Highlights This document is intended to: • Summarize information regarding the biologic underpinnings of chronic graft-versus-host disease (GVHD). • Identify critical gaps in our understanding of ...chronic GVHD. • Develop working hypotheses/overriding concepts for chronic GVHD development. • Highlight the utility and limitations of preclinical models of chronic GVHD and define criteria for the creation of new models to address limitations. • Create a platform for developing innovative clinical strategies for the prevention and treatment of chronic GVHD.
Autologous hematopoietic cell transplantation (AHCT) is often used as a consolidation for patients with peripheral T‐cell lymphomas (PTCLs) due to the poor prognosis associated with this heterogenous ...group of disorders. However, a significant number of patients will experience post‐AHCT disease relapse. Here, we report a retrospective study of consecutive 124 patients with PTCLs who underwent AHCT from 2008 to 2020. With a median follow‐up of 6.01 years following AHCT, 49 patients (40%) experienced disease relapse. As expected, more patients who were not in first complete remission experienced post‐AHCT relapse. Following relapse, majority of the patients (70%) receiving systemic therapies intended as bridging to curative allogeneic HCT. However, only 18 (53%) patients eventually underwent allogeneic HCT. The estimated 3‐year OS among patients proceeding to allogeneic HCT was 72% (95% CI 46%–87%). Our report details the pattern of post‐AHCT relapse and the management of relapsed disease using different therapeutic modalities.
Brentuximab vedotin and allogeneic transplant provides long term survival in relapsed PTCL patients after AHCT.
H-Y antigens are a group of minor histocompatibility antigens encoded on the Y-chromosome with homologous H-X antigens on the X-chromosome. The disparate regions of the H-Y antigens are highly ...immunogenic and play an important role in understanding human alloimmunity. In this review, we investigate the history of H-Y antigen discovery along with their critical contributions in transplantation and pregnancy. In hematopoietic cell transplantation, male recipients with female donors who become seropositive for B-cell responses as H-Y antibodies following transplantation have increased rates of chronic graft-versus-host disease and decreased rates of relapse. Conversely, female patients who receive male kidney allografts are more likely than other gender combinations to develop H-Y antibodies and reject their allografts. Finally, in the setting of pregnancy, mothers who initially gave birth to boys are more likely to have subsequent pregnancy complications, including miscarriages, in association with H-Y antibody development. H-Y antigens continue to serve as a model for alloimmunity in new clinical scenarios. Our development of more sensitive antibody detection and next-generation DNA sequencing promises to further advance our understanding and better predict the clinical consequences of alloimmunity.
Minor histocompatibility antigens (mHAs) are known targets of donor T cells after allogeneic hematopoietic stem cell transplantation (HSCT). In contrast, B-cell responses to mHAs have not been ...extensively characterized and the clinical significance of antibodies to mHAs is unknown. We tested 121 patients who underwent HSCT and 134 healthy donors for immunoglobulin G (IgG) antibodies against 5 mHAs encoded by genes on the Y chromosome (DBY, UTY, ZFY, RPS4Y, and EIF1AY). Antibodies to at least one H-Y protein developed in 52% of male patients with female donors compared with 8.7% of male patients with male donors (P < .0001), and in 41.4% of healthy females compared with 7.8% of healthy males (P < .0001). H-Y antibodies develop 4 to 12 months after transplantation and persist for long periods. The clinical significance of H-Y antibodies was characterized in 75 male patients with hematologic malignancies who received stem cells from female donors (F → M HSCT). The presence of H-Y antibodies correlated with chronic graft-versus-host disease (GVHD) by univariate (odds ratio OR = 15.5; P < .0001) and multivariable logistic regression analysis (OR = 56.5; P < .0001). Antibody response to Y-chromosome encoded histocompatibility antigens (H-Y antigens) was also associated with maintenance of disease remission (P < .0001). B cells may provide a new target for immune intervention in chronic GVHD.
B cells are known to play an important role in pathogenesis of human chronic graft vs. host disease (cGVHD). Our group has previously shown that IgG allo-antibodies recognize Y chromosome-encoded ...proteins (H–Y) and a dominant H–Y epitope, DEAD box protein (DBY-2) detectable 6–12 mo after transplant in male patients who receive grafts from female donors (F→M) hematopoietic cell transplantation (HCT). Here we present FACS studies of peripheral blood mononuclear cells collected 6 mo after transplant showing that 16 of 28 (57%) F→M HCT patients have circulating donor B cells that express B-cell receptor (mainly IgM and Igλ) specific for DBY-2. The detection of these DBY-2 B cells 6 mo after HCT are associated with cGVHD development (P = 0.004). Specifically, 15 of 16 F→M with DBY-2 B cells developed cGVHD. In contrast, cGVHD developed in only 5 of the 12 who did not have DBY-2 B cells detected. This demonstrates circulating human B cells binding an alloantigen (DBY-2) and that these DBY-2–specific B cells appear before development of cGVHD in roughly half of the F→M patients. Our study suggests that detection of anti–DBY-2 B cells may predict cGVHD and that this prediction may have clinical utility. Validation of this hypothesis will require larger prospective studies.
Identifying plasma biomarkers early after allo-HCT may become crucial to prevent and treat severe aGvHD. We utilized samples from 203 allo-HCT patients selected from the Blood & Marrow Transplant ...Clinical Trials Network (BMT CTN) to identify new biomarker models to predict aGvHD and overall mortality. Two new biomarkers (Gal-3 and LAG-3), and previously identified biomarkers (ST2/IL33R, IL6, Reg3A, PD-1, TIM-3, TNFR1) were screened. Increased Gal-3 levels measured at Day +7 post-transplant predicted the development of aGvHD (grade 2-4) in the total population AUC: 0.602; P = 0.045 while higher Day +14 levels predicted overall mortality due to toxicity among patients receiving reduced intensity conditioning P = 0.028 but not myeloablative conditioning. Elevated LAG-3 levels (Day +21) were associated with less severe aGvHD 159.1 ng/mL vs 222.0 ng/mL; P = 0.046. We developed a model utilizing Gal-3, LAG-3, and PD-1 levels at Days +14 and +21 with an improved performance to predict aGvHD and overall non-relapse mortality. We confirmed four informative biomarkers (Reg3A, ST2, TIM-3, and TNFR1) predict severe aGvHD at day +14 and day +21 (grade 3-4). In conclusion, the combination of Gal-3 alone or in combination with LAG-3, and PD-1 is a new informative model to predict aGvHD development and overall non-relapse mortality after allo-HCT.
•Overall survival and most safety outcomes with axi-cel were consistent across race/ethnicity in relapsed/refractory large B-cell lymphoma.•Real-world outcomes with CAR T-cell therapy are different ...in non-Hispanic Black patients, possibly related to barriers to access.
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Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting its use, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients who received axi-cel between 2017 and 2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 trials, respectively. Overall survival was consistent across race/ethnicity groups. However, non-Hispanic (NH) Black patients had lower overall response rate (OR, 0.37; 95% CI, 0.22-0.63) and lower complete response rate (OR, 0.57; 95% CI, 0.33-0.97) than NH White patients. NH Black patients also had a shorter progression-free survival vs NH White (HR, 1.41; 95% CI, 1.04-1.90) and NH Asian patients (HR, 1.67; 95% CI, 1.08-2.59). NH Asian patients had a longer duration of response than NH White (HR, 0.56; 95% CI, 0.33-0.94) and Hispanic patients (HR, 0.54; 95% CI, 0.30-0.97). There was no difference in cytokine release syndrome by race/ethnicity; however, higher rates of any-grade immune effector cell–associated neurotoxicity syndrome were observed in NH White patients than in other patients. These results provide important context when treating patients with R/R LBCL with CAR T-cell therapy across different racial and ethnic groups. ZUMA-1 and ZUMA-7 (ClinicalTrials.gov identifiers: #NCT02348216 and #NCT03391466, respectively) are registered on ClinicalTrials.gov.
Locke and colleagues describe the safety and efficacy outcomes of axicabtagene ciloleucel for large B-cell lymphoma across racial and ethnic groups for 1290 standard-of-care patients in the Center for International Blood and Marrow Transplant Research registry and 275 patients treated in clinical trials. While consistency in survival and most safety outcomes were evident across groups, non-Hispanic Black patients had significantly lower response rates and progression-free survival in routine practice, potentially reflecting barriers to access.
Here, we report on the results of a phase I/II trial (NCT00490529) for patients with mantle cell lymphoma who, having achieved remission after immunochemotherapy, were vaccinated with irradiated, ...CpG-activated tumor cells. Subsequently, vaccine-primed lymphocytes were collected and reinfused after a standard autologous stem cell transplantation (ASCT). The primary endpoint was detection of minimal residual disease (MRD) within 1 yr after ASCT at the previously validated threshold of ≥1 malignant cell per 10,000 leukocyte equivalents. Of 45 evaluable patients, 40 (89%) were found to be MRD negative, and the MRD-positive patients experienced early subsequent relapse. The vaccination induced antitumor CD8 T cell immune responses in 40% of patients, and these were associated with favorable clinical outcomes. Patients with high tumor PD-L1 expression after in vitro exposure to CpG had inferior outcomes. Vaccination with CpG-stimulated autologous tumor cells followed by the adoptive transfer of vaccine-primed lymphocytes after ASCT is feasible and safe.
Chimeric antigen receptor (CAR) T cells targeting CD22 (CD22-CAR) provide a therapeutic option for patients with CD22
malignancies with progression after CD19-directed therapies. Using on-site, ...automated, closed-loop manufacturing, we conducted parallel Phase 1b clinical trials investigating a humanized CD22-CAR with 41BB costimulatory domain in children and adults with heavily treated, relapsed/refractory (r/r) B-ALL. Of 19 patients enrolled, 18 had successful CD22-CAR manufacturing, and 16 patients were infused. High grade (3-4) cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS) each occurred in only one patient; however, three patients experienced immune-effector-cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Twelve of 16 patients (75%) achieved CR with an overall 56% MRD-negative CR rate. Duration of response was overall limited (median 77 days), and CD22 expression was downregulated in 4/12 (33%) available samples at relapse. In summary, we demonstrate that closed-loop manufacturing of CD22-CAR T cells is feasible and is associated with a favorable safety profile and high CR rates in pediatric and adult r/r B-ALL, a cohort with limited CD22-CAR reporting.
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