Advances in cell and gene therapy最新文献

Adult acute lymphoblastic leukemia management has traditionally relied upon pretreatment conventional risk factors for treatment decisions. Despite using intensive multiagent chemotherapy followed by a prolonged maintenance or allogeneic stem cell transplantation, these patients remain at a high risk of relapse. Improved techniques for detection of measurable residual disease (MRD) have tremendously changed the posttreatment disease burden assessment and evolved as a powerful predictor of relapse and survival superseding historical prognostic factors. Moreover, MRD measurement has become an integral part of risk stratification, prognosis assessment, intensification or de-escalation of treatment, monitoring of disease burden, and an endpoint in clinical trials. With existing approaches like allogeneic hematopoietic stem cell transplantation and emergence of novel agents (eg, blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor [CAR] T cells) that are highly effective in eradicating residual disease, understanding the role of MRD in treatment decisions is getting more and more important and complex. This review will highlight the advances that have been achieved in MRD monitoring over the years and the practical applications in different time points of treatment to provide a framework for rational management decisions by practicing hematologists and oncologists.

Graft-vs-host Disease (GVHD) is a frequent complication following allogeneic stem cell transplantation (allo-HCT). The National Institute of Health consensus group established new guidelines for the evaluation of chronic GVHD. However, GVHD assessment remains challenging due to its complexity and requirement for laborious evaluation. We, therefore, established a standardized approach for the assessment of chronic GVHD in accordance with the NIH consensus criteria (NCC) guidelines. At a single institution, all allograft recipients were evaluated for GVHD within the first-year post allo-HCT following a three-step workflow (real-time assessment, consensus review, and documentation). A GVHD adjudication committee was created and a dynamic electronic GVHD data capture form was developed guiding the clinician through a comprehensive review of systems following the NCC guidelines. We found that the assessment and reporting of GVHD reached 100% compliance. The establishment of an institutional GVHD adjudication committee enabled standardized assessment of GVHD. Our workflow can be adopted by other centers to create a similar framework for dedicated GVHD evaluation.

The advent of tyrosine kinase inhibitors (TKIs) has ushered in a new era in the management of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Although, as a group, these inhibitors have led to one of the most successful targeted therapies in leukemia, Ph+ ALL still remains a formidable disease. Unlike chronic myeloid leukemia (CML) where TKIs lead to dramatic long-lasting responses as single agents, the biology of Ph+ ALL is far more complex and adjunctive therapies are mandatory. These may include corticosteroids, chemotherapy, antibody-based therapies or, even, allogeneic hematopoietic cell transplantation. Clearly, other genes or mutations are in place that affect the outcome of Ph+ ALL. Additional chromosomal abnormalities are common in Ph+ ALL and have a varying impact on prognosis; some adverse, others less so. Genomic alterations have come into their own in the last decade and have increased our understanding of the mechanisms of resistance and differing responses to therapy. In this review, these genetic aberrations will be considered in some detail. In addition, innovations in current practice – including the use of immunological therapies – will be carefully reviewed. For the first time in decades, the long-held imperative requiring an allogeneic transplant for a curative approach in adult Ph+ ALL is now being questioned and clinical trials are underway to resolve this issue. However, despite much progress in the past two decades, both in the biology and therapy of Ph+ ALL, this disease still presents a compelling challenge and much remains to be overcome.

Significant progress has been made toward the development of effective therapies for multiple myeloma. Current treatment strategies include combinations of several different approved medication classes, including alkylating agents, proteasome inhibitors, immunomodulatory drugs, histone deacetylase inhibitors, and monoclonal antibodies. In this review, we highlight currently active clinical trials for patients with multiple myeloma. Additionally, we describe emerging strategies in the design of future trials, which will include new combinations of available therapies, targeted therapies, immune-based therapies such as chimeric antigen receptors T-cells (CAR-Ts), and drugs with novel mechanisms of action.

A new monograph from the World Health Organization (WHO) on the classification of lymphoid neoplasms was published recently (Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 2017). As there were other volumes pending in the fourth edition of the WHO series, the monograph on lymphoid neoplasms was published as a major revision of the fourth edition instead of a new fifth edition. Although there were few major changes in terms of adding many new entities, some of the provisional entities in 2008 edition were made definitive, some terminology was changed, and there was a major expansion of genetic and molecular information. Notably, in this revision much emphasis is placed on the notion of precursor lesions diagnosed in very early stages of tumorigenesis.

Adult T-cell leukemia-lymphoma (ATL) is a peripheral T-cell lymphoma caused by human T-cell lymphotropic virus type I. Previous retrospective studies suggested the presence of graft-vs-ATL (GV-ATL) effects associated with acute graft-vs-host disease (GVHD), which suggests that intentional induction of acute GVHD to facilitate the efficacy of GV-ATL effects might reduce the risk of relapse and contribute to improved survival after allogeneic hematopoietic stem cell transplantation. However, it is impractical to conduct a prospective study to assess the benefit of intentional induction of acute GVHD. In a simulation analysis using a Markov model, we assessed the impact on overall survival (OS) of changing the probability of overall acute GVHD and severe acute GVHD. When the probability of grade III-IV acute GVHD changed from 0% to 100%, the expected 2-year OS rate changed from 57.0% to 21.8% (48.2% of baseline at 2 years). When the probability of all grades of acute GVHD changed from 0% to 100%, the expected 2-year OS rate changed from 48.2% to 49.5%. In conclusion, increasing the probability of overall acute GVHD was beneficial only when the proportion of grade III-IV acute GVHD was lower than that in the original data. Based on the simulation results, preventive management of grade III-IV acute GVHD is mandatory to achieve the clinical benefit associated with grade I-II GVHD.

The majority of patients with B-cell non-Hodgkin lymphoma (NHL) can be cured with standard chemoimmunotherapy. However, patients who fail first line therapy have dismal outcomes, particularly if they have disease that is resistant to salvage therapy, including chemoimmunotherapy, radiation and/or autologous stem cell transplantation. Indolent B-NHLs, such as follicular lymphoma (FL), although not generally considered curable may be treated over many years with good prognosis. However, a subset of indolent B-NHLs can undergo histologic transformation into more aggressive subtypes with outcomes similar to aggressive B-NHLs. In recent years, T cells, genetically modified with chimeric antigen receptors, have demonstrated a remarkable capacity to induce complete and durable clinical responses in patients with chemotherapy-refractory lymphomas. Indeed, two autologous CD19-directed CAR-modified T-cell products have now been FDA-approved for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma and transformed FL, while a plethora of other CAR-T cell targets are being explored in ongoing clinical trials. The purpose of this review is to summarize the clinical efficacy and unique toxicities of individually developed CAR-T cell products for the treatment of lymphomas, and their evolution from the laboratory bench to commercialization.