Treatment of relapsed or refractory acute myeloid leukemia (AML) has presented challenges for hematologists for decades. Despite numerous clinical studies, outcomes are consistently disappointing ...with 5-year overall survival rates of ∼10%. Allogeneic hematopoietic cell transplantation at the time of second complete remission remains the only reliable option with curative potential. However, recent approval of several new agents has transformed treatment paradigms that had been in place for almost half a century in AML. This new therapeutic landscape provides the opportunity to revisit the approach to relapsed or refractory AML. Through illustrative cases, we describe our approach, which increasingly relies on specific disease biology. We focus on treatment outside of the context of clinical trials because such trials are not available in most parts of the world. Primarily, we consider age, fitness to tolerate intensive chemotherapy, remission duration, and presence of a targetable mutation to guide treatment. The coming years will inevitably bring new targets and agents that may prove most effective when combined with each other and/or chemotherapy. Future studies are needed to determine how best to implement this evolving armamentarium of treatment options, to elucidate mechanisms of resistance, and to continue the pursuit of novel drug discovery.
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Alloimmune T cells in transplantation DeWolf, Susan; Sykes, Megan
The Journal of clinical investigation,
06/2017, Letnik:
127, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Alloimmune T cells are central mediators of rejection and graft-versus-host disease in both solid organ and hematopoietic stem cell transplantation. Unique among immune responses in terms of its ...strength and diversity, the T cell alloresponse reflects extensive genetic polymorphisms between allogeneic donors and recipients, most prominently within the major histocompatibility complex (MHC), which encodes human leukocyte antigens (HLAs) in humans. The repertoire of alloreactive T cell clones is distinct for every donor-recipient pair and includes potentially thousands of unique HLA/peptide specificities. The extraordinary magnitude of the primary alloresponse and diversity of the T cell population mediating it have presented technical challenges to its study in humans. High-throughput T cell receptor sequencing approaches have opened up new possibilities for tackling many fundamental questions about this important immunologic phenomenon.
Alloimmune T cells in transplantation DeWolf, Susan; Sykes, Megan
The Journal of clinical investigation,
07/2017, Letnik:
127, Številka:
7
Journal Article
Recenzirano
Alloimmune T cells are central mediators of rejection and graft-versus-host disease in both solid organ and hematopoietic stem cell transplantation. Unique among immune responses in terms of its ...strength and diversity, the T cell alloresponse reflects extensive genetic polymorphisms between allogeneic donors and recipients, most prominently within the major histocompatibility complex (MHC), which encodes human leukocyte antigens (HLAs) in humans. The repertoire of alloreactive T cell clones is distinct for every donor-recipient pair and includes potentially thousands of unique HLA/peptide specificities. The extraordinary magnitude of the primary alloresponse and diversity of the T cell population mediating it have presented technical challenges to its study in humans. High-throughput T cell receptor sequencing approaches have opened up new possibilities for tackling many fundamental questions about this important immunologic phenomenon.
ABSTRACTAlloreactive T lymphocytes are the primary mediators of allograft rejection. The size and diversity of the HLA-alloreactive T cell repertoire has thus far precluded the ability to follow ...these T cells and thereby to understand their fate in human transplant recipients. This review summarizes the history, challenges, and recent advances in the study of alloreactive T cells. We highlight the historical development of assays to measure alloreactivity and discuss how high-throughput T cell receptor (TCR) sequencing-based assays can provide a new window into the fate of alloreactive T cells in human transplant recipients. A specific approach combining a classical in vitro assay, the mixed lymphocyte reaction, with deep T cell receptor sequencing is described as a tool to track the donor-reactive T cell repertoire for any specific HLA-mismatched donor-recipient pair. This assay can provide mechanistic insights and has potential as a noninvasive, highly specific biomarker for rejection and tolerance.
Diarrhea is a frequent but overlooked complication of kidney transplantation. Diarrhea is repeatedly neglected, often considered by patients and clinicians an unavoidable side effect of ...immunosuppressive regimens. It is, however, associated with a significant impairment in life quality. Severe and chronic posttransplant diarrhea may lead to dehydration, malabsorption, rehospitalization, immunosuppression, noncompliance, and a greater risk of graft loss and death. There is thus a need to optimize and standardize the management of posttransplant diarrhea with consistent diagnostic and therapeutic strategies. A recent study has suggested that the increased sensitivity of molecular tools might help in early pathogen identification and guidance of antimicrobial treatment. Most bacterial and protozoan infections are readily curable with appropriate antimicrobial agents; cryptosporidiosis and C. difficile infections may however be complicated by relapsing courses. In addition, identification of enteric viral genomes in stool has further reduced posttransplant diarrhea of unknown origin. Chronic norovirus-related posttransplant diarrhea, arising from the interplay of the virus and immunosuppressive drugs, has emerged as a new challenge in the field. Prospective and controlled studies are necessary to evaluate the efficacy and safety of innovative anti-norovirus therapeutics, as well as optimal immunosuppressive regimens, to enable viral clearance while preventing rejection and donor-specific antibody formation. This review seeks to provide a basis for the design of future clinical prospective studies.
Although allogeneic hematopoietic cell transplantation (allo-HCT) remains the backbone of curative treatment for the majority of fit adults diagnosed with AML, there is indeed a subset of patients ...for whom long-term remission may be achieved without transplantation. Remarkable changes in our knowledge of AML biology in recent years has transformed the landscape of diagnosis, management, and treatment of AML. Specifically, markedly increased understanding of molecular characteristics of AML, the expanded application of minimal/measurable residual diseases testing, and an increased armamentarium of leukemia-directed therapeutic agents have created a new paradigm for the medical care of patients with AML. An attempt is herein made to decipher the decision to proceed to transplant for patients with AML in first complete remission on the basis of the current best available evidence. The focus is on factors affecting the biology and treatment of AML itself, rather than on variables related to allo-HCT, an area characterized by significant advancements that have reduced overall therapy-related complications. This review seeks to focus on areas of particular complexity, while simultaneously providing clarity on how our current knowledge and treatment strategies may, or may not, influence the decision to pursue allo-HCT in patients with AML.
Immunocompromised individuals and particularly those with hematologic malignancies are at increased risk for SARS-CoV-2-associated morbidity and mortality due to immunologic deficits that limit ...prevention, treatment, and clearance of the virus. Understanding the natural history of viral infections in people with impaired immunity due to underlying conditions, immunosuppressive therapy, or a combination thereof has emerged as a critical area of investigation during the COVID-19 pandemic. Studies focused on these individuals have provided key insights into aspects of innate and adaptive immunity underlying both the antiviral immune response and excess inflammation in the setting of COVID-19. This review presents what is known about distinct states of immunologic vulnerability to SARS-CoV-2 and how this information can be harnessed to improve prevention and treatment strategies for immunologically high-risk populations.
Vardhana and colleagues discuss how discrete immunological defects in individuals with cancer and other immunosuppressive conditions have informed our understanding of the role of the immune system in protection and toxicity from SARS-CoV-2. They discuss how these immune defects affect the protective impact of vaccination strategies in these individuals and provide insight to limit COVID-19-associated morbidity in this high-risk population.
T cell responses to allogeneic major histocompatibility complex antigens present a formidable barrier to organ transplantation, necessitating long-term immunosuppression to minimize rejection. ...Chronic rejection and drug-induced morbidities are major limitations that could be overcome by allograft tolerance induction. Tolerance was first intentionally induced in humans via combined kidney and bone marrow transplantation (CKBMT), but the mechanisms of tolerance in these patients are incompletely understood. We now establish an assay to identify donor-reactive T cells and test the role of deletion in tolerance after CKBMT. Using high-throughput sequencing of the T cell receptor B chain CDR3 region, we define a fingerprint of the donor-reactive T cell repertoire before transplantation and track those clones after transplant. We observed posttransplant reductions in donor-reactive T cell clones in three tolerant CKBMT patients; such reductions were not observed in a fourth, nontolerant, CKBMT patient or in two conventional kidney transplant recipients on standard immunosuppressive regimens. T cell repertoire turnover due to lymphocyte-depleting conditioning only partially accounted for the observed reductions in tolerant patients; in fact, conventional transplant recipients showed expansion of circulating donor-reactive clones, despite extensive repertoire turnover. Moreover, loss of donor-reactive T cell clones more closely associated with tolerance induction than in vitro functional assays. Our analysis supports clonal deletion as a mechanism of allograft tolerance in CKBMT patients. The results validate the contribution of donor-reactive T cell clones identified before transplant by our method, supporting further exploration as a potential biomarker of transplant outcomes.
Introduction Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of large B-cell lymphomas (LBCL), demonstrating remarkable efficacy. However, CAR-T therapy is also ...associated with significant toxicities, some arising from relative immunologic incompetence after treatment. A key knowledge gap persists regarding how the immune landscape changes post-CAR-T, defined as immune reconstitution (IR), and the influence of IR on patient outcomes. In this study, we set out to describe patterns and determinants of IR following CAR-T as well as impacts of IR on outcomes. Methods Adult patients with primary or transformed LBCL treated with CD19-CAR-T cells, namely axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel), between 2017 and 2022 were included in this single center retrospective study. Immune cell levels were measured at various timepoints after CAR-T. Median cell counts and interquartile range (IQR) at pre-specified time windows (using the first available observation) were used to describe temporal IR patterns. Multivariable generalized estimating equation (GEE) models with cubic time variables were used to investigate the association between cell count trajectory and baseline characteristics. A multivariable Cox model with longitudinal cell count as a time-varying covariate was utilized to assess the association between IR and overall survival (OS), adjusted for confounding factors. Kaplan-Meier (KM) curves were generated for visualization. Results A total of 210 patients were included, of whom 153 had at least one CD4+ T cell measurement from time of CAR-T. The median age was 65 (range 20-86) and most were male (65.7%) and diagnosed with diffuse large B-cell lymphoma (79.5%). Axi-cel (49.5%) was the most common product, followed by tisa-cel (28.6%) and liso-cel (21.9%). Lymphodepletion was mostly cyclophosphamide and fludarabine (82.4%). Of the 210 patients, 58.1% achieved a complete response (CR) and 17.1% a partial response by 100 days after CAR-T. Following CAR-T, CD3+ T cells were the most abundant circulating lymphocyte. By 30 days (±15 days) after CAR-T, median (IQR) values of CD3+ T cells, B cells, and NK cells were 445 (162-776), 0 (0-0), and 90 cells/ul (57-146), respectively; by 60 days (±15 days), median (IQR) values were 498 (220-706), 0 (0-0), and 104 cells/ul (69-169), respectively. Proportions of CD4+ and CD8+ T cells remained similar through one year after CAR-T, with CCR7-45RA+ TEMRA and CCR7-45RA- effector memory cells dominating among CD8's, and CCR7-45RA- effector memory cells being the most abundant among CD4's. Regulatory T cells (CD25+CD127-) comprised about 10% of the CD4+ T cell lymphocyte population, with a median (IQR) of 9 cells/ul (4.5-15.5) by day 30 (±15 days) after CAR-T. Finally, receipt of tisa-cel was associated with greater levels of CD4+ EM T cells compared with axi-cel and liso-cel (median IQR: 253 158-406 vs 81 51-138 and 113 cells/ul 88-154, respectively), by 30 days (±15 days) after CAR-T. According to a multivariable GEE model, patients receiving tisa-cel had significantly higher CD4+ count trajectories compared to those receiving axi-cel or liso-cel ( p<0.001 for both) ( Figure A). In addition, patients with more extensive pre-treatment (i.e., 6+ prior lines) had significantly lower CD4+ count trajectories compared to those who received 2-3 or 4-5 prior lines ( p=0.015 and p=0.004, respectively). A multivariable Cox model, moreover, indicated that a higher CD4+ count (in units of 50 cells/ul) was significantly associated with better OS (adjusted HR: 0.845; 95% CI, 0.745-0.960; p=0.010), adjusted for product and prior lines of therapy. KM curves by patients above or below the median of the last observed CD4+ count further demonstrated this significant association between longitudinal IR and OS ( Figure B). Conclusion In this single-center retrospective study, we extensively characterized the immune environment at time of and following CAR-T. To the best of our knowledge, this is the largest study of its kind. Additionally, we identified several factors that impact IR, which in turn shapes OS. In doing so, we show that CD4+ T lymphocytes are key players in disease response post-CAR-T and suggest that tracking CD4+ recovery following CAR-T may provide both diagnostic and therapeutic benefit.
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