J Clin Oncol
PURPOSE: The rho-associated coiled-coil-containing protein kinase-2 (ROCK2) signaling pathway regulates the Th17/regulatory T cells balance and controls profibrotic pathways. Selective ROCK2 inhibition with belumosudil (KD025) may offer a novel approach to the management of chronic graft-versus-host disease (cGVHD). PATIENTS AND METHODS: A phase IIa, open-label, dose-finding study of belumosudil enrolled 54 patients with cGVHD who had received one to three prior lines of therapy (LOTs). The primary end point was overall response rate (ORR). RESULTS: The median time from cGVHD diagnosis to enrollment was 20 months. Seventy-eight percent of patients had severe cGVHD, 50% had 4 organs involved, 73% had cGVHD refractory to their last LOT, and 50% had received 3 prior LOTs. With an overall median follow-up of 29 months, the ORR (95% CI) with belumosudil 200 mg once daily, 200 mg twice daily, and 400 mg once daily was 65% (38% to 86%), 69% (41% to 89%), and 62% (38% to 82%), respectively. Responses were clinically meaningful, with a median duration of response of 35 weeks, and were associated with quality-of-life improvements and corticosteroid (CS) dose reductions. CS treatment was discontinued in 19% of patients. The failure-free survival rate was 76% (62% to 85%) and 47% (33% to 60%) at 6 and 12 months, respectively. The 2-year overall survival rate was 82% (69% to 90%). Belumosudil was well-tolerated, with low rates of cytopenia. There were no unexpected adverse events and no apparent increased risk of infection, including cytomegalovirus infection and reactivation. CONCLUSION: Belumosudil treatment resulted in a high ORR and overall survival rate and demonstrated quality-of-life improvements, CS dose reductions, and limited toxicity. Data from the study indicated that belumosudil may prove to be an effective therapy for patients with treatment-refractory cGVHD.
Bone Marrow Transplant
Allogeneic hematopoietic stem cell transplantation (HSCT) recipients often experience deficits in positive psychological well-being (PPWB) due to intensive treatment and follow-up care. Positive psychology interventions (PPIs) that promote PPWB via deliberate and systematic exercises (e.g., writing a gratitude letter) have consistently improved PPWB in medical populations, yet have never been studied in early HSCT recovery. In this single-arm, proof-of-concept study, we assessed the feasibility and acceptability of a novel eight-session, telephone-delivered PPI in early HSCT recovery. A priori, we defined feasibility as >50% of eligible patients enrolling in the study and >50% of participants completing 5/8 sessions, and acceptability as mean ease and utility scores of weekly participant ratings of PP exercises as 7/10. Of 45 eligible patients, 25 (55.6%) enrolled, 20 (80%) completed baseline assessments, 15 (75%) started the intervention, and 12 (60%) completed the intervention and follow-up assessments. The intervention was feasible (55.6% of eligible participants enrolled; 60% of baseline assessment completers finished 5/8 sessions) and led to very small-to-medium effect-size improvements in patient-reported outcomes. A novel, eight-week, telephone-delivered PPI was feasible and acceptable in allogeneic HSCT recipients. Larger, randomized studies are needed to examine the efficacy of PPIs for improving outcomes in this population.
Transplant Cell Ther
BACKGROUND: Minor histocompatibility antigens (mHA), which are recipient derived peptide epitopes presented on the cell surface, are known to mediate GVHD; however, there are no current methods to associate mHA features with GVHD risk. This deficiency is due in part to the lack of technological means to accurately predict, let alone confirm, the tremendous number of potential mHA in each individual transplant. Prior studies have shown that different HLA molecules present varying fractions of candidate peptide epitopes; however, the genetic "distance" between HLA matched donors and recipients is relatively constrained. From these two observations it is possible that the HLA type for a donor / recipient pair would provide a surrogate measurement of the number of predicted mHA, which could relate to GVHD risk OBJECTIVE: Because different HLA molecules present variable numbers of peptide antigens, a predicted cumulative peptide binding efficiency can be calculated for individual donor / recipient pairs (DRPs) based upon the pair's HLA type. The purpose of this study was to test if cumulative peptide binding efficiency was associated with risk of acute GVHD (aGVHD) or relapse. STUDY DESIGN: This retrospective CIBMTR study evaluated a total of 3242 HLA matched DRPs were analyzed for predicted cumulative peptide binding efficiency using their HLA types and were divided into tertiles based upon their score. Univariable and multivariable analyses was performed to test for associations between cumulative peptide binding efficiency for DRPs, divided in the HLA-matched related (MRD) and HLA-matched unrelated (MUD) cohorts, and the primary outcomes of aGVHD and relapse. Secondary outcomes investigated included overall survival (OS), disease free survival (DFS) and treatment related mortality (TRM). RESULTS: Using a computationally generated peptidome as a test dataset, the tested series of HLA class I displayed peptide binding frequencies ranging from 0.1% to 3.8% of the full peptideone, and HLA class II molecules had peptide binding frequencies of 12% to 77% across the HLA-DRB1 allotypes. By increasing binding efficiency tertile, the cumulative incidence of aGVHD at 6 months for MUD patients was 41%, 41% and 45% for HLA class I (p=0.336) and 44%, 41% and 42% for HLA class II (p=0.452). The cumulative incidence of relapse at 3 years for MUD patients was 36%, 38%, and 38% for HLA class I (p=0.533) and 37%, 37% and 38% for HLA class II (p=0.896). The findings were similar for MRD patients. Multivariable analysis did not identify any impact of peptide binding efficiency on aGVHD or relapse for MUD or MRD patients CONCLUSION: While GVHD is mediated by minor antigen mismatches in the context of HLA-matched allo-HCT, peptide binding efficiency, which was used as a surrogate measurement for predicted number of binding antigens, did not provide additional clinical information for GVHD risk assessment. The negative result may be due to the limitations of this surrogate marker or it is possible that GVHD is driven by a subset of immunogenic mHA. Further research should be directed into direct mHA epitope and immunogenicity prediction.
Bone Marrow Transplant
Acute myeloid leukemia (AML) patients often undergo allogeneic hematopoietic cell transplantation (alloHCT) in first complete remission (CR). We examined the effect of depth of clinical response, including incomplete count recovery (CRi) and/or measurable residual disease (MRD), in patients from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry. We identified 2492 adult patients (1799 CR and 693 CRi) who underwent alloHCT between January 1, 2007 and December 31, 2015. The primary outcome was overall survival (OS). Multivariable analysis was performed to adjust for patient-, disease-, and transplant-related factors. Baseline characteristics were similar. Patients in CRi compared to those in CR had an increased likelihood of death (HR: 1.27; 95% confidence interval: 1.13-1.43). Compared to CR, CRi was significantly associated with increased non-relapse mortality (NRM), shorter disease-free survival (DFS), and a trend toward increased relapse. Detectable MRD was associated with shorter OS, shorter DFS, higher NRM, and increased relapse compared to absence of MRD. The deleterious effects of CRi and MRD were independent. In this large CIBMTR cohort, survival outcomes differ among AML patients based on depth of CR and presence of MRD at the time of alloHCT. Further studies should focus on optimizing post-alloHCT outcomes for patients with responses less than CR.
Annu Rev Biomed Eng
Gene therapy makes it possible to engineer chimeric antigen receptors (CARs) to create T cells that target specific diseases. However, current approaches require elaborate and expensive protocols to manufacture engineered T cells ex vivo, putting this therapy beyond the reach of many patients who might benefit. A solution could be to program T cells in vivo. Here, we evaluate the clinical need for in situ CAR T cell programming, compare competing technologies, review current progress, and provide a perspective on the long-term impact of this emerging and rapidly flourishing biotechnology field. Expected final online publication date for the Annual Review of Biomedical Engineering, Volume 23 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
J Clin Oncol
We studied mucosal immune responses in six HIV-1 vaccine trials investigating different envelope (Env)-containing immunogens. Regimens were classified into four categories: DNA/vector, DNA/vector plus protein, protein alone, and vector alone. We measured HIV-1-specific IgG and IgA in secretions from cervical (n = 111) and rectal swabs (n = 154), saliva (n = 141), and seminal plasma (n = 124) and compared to corresponding blood levels. Protein-containing regimens had up to 100% response rates and the highest Env-specific IgG response rates. DNA/vector groups elicited mucosal Env-specific IgG response rates of up to 67% that varied across specimen types. Little to no mucosal IgA responses were observed. Overall, gp41- and gp140-specific antibodies dominated gp120 mucosal responses. In one trial, prior vaccination with a protein-containing immunogen maintained durability of cervical and rectal IgG for up to 17 years. Mucosal IgG responses were boosted after revaccination. These findings highlight a role for protein immunization in eliciting HIV-1-specific mucosal antibodies and the ability of HIV-1 vaccines to elicit durable HIV-1-specific mucosal IgG.
Data are limited regarding risk factors for lower respiratory tract infection (LRTI) caused by seasonal human coronaviruses (HCoVs) and the significance of virologic documentation by bronchoalveolar lavage (BAL) on outcomes in hematopoietic cell transplant (HCT) recipients. We retrospectively analyzed patients undergoing allogeneic HCT (4/2008-9/2018) with HCoV (OC43/NL63/HKU1/229E) detected by polymerase chain reaction during conditioning or post-HCT. Risk factors for all manifestations of LRTI and progression to LRTI among those presenting with HCoV upper respiratory tract infection (URTI) were analyzed by logistic regression and Cox proportional hazard models, respectively. Mortality rates following HCoV LRTI were compared according to virologic documentation by BAL. A total of 297 patients (61 children and 236 adults) developed HCoV infection as follows: 254 had URTI alone, 18 presented with LRTI, and 25 progressed from URTI to LRTI (median, 16 days; range, 2-62 days). Multivariable logistic regression analyses showed that male sex, higher immunodeficiency scoring index, albumin <3 g/dL, glucose >150 mg/dL, and presence of respiratory copathogens were associated with occurrence of LRTI. Hyperglycemia with steroid use was associated with progression to LRTI (P < .01) in Cox models. LRTI with HCoV detected in BAL was associated with higher mortality than LRTI without documented detection in BAL (P < .01). In conclusion, we identified factors associated with HCoV LRTI, some of which are less commonly appreciated to be risk factors for LRTI with other respiratory viruses in HCT recipients. The association of hyperglycemia with LRTI might provide an intervention opportunity to reduce the risk of LRTI.
Clin Cancer Res
PURPOSE: Enzalutamide is a second-generation androgen receptor (AR) inhibitor which has improved overall survival (OS) in metastatic castration resistant prostate cancer (CRPC). However, nearly all patients develop resistance. We designed a phase 2 multicenter study of enzalutamide in metastatic CRPC incorporating tissue and blood biomarkers to dissect mechanisms driving resistance. EXPERIMENTAL DESIGN: Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy and then initiated enzalutamide 160 mg daily. A repeat metastasis biopsy was obtained at radiographic progression from the same site when possible. Blood for circulating tumor cell (CTC) analysis was collected at baseline and progression. The primary objective was to analyze mechanisms of resistance in serial biopsies. Whole exome sequencing was performed on tissue biopsies. CTC samples underwent RNA sequencing. RESULTS: 65 patients initiated treatment, of whom 22 (33.8%) had received prior abiraterone. Baseline biopsies were enriched for alterations in AR (mutations, amplifications) and tumor suppression genes (PTEN, RB1, and TP53) which were observed in 73.1% and 92.3% of baseline biopsies, respectively. Progression biopsies revealed increased AR amplifications (64.7% at progression versus 53.9% at baseline) and BRCA2 alterations (64.7% at progression versus 38.5% at baseline). Genomic analysis of baseline and progression CTC samples demonstrated increased AR splice variants, AR regulated-genes, and neuroendocrine markers at progression. CONCLUSIONS: Our results demonstrate that a large proportion of enzalutamide-treated patients have baseline and progression alterations in the AR pathway and tumor suppressor genes. We demonstrate an increased number of BRCA2 alterations post-enzalutamide highlighting importance of serial tumor sampling in CRPC.
Am J Clin Oncol
PURPOSE: As patients with mediastinal lymphoma are typically young with curable disease, advanced radiation techniques such as proton therapy are often considered to minimize subacute and late toxicity. However, it is unclear which mediastinal lymphoma patients are treated with proton therapy. Within a prospective, multi-institutional proton registry, we characterized mediastinal lymphoma patients treated with proton therapy and assessed concordance with consensus recommendations published in 2018 by the International Lymphoma Radiation Oncology Group (ILROG). METHODS: Eligible patients included those with lymphoma of the mediastinum treated exclusively with proton therapy for whom digital imaging and communications in medicine (DICOM) treatment data were available for review. Given the challenge with reliably visualizing the left mainstem coronary artery, the inferior-most aspect of the left pulmonary artery (PA) was used as a surrogate. Extent of disease was characterized as upper mediastinum (above level of left PA), middle mediastinum (below left PA but at or above level of T8), or low mediastinum (below T8). RESULTS: Between November 2012 and April 2019, 56 patients were treated and met inclusion criteria. Patients treated with proton therapy were young (median, 24y; range: 12 to 88), with over half being female (55%). Patients were most commonly treated at initial diagnosis (86%) and had Hodgkin lymphoma (79%). Most patients (96%) had mediastinal disease that extended down to the level of the heart: 48% had middle and 48% had low mediastinal involvement. Nearly all patients (96%) met the ILROG consensus recommendations: 95% had lower mediastinal disease, 46% were young females, and 9% were heavily pretreated. Heart (mean) and lung dose (mean, V5, V20) were significantly associated with lowest extent of mediastinal disease. CONCLUSIONS: Mediastinal lymphoma patients treated with proton therapy are typically young with lower mediastinal involvement. Within a prospective, multi-institutional proton registry, nearly all treated patients fit the ILROG consensus recommendations regarding which mediastinal lymphoma patients may most benefit from proton therapy.