Advances in cell and gene therapy最新文献

Hematopoietic stem cell transplant (HCT) is used with increasing frequency for the treatment of malignant and nonmalignant diseases. Thrombocytopenia is a common complication following HCT and is associated with decreased survival. Supportive care with platelet transfusion requires significant resources, reduces quality of life, and is associated with several adverse effects including transfusion reaction, infection, and alloimmunization. Thrombopoeitin receptor agonists (TPO-RA) have been found to be safe and effective for the treatment of immune mediated thrombocytopenia, thrombocytopenia related to bone marrow failure syndromes, and thrombocytopenia of chronic liver disease. We hereby discuss in this review the evidence for use of TPO-RA for the management of thrombocytopenia after HCT.

Oncolytic virotherapy has been tested in numerous early phase clinical studies. However, the antitumor activity of oncolytic viruses thus far has been limited. Numerous strategies are being explored to enhance their antitumor activity by activating the adaptive arm of the immune system. We reasoned that it might also be possible to engineer oncolytic viruses to redirect tumor-associated macrophages to tumor cells for therapeutic benefit. We engineered an oncolytic vaccinia virus (VV) to disrupt the CD47/SIRPα interaction by expressing a chimeric molecule that consists of the ectodomain of SIRPα and the Fc domain of IgG4 (SIRPα-Fc-VV). SIRPα-Fc-VV readily replicated in tumor cells and redirected M1 as well as M2 macrophages to tumor cells in vitro. In contrast, control VVs that either encoded YFP (YFP-VV) or SIRPα (SIRPα-VV) did not. In vivo, SIRPα-Fc-VV had greater antitumor activity than YFP-VV and SIRPα-VV in an immune competent osteosarcoma model resulting in a significant survival advantage. Pretreatment with cytoxan further augmented the antitumor activity of SIRPα-Fc-VV. Thus, arming oncolytic viruses with SIRPα-Fc may present a promising strategy to enhance their antitumor activity for the virotherapy of solid tumors.

The clinical manifestations of excess production of proinflammatory cytokines associated with hematopoietic cell therapy are being increasingly recognized. While these manifestations are all forms of a cytokine release syndrome (CRS), the terminology to date has focused on the clinical scenarios in which they occur (eg, graft vs host disease [GVHD] or engraftment syndrome [ES] following hematopoietic cell transplantation or CRS following immune effector cell therapy). The data regarding cytokine profiles in these conditions are limited by the variable methods of assessment and which cytokines are measured. Overlapping cytokine profiles are seen in these conditions, but distinct differences in the profiles have also been described (eg, for acute GVHD and ES). Targeted interventions have been developed based on these profiles with some (eg, anti-interleukin-6 receptor antibody therapy for CRS after immune effector cell therapy) showing more promise than others. Future strategies include the evaluation of monoclonal antibodies against more recently described cytokines and the increasing use of less specific inhibitors of cytokine production such as the Janus Kinase/Transducer and Activator of Transcription signaling inhibitors.

While the treatment landscape of multiple myeloma has evolved and expanded over the past decade, autologous hematopoietic cell transplantation remains an integral part of myeloma therapy. The availability of sensitive minimal residual disease (MRD) testing has allowed us to characterize the depth of response beyond traditional response assessment. It also provides an exceptional platform to rapidly study the benefit of each intervention and systemically appraise its incremental benefit. While relatively early in its development as a decision-making tool and faced with challenges such as standardization, it is prime time for MRD testing. The continued incorporation of MRD based endpoints into clinical trials and ultimately, into clinical practice, will result in individualized treatment strategies tailored to each patient resulting in minimum necessary treatment to obtain sustained disease control and long-term survival.

The overall survival (OS) in multiple myeloma (MM) has almost quadrupled over the past 2 decades. This improvement could be attributed to the introduction of novel agents in the schema of therapy which includes the following phases: induction, high dose melphalan/stem cell transplant, optional posttransplant consolidation and maintenance (Barlogie Total-Therapy schema). Because disease relapse is inevitable, additional treatment is generally needed to achieve remission. Emerging evidence suggests that assessment of minimal residual disease status following induction or autologous stem cell transplant could be predictive of duration of progression-free survival as well as OS. In an effort to prolong duration of first remission, various drug combinations are being evaluated in the front-line setting. The purpose of this paper is to provide a succint review of the current treatment paradigm of newly diagnosed MM and highlight the preliminary findings from some of the ongoing clinical trials which are likely to change current practice.

Multiple myeloma(MM) is an incurable plasma cell malignancy. Despite an improvement in OS over the past 2 decades, most patients do experience disease relapse. A subset of patients who experience an early disease relapse within 1-2 years posttransplant, and considered functional high-risk. Recent findings implicated high-risk cytogenetic features and minimal residual disease as negative prognostic factors, each independently associated with early relapse among autologous stem cell transplant recipients(ASCT). The spectrum of disease relapse could range from asymptomatic/biochemical to more aggressive forms such as plasma cell leukemia. Hence, it is imperative that therapy be tailored based on these patterns of relapse upon presentation. The past few years have witnessed an explosion in the armamentarium of second-line agents for the treatment of relapsed MM. Accordingly, choosing the optimal regimen has become quite challenging for the practicing clinician. In this review, we outline the approach for therapy selection, which takes into account underlying comorbid conditions, duration of response, presence of high-risk features, etc Due to a better understanding of disease biology coupled with the advances in molecular techniques, the treatment landscape of relapsed MM (posttransplant) will most likely continue to evolve. Novel agents with distinct modes of action, such as immune therapies and novel oral agents are undergoing investigation in the relapsed setting. Once approved, these agents could potentially alter the course of the disease and possibly challenge the role of ASCT.

Coronavirus disease 2019 (COVID-19) is a highly transmissible viral illness caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). This virus triggered a pandemic crisis for health care systems worldwide. Initial experience from China indicated that patients with cancer had a higher risk of COVID-19 infection and poorer outcomes after developing COVID-19 than individuals without cancer.¹ Patients with hematologic malignancy or receiving transplantation are immunosuppressed and may be particularly vulnerable to viral infections, and the hematology community faces unprecedented challenges.

The rapidly expanding COVID-19 pandemic has affected all aspects of medical activity, including hematopoietic stem cell transplantation (HSCT). Based on our current experience, preventive work of novel coronavirus is extremely important to mitigate its impact. Outside the epicentre (Wuhan), transplantation activity in China was not halted. We recommend preservation of transplantation activity under the premise of ensuring safety. This comment describes the possible impact of the current COVID-19 pandemic on transplantation activity and introduces interim precautions in our centre during the outbreak period.

During the outbreak, we maintained 80% of the transplant status. None of the patients or staff in our centre have been diagnosed with COVID-19, which demonstrates the importance and effectiveness of our preventive measures. We recommend preservation of transplant activity to the extent that the outbreak of COVID-19 allows. Otherwise, numerous patients will miss the optimal opportunity of transplantation and have poor prognosis. In addition to preserving transplantation activity, ensuring the safety of transplantation is a top priority. As mentioned above, transplantation is a procedure involving many aspects, and maximum emphasis should be placed on radical preventive and screening measures for each section of transplantation.

The comment was approved by the Institutional Review Board of Peking University People's Hospital.

The authors declare no competing financial interests.

X.-J. H. designed the review; Z.-L. X. and X.-J. H. wrote the manuscript; and they gave final approval for the manuscript.

Autologous stem cell transplantation has been part of standard of treatment in multiple myeloma for 2 decades. The data showed improving progression-free survival and overall survival. Despite the improvement of new drugs, myeloma patients continue to relapse New cell therapy, chimeric antigen receptor T-cell therapy have been explored in heavily pretreated patients. In this commentary, we highlight studies presented at the American Society of Hematology (ASH) Annual Meeting held in Orlando, FL in December 2019.

Apheresis platelets are a product with high cost and limited supply commonly used for hematopoietic transplant patients. There is potential for both transfusion reactions and refractoriness associated with this product. Therefore, transfusion guideline compliance is closely monitored. This is a quality assurance review of a prospective platelet audit covering an 18-month period. Audit records created by trainees in their first post graduate year (PGY1) were compared to subsequent years. Multivariate regression analysis considered the variables of patient age, sex, PGY level, and platelet count. Financial modeling was derived for best case (low cost), base case (average cost), and worst case (high cost) scenarios. There were 1931 platelet doses requiring approval with 1122 (58%) compliant with hospital transfusion policy and 809 (42%) not compliant. Products ordered but not compliant with hospital policy were appropriately held from release by PGY1 physicians for 186/428 (43%) doses and 279/381 (73%) doses by PGY > 1 physicians (P < .01). Multivariate analysis demonstrated significance only in the categories of PGY level and platelet count. The ordered doses not compliant with hospital policy had an estimated minimal cost of $404 500. There were a disproportionately higher number of platelets released by the PGY1 group. Potential mitigation strategies for this include a closer level of oversight or hiring a patient blood manager to provide real-time metrics. Prevention of unnecessary transfusions is important in hematopoietic transplant patients both to prevent infections and decrease foreign antigen exposure and transfusion refractoriness.