Peiman Hematti

Increasing Incidence of Chronic Graft-versus-Host Disease in Allogeneic Transplantation: A Report from the Center for International Blood and Marrow Transplant Research

Although transplant practices have changed over the last decades, no information is available on trends in incidence and outcome of chronic graft-versus-host disease (cGVHD) over time. This study used the central database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to describe time trends for cGVHD incidence, nonrelapse mortality, and risk factors for cGVHD. The 12-year period was divided into 3 intervals, 1995 to 1999, 2000 to 2003, and 2004 to 2007, and included 26,563 patients with acute leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. Multivariate analysis showed an increased incidence of cGVHD in more recent years (odds ratio = 1.19, P < .0001), and this trend was still seen when adjusting for donor type, graft type, or conditioning intensity. In patients with cGVHD, nonrelapse mortality has decreased over time, but at 5 years there were no significant differences among different time periods. Risk factors for cGVHD were in line with previous studies. This is the first comprehensive characterization of the trends in cGVHD incidence and underscores the mounting need for addressing this major late complication of transplantation in future research.

Acute toxicities of unrelated bone marrow versus peripheral blood stem cell donation: results of a prospective trial from the NMDP

Although peripheral blood stem cells (PBSCs) have replaced bone marrow (BM) as the most common unrelated donor progenitor cell product collected, a direct comparison of concurrent PBSC versus BM donation experiences has not been performed. We report a prospective study of 2726 BM and 6768 PBSC donors who underwent collection from 2004 to 2009. Pain and toxicities were assessed at baseline, during G-CSF administration, on the day of collection, within 48 hours of donation, and weekly until full recovery. Peak levels of pain and toxicities did not differ between the 2 donation processes for most donors. Among obese donors, PBSC donors were at increased risk of grade 2 to 4 pain as well as grade 2 to 4 toxicities during the pericollection period. In contrast, BM donors were more likely to experience grade 2 to 4 toxicities at 1 week and pain at 1 week and 1 month after the procedure. BM donors experienced slower recovery, with 3% still not fully recovered at 24 weeks, whereas 100% of PBSC donors had recovered. Other factors associated with toxicity included obesity, increasing age, and female sex. In summary, this study provides extensive detail regarding individualized risk patterns of PBSC versus BM donation toxicity, suggesting donor profiles that can be targeted with interventions to minimize toxicity.

Versican-Derived Matrikines Regulate Batf3–Dendritic Cell Differentiation and Promote T Cell Infiltration in Colorectal Cancer

Colorectal cancer originates within immunologically complex microenvironments. To date, the benefits of immunotherapy have been modest, except in neoantigen-laden mismatch repair–deficient tumors. Approaches to enhance tumor-infiltrating lymphocytes in the tumor bed may substantially augment clinical immunotherapy responses. In this article, we report that proteolysis of the tolerogenic matrix proteoglycan versican (VCAN) strongly correlated with CD8+ T cell infiltration in colorectal cancer, regardless of mismatch repair status. Tumors displaying active VCAN proteolysis and low total VCAN were associated with robust (10-fold) CD8+ T cell infiltration. Tumor-intrinsic WNT pathway activation was associated with CD8+ T cell exclusion and VCAN accumulation. In addition to regulating VCAN levels at the tumor site, VCAN proteolysis results in the generation of bioactive fragments with novel functions (VCAN-derived matrikines). Versikine, a VCAN-derived matrikine, enhanced the generation of CD103+CD11chiMHCIIhi conventional dendritic cells (cDCs) from Flt3L-mobilized primary bone marrow–derived progenitors, suggesting that VCAN proteolysis may promote differentiation of tumor-seeding DC precursors toward IRF8- and BATF3-expressing cDCs. Intratumoral BATF3-dependent DCs are critical determinants for T cell antitumor immunity, effector T cell trafficking to the tumor site, and response to immunotherapies. Our findings provide a rationale for testing VCAN proteolysis as a predictive and/or prognostic immune biomarker and VCAN-derived matrikines as novel immunotherapy agents.

Bioengineering Solutions for Manufacturing Challenges in CAR T Cells

The next generation of therapeutic products to be approved for the clinic is anticipated to be cell therapies, termed “living drugs” for their capacity to dynamically and temporally respond to changes during their production ex vivo and after their administration in vivo. Genetically engineered chimeric antigen receptor (CAR) T cells have rapidly developed into powerful tools to harness the power of immune system manipulation against cancer. Regulatory agencies are beginning to approve CAR T cell therapies due to their striking efficacy in treating some hematological malignancies. However, the engineering and manufacturing of such cells remains a challenge for widespread adoption of this technology. Bioengineering approaches including biomaterials, synthetic biology, metabolic engineering, process control and automation, and in vitro disease modeling could offer promising methods to overcome some of these challenges. Here, we describe the manufacturing process of CAR T cells, highlighting potential roles for bioengineers to partner with biologists and clinicians to advance the manufacture of these complex cellular products under rigorous regulatory and quality control.

Survival and Late Effects after Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancy at Less than Three Years of Age

Very young children undergoing hematopoietic cell transplantation (HCT) are a unique and vulnerable population. We analyzed outcomes of 717 patients from 117 centers who survived relapse free for ≥1 year after allogeneic myeloablative HCT for hematologic malignancy at <3 years of age, between 1987 and 2012. The median follow-up was 8.3 years (range, 1.0 to 26.4 years); median age at follow-up was 9 years (range, 2 to 29 years). Ten-year overall and relapse-free survival were 87% (95% confidence interval [CI], 85% to 90%) and 84% (95% CI, 81% to 87%). Ten-year cumulative incidence of relapse was 11% (95% CI, 9% to 13%). Of 84 deaths, relapse was the leading cause (43%). Chronic graft-versus-host-disease 1 year after HCT was associated with increased risk of mortality (hazard ratio [HR], 2.1; 95% CI, 1.3 to 3.3; Pu2009=u2009.0018). Thirty percent of patients experienced ≥1 organ toxicity/late effect >1 year after HCT. The most frequent late effects included growth hormone deficiency/growth disturbance (10-year cumulative incidence, 23%; 95% CI, 19% to 28%), cataracts (18%; 95% CI, 15% to 22%), hypothyroidism (13%; 95% CI, 10% to 16%), gonadal dysfunction/infertility requiring hormone replacement (3%; 95% CI, 2% to 5%), and stroke/seizure (3%; 95% CI, 2% to 5%). Subsequent malignancy was reported in 3.6%. In multivariable analysis, total body irradiation (TBI) was predictive of increased risk of cataracts (HR, 17.2; 95% CI, 7.4 to 39.8; Pu2009<u2009.001), growth deficiency (HR, 3.5; 95% CI, 2.2 to 5.5; Pu2009<u2009.001), and hypothyroidism (HR, 5.3; 95% CI, 3.0 to 9.4; Pu2009<u2009.001). In summary, those who survived relapse free ≥1 year after HCT for hematologic malignancy at <3 years of age had favorable overall survival. Chronic graft-versus-host-disease and TBI were associated with adverse outcomes. Future efforts should focus on reducing the risk of relapse and late effects after HCT at early age.

Significant Improvements in the Practice Patterns of Adult Related Donor Care in US Transplantation Centers

Recent investigations have found a higher incidence of adverse events associated with hematopoietic cell donation in related donors (RDs) who have morbidities that if present in an unrelated donor (UD) would preclude donation. In the UD setting, regulatory standards ensure independent assessment of donors, one of several crucial measures to safeguard donor health and safety. A survey conducted by the Center for International Blood and Marrow Transplant Research (CIBMTR) Donor Health and Safety Working Committee in 2007 reported a potential conflict of interest in >70% of US centers, where physicians had simultaneous responsibility for RDs and their recipients. Consequently, several international organizations have endeavored to improve practice through regulations and consensus recommendations. We hypothesized that the changes in the 2012 Foundation for the Accreditation of Cellular Therapy and the Joint Accreditation Committee-International Society for Cellular Therapy and European Society for Blood and Marrow Transplantation standards resulting from the CIBMTR study would have significantly impacted practice. Accordingly, we conducted a follow-up survey of US transplantation centers to assess practice changes since 2007, and to investigate additional areas where RD care was predicted to differ from UD care. A total of 73 centers (53%), performing 79% of RD transplantations in the United States, responded. Significant improvements were observed since the earlier survey; 62% centers now ensure separation of RD and recipient care (Pxa0<xa0.0001). This study identifies several areas where RD management does not meet international donor care standards, however. Particular concerns include counseling and assessment of donors before HLA typing, with 61%xa0centers first disclosing donor HLA results to an individual other than the donor, the use of unlicensed mobilization agents, and the absence of long-term donor follow-up. Recommendations for improvement arexa0made.

Corneal Mesenchymal Stromal Cells Are Directly Antiangiogenic via PEDF and sFLT-1

Purpose To evaluate the angiogenic properties of corneal derived mesenchymal stromal cells (Co-MSC). Methods Co-MSCs were extracted from human cadaver, and wild-type (C57BL/6J) and SERPINF1−/− mice corneas. The MSC secretome was collected in a serum-free medium. Human umbilical vein endothelial cell (HUVEC) tube formation and fibrin gel bead assay (FIBA) sprout formation were used to assess the angiogenic properties of Co-MSC secretome. Complete corneal epithelial debridement was used to induce corneal neovascularization in wild-type mice. Co-MSCs embedded in fibrin gel was applied over the debrided cornea to evaluate the angiogenic effects of Co-MSCs in vivo. Immunoprecipitation was used to remove soluble fms-like tyrosine kinase-1 (sFLT-1) and pigment epithelium-derived factor (PEDF, SERPINF1 gene) from the Co-MSC secretome. Results Co-MSC secretome significantly inhibited HUVECs tube and sprout formation. Co-MSCs from different donors consistently contained high levels of antiangiogenic factors including sFLT-1 and PEDF; and low levels of the angiogenic factor VEGF-A. In vivo, application of Co-MSCs to mouse corneas after injury prevented the development of corneal neovascularization. Removing PEDF or sFLT-1 from the secretome significantly diminished the antiangiogenic effects of Co-MSCs. Co-MSCs isolated from SERPINF1−/− mice had significantly reduced antiangiogenic effects compared to SERPINF1+/+ (wild-type) Co-MSCs. Conclusions These results illustrate the direct antiangiogenic properties of Co-MSCs, the importance of sFLT-1 and PEDF, and their potential clinical application for preventing pathologic corneal neovascularization.

Cornea‐Derived Mesenchymal Stromal Cells Therapeutically Modulate Macrophage Immunophenotype and Angiogenic Function

Macrophages are crucial drivers of inflammatory corneal neovascularization and thus are potential targets for immunomodulatory therapies. We hypothesized that therapeutic use of cornea‐derived mesenchymal stromal cells (cMSCs) may alter the function of macrophages. We found that cMSCs can modulate the phenotype and angiogenic function of macrophages. In vitro, cMSCs induce apoptosis of macrophages while preferentially promoting a distinct CD14hiCD16hiCD163hiCD206hi immunophenotype that has significantly reduced angiogenic effects based on in vitro angiogenesis assays. In vivo, application of cMSCs to murine corneas after injury leads to reduced macrophage infiltration and higher expression of CD206 in macrophages. Macrophages cocultured (“educated”) by cMSCs express significantly higher levels of anti‐angiogenic and anti‐inflammatory factors compared with control macrophages. In vivo, injured corneas treated with cMSC‐educated macrophages demonstrate significantly less neovascularization compared with corneas treated with control macrophages. Knocking down the expression of pigment epithelial derived factor (PEDF) in cMSCs significantly abrogates its modulating effects on macrophages, as shown by the reduced rate of apoptosis, decreased expression of sFLT‐1/PEDF, and increased expression of vascular endothelial growth factor‐A in the cocultured macrophages. Similarly, cMSCs isolated from PEDF knockout mice are less effective compared with wild‐type cMSCs at inhibiting macrophage infiltration when applied to wild‐type corneas after injury. Overall, these results demonstrate that cMSCs therapeutically suppress the angiogenic capacity of macrophages and highlight the role of cMSC secreted PEDF in the modulation of macrophage phenotype and function. Stem Cells 2018;36:775–784

Risk of acute myeloid leukemia and myelodysplastic syndrome after autotransplants for lymphomas and plasma cell myeloma

BACKGROUNDnExposures to DNA-damaging drugs and ionizing radiations increase risks of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).nnnMETHODSn9028 recipients of hematopoietic cell autotransplants (1995-2010) for Hodgkin lymphoma (HL; nu2009=u2009916), non-Hodgkin lymphoma (NHL; nu2009=u20093546) and plasma cell myeloma (PCM; nu2009=u20094566), reported to the CIBMTR, were analyzed for risk of subsequent AML or MDS.nnnRESULTSn335 MDS/AML cases were diagnosed posttransplant (3.7%). Variables associated with an increased risk for AML or MDS in multivariate analyses were: (1) conditioning with total body radiation versus chemotherapy alone for HL (HRu2009=u20094.0; 95% confidence interval [1.4, 11.6]) and NHL (HRu2009=u20092.5 [1.1, 2.5]); (2) ≥3 versus 1 line of chemotherapy for NHL (HRu2009=u20091.9 [1.3, 2.8]); and (3) subjects with NHL transplanted in 2005-2010 versus 1995-1999 (HRu2009=u20092.1 [1.5, 3.1]). Using Surveillance, Epidemiology and End Results (SEER) data, we found risks for AML/MDS in HL, NHL and PCM to be 5-10 times the background rate. In contrast, relative risks were 10-50 for AML and approximately 100 for MDS in the autotransplant cohort.nnnCONCLUSIONSnThere are substantial risks of AML and MDS after autotransplants for HL, NHL and PCM.

Donor body mass index does not predict graft versus host disease following hematopoietic cell transplantation

Correspondence: Donor body mass index does not predict graft versus host disease following hematopoietic cell transplantation