γδ T lymphocytes. Methods Patients with advanced haematological malignancies who are not eligible for allogeneic transplantation received peripheral blood mononuclear cells from half-matched family donors. For that, a single unstimulated leukapheresis product was incubated with both the anti-CD4 and anti-CD8 antibodies conjugated to paramagnetic particles. The depletion procedure was performed on a fully automated CliniMACS® device according to the manufacturer’s instructions. On average, patients received 2.17 × 10 6 /kg (range 0.9-3.48) γδ T cells with <1% CD4- or CD8-positive cells remaining in the product. All patients received prior lymphopenia-inducing chemotherapy (fludarabine 20-25 mg/m 2  day -6 until day -2 and cyclophosphamide 30-60 mg/kg day -6 and -5) and were treated with 4 mg zoledronate on day 0 and 1.0x10 6 IU/m 2 IL-2 on day +1 until day +6 for the induction of γδ T cell proliferation in vivo . Results This resulted in a marked in vivo expansion of donor γδ T cells and, to a lower extent, natural killer cells and double-negative αβ T cells (mean 68-fold, eight-fold, and eight-fold, respectively). Proliferation peaked by around day +8 and donor cells persisted up to 28 days. Although refractory to all prior therapies, three out of four patients achieved a complete remission, which lasted for 8 months in a patient with plasma cell leukaemia. One patient died from an infection 6 weeks after treatment. Conclusion This pilot study shows that adoptive transfer and in vivo expansion of haploidentical γδ T lymphocytes is feasible and suggests a potential role of these cells in the treatment of haematological diseases.

Background Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, have achieved good efficacy in EGFR mutation-positive non-small-cell lung cancer (NSCLC) patients, but eventual drug resistance is inevitable. Thus, new TKI-based combination therapies should be urgently explored to extend the overall survival time of these patients. CD8 + CD56+ natural killer T (NKT) cells are a natural and unique subset of lymphocytes in humans that present characteristics of T and NK cells and exert cytotoxicity on tumour cells in a granzyme B-dependent manner. The aim of this trial was to explore the efficacy and safety of CD8 + CD56+ NKT cell immunotherapy combined with gefitinib in patients with advanced EGFR-mutated NSCLC. Methods The study was designed as a prospective, randomized, controlled, open-label, phase I/II trial that includes 30 patients with EGFR mutation-positive stage III/IV NSCLC. All patients will be randomized in blocks at a 1:1 ratio and treated with gefitinib 250 mg/day monotherapy or combination therapy with allogeneic CD8 + CD56+ NKT cell infusions twice per month for 12 cycles or until disease progression occurs. The effectiveness of this treatment will be evaluated based on by progression-free survival (PFS), the time to progression (TTP), overall response rate (ORR), disease control rate (DCR) and overall survival (OS). The safety of the trail is being assessed based on adverse events (AEs). Recruitment and data collection, which started in December 2017, are ongoing. Discussion Although immunotherapy, including programmed death-1/programmed death-1 ligand (PD-1/PD-L1) immunotherapy, has been used for NSCLC treatment with or without EGFR-TKIs, its clear efficacy still has not been shown. Assessing the safety and therapeutic potential of allogeneic CD8 + CD56+ NKT killer cells in combination with EGFR-TKIs in NSCLC will be of great interest. Trial registration This trial (Phase I/II Trails of NKT Cell in Combination With Gefitinib For Non Small Cell Lung Cancer) was registered on 21 November 2017 with www.chictr.org.cn , ChiCTR-IIR-17013471 .

Purpose of reviewWe review the cardiovascular toxicities associated with cancer immune therapies and discuss the cardiac manifestations, potential mechanisms, and management strategies.Recent findingsThe recent advances in cancer immune therapy with immune checkpoint inhibitors and adoptive cell transfer have improved clinical outcomes in numerous cancers. The rising use of cancer immune therapy will lead to a higher incidence in immune-related adverse events. Recent studies have highlighted several reports of severe cases of acute cardiotoxic events with immune therapy including fulminant myocarditis. We believe that immune-mediated myocarditis is a driving mechanism behind these cardiovascular toxicities and requires vigilant screening and prompt management with corticosteroids and immune-modulating drugs, especially with combination immune therapies.SummaryWhile the incidence of serious cardiovascular toxicities with immune therapy appears low, these can be life-threatening especially when manifesting as acute immune-mediated myocarditis. Further collaborative studies are needed to effectively identify, characterize, and manage these events.

HLA-mismatched natural killer (NK) cells have shown efficacy in acute myeloid leukemia, and their adoptive transfer in patients with other malignancies has been proven safe. This phase I clinical trial was designed to evaluate safety (primary endpoint) and possible clinical efficacy (secondary endpoint) of repetitive administrations of allogeneic, in vitro activated and expanded NK cells along with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Patients with unresectable, locally advanced/metastatic NSCLC receiving 1st/2nd line chemotherapy were eligible to receive 2–4 doses of activated NK cells from two relative donors. Donor’s CD56 + cells were cultured for 20–23 days with interleukin-15 (IL-15) and hydrocortisone (HC) and administered intravenously between chemotherapy cycles. Premedication with corticosteroids and/or H1 inhibitors was allowed. Sixteen patients (performance status 0–1) with adenocarcinoma ( n  = 13) or squamous cell carcinoma ( n  = 3) at stage IIIb ( n  = 5) or IV ( n  = 11) receiving 1st ( n  = 13) or 2nd ( n  = 3) line treatment were enrolled. Fifteen patients received 2–4 doses of allogeneic activated NK cells (0.2–29 × 10 6 /kg/dose, median 4.15 × 10 6 /kg/dose). No side effects (local or systemic) were observed. At a median 22-month follow-up (range, 16.5–26 months) 2 patients with partial response and 6 patients with disease stabilization were recorded. Median progression free survival and overall survival were 5.5 and 15 months, respectively. A 56% 1-year survival and a 19% 2-year survival were recorded. In conclusion, repetitive infusions of allogeneic, in vitro activated and expanded with IL-15/HC NK cells, in combination with chemotherapy are safe and potentially clinically effective.

Liver transplantation (LT) has become the best chance and a routine practice for patients with end-stage liver disease and small hepatocellular carcinoma. However, life-long immunosuppressive regimens could lead to many post-LT complications, including cancer recurrence, infections, dysmetabolic syndrome, and renal injury. Impeccable management of immunosuppressive regimens is indispensable to ensure the best long-term prognosis for LT recipients. This is challenging for these patients, who probably have a post-LT graft survival of more than 10 or even 20 years. Approximately 20% of patients after LT could develop spontaneous operational tolerance. They could maintain normal graft function and histology without any immunosuppressive regimens. Operational tolerance after transplantation has been an attractive and ultimate goal in transplant immunology. The liver, as an immunoregulatory organ, generates an immune hyporesponsive microenvironment under physiological conditions. In this regard, LT recipients may be ideal candidates for studies focusing on operative tolerance. Cell-based strategies are one of the most promising methods for immune tolerance induction, including chimerism induced by hematopoietic stem cells and adoptive transfer of regulatory T cells, regulatory dendritic cells, regulatory macrophages, regulatory B cells, and mesenchymal stromal cells. The safety and the efficacy of many cell products have been evaluated by prospective clinical trials. In this review, we will summarize the latest perspectives on the clinical application of cell-based strategies in LT and will address a number of concerns and future directions regarding these cell products.

Posttransplant smooth muscle tumors (PTSMTs) are rare Epstein–Barr virus (EBV)-associated neoplasms, mostly occurring after solid organ transplantation. Current therapeutic strategies include surgery and reduction of immunosuppressive medication. We describe for the first time a novel treatment approach for PTSMT by adoptive cell transfer (ACT) of EBV-specific T cells to a 20-year-old patient with a medical history of cardiac transplantation, posttransplant lymphoproliferative disease, and multilocular PTSMT. During ACT, mild cytokine release syndrome occurred, while no unexpected safety signals were recorded. We observed in vivo expansion of EBV-specific T cells and reduction of EBV viremia. Best response was stable disease after 4 months with reduction of EBV viremia and normalization of lactate dehydrogenase levels. ACT with EBV-specific T cells may be a safe and efficacious therapeutic option for PTSMT that warrants further exploration.

BK virus (BKV)-hemorrhagic cystitis (HC) is a well-known and rarely fatal complication of hematopoietic stem cell transplantation (HSCT). Treatment for BKV-HC is limited, but virus-specific T-cells (VST) represent a promising therapeutic option feasible for use posttransplant. We report on the case of a 16-year-old male with dedicator of cytokinesis 8 (DOCK8) deficiency who underwent haploidentical HSCT complicated by severe BKV-HC, catastrophic renal hemorrhage, and VST-associated cytokine release syndrome (CRS). Gross hematuria refractory to multiple interventions began with initiation of posttransplant cyclophosphamide (PT/Cy). Complete left renal arterial embolization (day +43) was ultimately indicated to control intractable renal hemorrhage. Subsequent infusion of anti-BK VSTs was complicated by CRS and progressive multiorgan failure, with postmortem analysis confirming diagnosis of hepatic sinusoidal obstruction syndrome (SOS). This case illustrates opportunities for improvement in the management of severe BKV-HC posttransplant while highlighting rare and potentially life-threatening complications of BKV-HC and VST therapy.

This phase I study evaluated the feasibility of expanding HER-2/neu (HER2) vaccine-primed peripheral blood T-cells ex vivo and assessed the safety of T-cell infusions. Eight patients with HER2 + treatment refractory metastatic cancers were enrolled. T-cells could be expanded to predefined parameters in seven patients (88 %). Ninety-two percent of adverse events were grade 1 or 2. Three of seven patients developed infusion-related inflammatory reactions at their disease sites. HER2-specific T-cells significantly increased in vivo compared to pre-infusion levels ( p  = 0.010) and persisted in 4/6 patients (66 %) over 70 days after the first infusion. Partial clinical responses were observed in 43 % of patients. Levels of T-regulatory cells in peripheral blood prior to infusion ( p  < 0.001), the level of HER2-specific T-cells in vivo ( p  = 0.030), and development of diverse clonal T-cell populations ( p  < 0.001) were associated with response. The generation of HER2 vaccine-primed autologous T-cells for therapeutic infusion is feasible and well tolerated. This approach provides a foundation for the application of T-cell therapy to additional solid tumor types.