Advances in cell and gene therapy最新文献

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.

Chronic Graft Versus Host Disease (cGVHD) occurs in over 50-70% of patients undergoing hematopoietic stem-cell transplantation (HSCT) and is the leading cause of late non-relapse mortality. cGVHD typically has insidious multi-organ involvement and has been associated with a worse quality of life, functional status, and increased risk of subsequent comorbidities. The last several years have seen advances in the understanding of the disease, which provided a framework for the design of translational and clinical studies with newer agents currently at different phases which that may hopefully change the course of the disease. This review provides an overview of more commonly used and newer second line options for the management of cGVHD.

Cytomegalovirus (CMV) remains a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Despite this knowledge, a number of CMV-related diagnostic and therapeutic issues remain critical. No uniform guidance exists for the best strategy to monitor and prevent CMV infection and disease. In particular, we lack standard threshold values for assessing the CMV DNAemia in the monitoring of CMV infection; there is no consensus in the adoption of immunoglobulin therapy and adoptive transfer of HSCT donor-derived CMV-specific T cells. Furthermore, antiviral drugs used in the preemptive therapy are characterized by high levels of toxicity. Of interest, recent availability of new drugs will probably modify the antiviral strategy in a large proportion of patients. The uncertainty in the management of CMV infections is further complicated by the continuous evolution in the transplantation strategies and the consequent infectious risk. This paper will focus on challenging issues in the monitoring, prevention, and treatment of CMV infections in allo-HSCT populations. Assessment of pretransplant CMV status, immunological monitoring after transplant, and CMV disease prevention and therapy strategies will be discussed.

Chronic lymphocytic leukemia (CLL) has experienced a revolution over the past few decades with a marked expansion in therapeutic options and improvement in outcomes. This success can be attributed to an improved understanding of the molecular and genetic underpinnings of disease pathogenesis and the emergence of a variety of effective, well-tolerated, targeted therapies. The field is now continuing to evolve with an improved understanding of prognostic and predictive biomarkers of response, exploration of novel combination strategies with the goal of inducing deeper and more durable remissions, and the development of next-generation and immune-based agents. Here, we review the recent advances in CLL therapy as well as the novel therapeutic innovations that are likely to contribute to the rapidly evolving treatment paradigms in this disease.

Targeted immunotherapeutic approaches have become an attractive, novel therapy in the treatment of chemotherapy resistant or relapsed high-risk acute lymphoblastic leukemia (ALL). Many of these therapies, chimeric antigen receptor (CAR) T cells, and bispecific T-cell engagers (BiTE) in particular, rely on surface expression of the antigen for activity and efficacy. As such, antigen loss is a growing problem in this relapsed population. We present a case of relapsed, refractory B-ALL that has immunophenotypic variability in the leukemia blasts in response to the sequential targeted immunotherapies received. This case additionally describes a bolstered CAR-T cell expansion after the patient received subsequent blinatumomab therapy, suggesting a potential strategy for utilization of multiagent immunotherapies to have synergistic approaches to eradicate disease and prolong remission in patients with relapsed hematologic malignancies (Anti-CD22 chimeric receptor T cells in pediatric and young adult patients with recurrent or relapsed CD22-expressing B-cell malignancies. clinicaltrials.gov NCT02315612).

In the latest World Health Organization classification of myeloid neoplasms, chronic myelomonocytic leukemia (CMML) exists as a separate entity under the category of myelodysplastic/myeloproliferative (MDS/MPN) overlap syndromes. Outcomes remain uniformly poor with a median overall survival of ~2 years and an inherent risk of transformation into acute myeloid leukemia (15%-20% over 5 years). Due to unique biologic characteristics such as overlapping features of myelodysplasia and myeloproliferation, and clinical diversity despite relative genomic homogeneity, CMML represents a unique model to study chronic myeloid tumor biology. Recent advances have focused on understanding the role of putative genomic abnormalities, in particular, clonal evolution of pathogenic alterations in genes regulating the epigenome (TET2), chromatin architecture (ASXL1), spliceosome complex (SRSF2, SF3B1), and cell signaling (NRAS, KRAS, CBL, JAK2). Disease prognostication has evolved from purely clinical prognostic models to those incorporating pathogenic gene variants. Therapeutic options in this disease remain dismal with only two agents approved by the United States Food and Drug Administration, namely 5-azacitidine and decitabine. Allogeneic hematopoietic stem cell transplantation remains the sole curative option in this disease; however, is associated with substantial treatment-related morbidity and mortality. Future areas of research include opportunities to further improve disease prognostication by employing novel technologies such as machine learning, incorporation of methylation and cytokine signatures, in addition to gene mutations; insights into clonal origins of this disease, and novel therapeutic strategies.

Multiple myeloma (MM) is a malignant disease of plasma cells that is also characterized by immune dysregulation. There are several factors that contribute to an immunosuppressive milieu that allows tumor progression, including alterations in natural killer (NK) cells such as a decreased expression of activating receptors. NK cells play an important role in immunosurveillance against cancer. The mainstays of myeloma therapy, such as proteasome inhibitors and immunomodulatory drugs, up-regulate the expression of activating receptors (NKG2D, DNAM-1) on NK cells thereby augmenting their activity against malignant plasma cells. Cellular therapy incorporating NK cells in both the transplant and nontransplant setting offers exciting opportunities for the future. Chimeric antigen receptor (CAR)-transduced-NK cells and bispecific antibodies utilizing NK cells have already been explored in other hematologic malignancies and hold great potential against myeloma. Future clinical studies will help in clarifying the issues related to dose, frequency, long-term safety, and efficacy of NK cell therapy in multiple myeloma.