Outline
- Abstract
- 1 Introduction
- 2 Pathobiology of Agvhd (fig. 1)
- 3 Strategies to Prevent Agvhd
- 4 Treatment of Agvhd
- 5 Selected Novel Approaches/proposals for Prevention
- And Treatment of Acute Gvhd (table 1)
- 6 Chronic Graft Versus Disease
- 7 Antitumor Post-Transplant Immune Manipulation (table 2)
- 8 Conclusions
- References
رئوس مطالب
- چکیده
- 1 مقدمه
- پیوند سلول های بنیادی هماتوپویتیک (خون ساز)
- پیوند در برابر بیماری میزبان و پیوند در برابر اثر تومور
- GVHD حاد
- GVHD مزمن
- 2 پاتوبیولوژی aGVHD (شکل 1)
- سلول های موثر
- آسیب بافت : سیتوکین ها ، پروفین ها و FasL.
- پیوند سلول های T با استفاده از سلول های ارائه دهنده ی آنتی ژن
- پیوند سلول T: آیا APC ها تخصصی واقعا مورد نیاز می باشند ؟
- مولکول های محرک
- گیرنده های ایمنی اصلی
- آنتی ژن های هدف
- انتقال
- 3 یافتن بهترین دهنده ی سازگار
- سایر عوامل تاثیر گذار بر شیوع GVHD
- پیشگیری استاندارد
- روش های دارویی جدید
- تابش لنفاوی کل / ATG
- سیکلوفسفامید پس از پیوند
- درمان های آنتی بادی مبتنی بر سیتوکین
- پنتوستاتین (Pentostatin)
- ماراویروک (Maraviroc)
- 4 درمان aGVHD
- درمان اولیه
- مطالعات درمان های سرکوب کننده برای GVHD مقاوم در برابر استروئید
- 5 روش ها / پیشنهادات انتخاب شده ی جدید برای جلوگیری و درمان GVHD حاد
- 6 پیوند مزمن در برابر بیماری
- پیامد های بیماری زایی و پیوندی
- سلول های B و cGVHD
- BAFF و هموستاز سلول B در cGVHD
- هدف قرار دادن مستقیم و غیرمستقیم سلول های T تنظیمی
- درمان اولیه ی GVHD
- مهار mTOR
- درمان دوم cGVHD
- cGVHD: مداخلات خاص عضو
- 7 اعمال ایمنی پس از پیوند ضد تومور
- مولکول های سیستم ایمنی
- مهار کننده های تیروزین کیناز
- عوامل هایپومتیلیتینگ ( Hypomethylating)
- آنتی بادی های ضد لنفوم
- مبارزه با تحمل
- سیتوکین به عنوان یک عامل تقویت
- واکسن های ضد تومور
- مهندسی سلول T
- سلول های کشنده ی طبیعی و تزریق لنفوسیت سیتوتوکسیک
- تزریق لنفوسیت دهنده
- DLI در لوسمی میلوئید مزمن
- DLI در میلوما چند فاز
- DLI در لوسمی میلوئیدی حاد
- DLI در لنفوم
- DLI در لوسمی لنفوبلاستیک حاد
- استراتژی های تکاملی برای DLI
- 8 نتیجه گیری
Abstract
Allogeneic stem cell transplantation (allo-HCT) is a procedure with the potential to cure many malignant and nonmalignant diseases. The adoptive transfer of a donor immune system into a transplant recipient can result in allorecognition and reactivity of donor immune cells against host target tissues. This can lead to an immune attack against normal tissues in the recipient (graft-versus-host disease, GVHD) but also against the neoplastic cells themselves (graft-versus-tumor effect, GVT). While GVHD has long been recognized as a significant cause of morbidity and mortality after allo-HCT, there has been little progress in advancing the standards of care for GVHD prophylaxis and therapy, which have remain unchanged for more than two decades. Given the more recent recognition that much of the curative benefit of allo-HCT results from the GVT effect, rather than from the cytoreductive effects of conditioning chemotherapy, multiple strategies to take advantage of the GVT effect that aim to limit morbidity and mortality due to GVHD are under investigation, including cellular therapies employing the use of native or engineered graft populations enriched for antitumor responses, and employing donor lymphocyte infusions. Another critical question is how strategies to prevent and/or treat GVHD may be designed to limit the suppression of beneficial T cell responses against pathogens critical to limiting infections in the post-HCT setting. Research in murine models and human subjects has uncovered a great deal regarding the mechanisms of GVHD initiation and persistence, including clinical factors and graft constituents responsible for the acute and chronic forms of GVHD. A variety of cellular mediators, from antigen-presenting cells to effectors, including alloreactive T cells and B cells, have been characterized. Regulatory populations, including CD4+ regulatory T cells and invariant NKT cells, have also been shown to be capable of ameliorating GVHD intensity and survival in model systems. Given this clearer understanding of GVHD pathophysiology, a variety of novel clinical strategies are in development, from those utilizing classical inhibitors of T cell reactivity, to monoclonal antibody therapies to more novel approaches targeting specific signaling pathways in T cells and other mediators of inflammation. Recent meaningful progress has also been made in approaches using adoptive cellular therapies to decrease GVHD while maintaining or specifically augmenting GVT responses. These strategies bring promise for a future wherein more patients can receive allo-HCT for both malignant and nonmalignant diseases, with reduced rates of complications and improved overall survival.
Conclusions
Dramatic improvements in HCT, especially the widespread adoption of reduced intensity conditioning regimens (given our understanding of the importance of GVL responses) have substantially expanded transplant utilization with reduced treatment- related morbidity and mortality. However, five decades into the HCT era, GVHD, and relapse continue to remain vexing problems, resulting in symptom burden and mortality even when the transplant outcome is otherwise successful. The dissection of GVHD from effective GVL and pathogen-specific T cell responses remains a central intellectual challenge and may provide genuine hope for improved transplant approaches. Until then, the focus of clinical trials should be the prevention of GVHD, both the acute and the chronic forms, and on improved studies of initial therapy in both the acute and chronic settings. Adoptive cellular therapies (e.g., using TREG, transduced T cells, or innate immune cells including NK and iNKT cells) are also promising, although pharmacologic interventions that selectively inhibit alloreactivity, while sparing GVL-inducing cells and TREG are also highly desirable strategies. Promotion of tolerance is another mechanism that may reduce GVHD, especially cGVHD. All of these strategies will benefit from an improved understanding of GVHD biomarkers (e.g., promising candidates including TNFR1, HGF, soluble CD25, BAFF, and others) that may facilitate preemptive treatment and early dose escalation or de-escalation of immunosuppression [56, 171–174]. Development of improved animal models that better replicate the human condition, and facilitate a better understanding of cGVHD, will also provide great benefit.
While this review has focused on immunotherapeutic strategies, optimization of conditioning regimens continues to be a priority. Incorporation of agents including gemcitabine [175–177], bendamustine [178] for lymphomas or novel agents like proteasome inhibitors; HDAC inhibitors in myelomas; or Btk or PI3Kδ inhibitors in lymphoid malignancies may also improve outcomes. Antibodies or immunotoxins (brentuximab, anti-CD22 immunotoxins, etc.) are also likely to be increasingly utilized in pre- and post-transplant conditioning and maintenance therapies. Additionally, targeting of putative cancer stem cell pathways (Notch, Hedgehog, β-catenin, etc.) during conditioning may also improve outcomes. Post-transplant maintenance/consolidation treatments have already given good results (e.g., lenalidomide, imatinib) and other promising strategies (e.g., hypomethylating agents in leukemias) are also being developed. Many of these strategies may have intended or unintended immunologic consequences, which should be assessed systematically when clinical trials of these agents are conducted.
In many settings, detection of early relapse before overt clinical signs are evident (e.g., by chimerism or by MRD evaluation) may allow us to more successfully modify the immune environment or apply novel agents. Overall, it is expected that a combination of these diverse new approaches in the next decade will substantially improve post-HCT disease control while decreasing early mortality and late effects of HCT, which may impair immune function and quality of life. To accomplish these aims, thoughtful and systematic basic, translational and clinical studies will be needed. These studies will require the careful cooperation of academic institutions, industry partners and regulatory agencies, but will yield a promising future for the rapidly growing field of HCT.