Regression of renal cell carcinoma by T cell receptor-engineered T cells targeting a human endogenous retrovirus.

BACKGROUND: We discovered a novel human endogenous retrovirus (CT-RCC HERV-E) that was selectively expressed in most clear cell renal cell carcinomas (ccRCC) and served as a source of antigens for T cell-mediated killing. Here, we described the cloning of a novel T cell receptor (TCR) targeting a CT-RCC HERV-E-derived antigen specific to ccRCC and characterized antitumor activity of HERV-E TCR-transduced T cells (HERV-E T cells). METHODS: We isolated a CD8+ T cell clone from a patient with immune-mediated regression of ccRCC post-allogeneic stem cell transplant that recognized the CT-RCC-1 HERV-E-derived peptide in an HLA-A11-restricted manner. We used 5'Rapid Amplification of cDNA Ends (RACE) to clone the full length HERV-E TCR and generated retrovirus encoding this TCR for transduction of T cells. We characterized HERV-E T cells for phenotype and function in vitro and in a murine xenograft model. Lastly, we implemented a good manufacturing practice-compliant method for scalable production of HERV-E T cells. RESULTS: The HLA-A11-restricted HERV-E-reactive TCR exhibited a CD8-dependent phenotype and demonstrated specific recognition of the CT-RCC-1 peptide. CD8+ T cells modified to express HERV-E TCR displayed potent antitumor activity against HLA-A11+ ccRCC cells expressing CT-RCC HERV-E compared with unmodified T cells. Killing by HERV-E T cells was lost when cocultured against HERV-E knockout ccRCC cells. HERV-E T cells induced regression of established ccRCC tumors in a murine model and improved survival of tumor-bearing mice. Large-scale production of HERV-E T cells under good manufacturing practice conditions generated from healthy donors retained specific antigen recognition and cytotoxicity against ccRCC. CONCLUSIONS: This is the first report showing that human ccRCC cells can be selectively recognized and killed by TCR-engineered T cells targeting a HERV-derived antigen. These preclinical findings provided the foundation for evaluating HERV-E TCR-transduced T cell infusions in patients with metastatic ccRCC in a clinical trial (NCT03354390).

Structural Bone Grafting with Reverse Shoulder Arthroplasty for Osteoarthritis with Severe Glenoid Bone Loss: outcomes using a long post.

INTRODUCTION: Severe posterior glenoid bone loss with glenohumeral osteoarthritis with an intact rotator cuff can be managed with reverse shoulder arthroplasty but requires lateralization and version correction to avoid potential complications, such as instability, notching and implant failure. Angled bone grafting with humeral head autograft can provide durable glenoid bone stock, but results have been mixed. The purpose of this study was to evaluate patient-reported and objective outcomes as well as complication and failure rates for patients who underwent angled humeral head autografting for severe retroversion. METHODS: All patients who underwent a primary RSA with angled humeral head autograft and Stryker Tornier long central post baseplate for severe glenoid bone loss in the setting of glenohumeral osteoarthritis with an intact rotator cuff at our institution between November 2018 and February of 2022 were identified. Individuals with a primary diagnosis of osteoarthritis and preoperative glenoid retroversion of ≥30° were included. Patients undergoing revision procedures, planned two-stage arthroplasty were excluded. Differences in pre- and postoperative range of motion, as well as patient-reported outcomes were assessed. Intraoperative complications, postoperative complications, and re-operation rates were analyzed. RESULTS: A total of 24 shoulders in 23 patients (61% male), with a mean age of 65.6 years were included. Average preoperative retroversion was 37.4° (range: 30° - 51°). Mean follow-up was 2.9 years (range: 2 - 4.3 years). Significant improvements were found in flexion, abduction, and external rotation. Patient-reported subjective outcomes were excellent, with average ASES score of 93.6 and average SSV 93.8%. Sixteen (67%) shoulders received postoperative CT scans and all were found to have incorporated. Complications included one shoulder hematoma requiring incision and drainage without revision, and a post-traumatic fracture of the inferior glenoid screw at 11 months, requiring revision RSA with bone grafting. No atraumatic catastrophic failures occurred due to component loosening. CONCLUSION: This study suggests that using angled humeral head bone grafting is a good solution for version correction in extreme posterior glenoid bone loss. Significant improvements are reported in ROM, pain, and subjective functional scores, with excellent graft incorporation rates and a low complication profile at early follow-up. Further work should focus on gathering higher levels of evidence, detailed radiographic analyses and exploring humeral head bone grafting for other indications.

Total Wrist Arthroplasty as a Motion-Sparing Option for Distal Radius Malunion in a Patient of Advanced Age: A Case Report.

CASE: A 62-year-old woman presented with wrist pain secondary to a distal radius fracture malunion 4 months after a fall onto an outstretched hand. She was not an ideal candidate for osteotomy and bone graft because of the degree of displacement and osteoporosis, so after nonoperative treatment was unsuccessful, she was offered total wrist arthroplasty (TWA) or arthrodesis and opted for TWA. CONCLUSION: At 14-month follow-up, the patient reported significant improvement in her pain and function. The current generation of TWA implants may allow use in the management of symptomatic distal radius malunions in older, low-demand patients.

New-Onset Post-Transplant Diabetes Mellitus after Allogeneic Hematopoietic Cell Transplant Is Initiated by Insulin Resistance, Not Immunosuppressive Medications.

New-onset post-transplant diabetes mellitus (PTDM) occurs frequently after allogeneic hematopoietic cell transplant (HCT). Although calcineurin inhibitors and corticosteroids are assumed to be the cause for hyperglycemia, patients developing PTDM have elevated fasting C-peptide levels before HCT and before immunosuppressive medications. To determine if PTDM results from established insulin resistance present before transplant, we performed oral glucose tolerance tests (OGTTs) and measured whole body, peripheral, and hepatic insulin sensitivity with euglycemic hyperinsulinemic clamps before and 90 days after HLA-identical sibling donor HCT in 20 patients without pretransplant diabetes. HCT recipients were prospectively followed for the development of new-onset PTDM defined as a weekly fasting blood glucose ≥ 126 mg/dL or random blood glucose ≥ 200 mg/dL. During the first 100 days all patients received calcineurin inhibitors, and 11 individuals (55%) were prospectively diagnosed with new-onset PTDM. PTDM diagnosis preceded corticosteroid treatment. During the pretransplant OGTT, elevated fasting (87 mg/dL versus 101 mg/dL; P = .005) but not 2-hour postprandial glucose levels predicted PTDM diagnosis (P = .648). In response to insulin infusion during the euglycemic hyperinsulinemic clamp, patients developing PTDM had lower whole body glucose utilization (P = .047) and decreased peripheral/skeletal muscle uptake (P = .031) before and after transplant, respectively, when compared with non-PTDM patients. Hepatic insulin sensitivity did not differ. Survival was decreased in PTDM patients (2-year estimate, 55% versus 100%; P = .039). Insulin resistance before HCT is a risk factor for PTDM independent of immunosuppression. Fasting pretransplant glucose levels identified PTDM susceptibility, and peripheral insulin resistance could be targeted for prevention and treatment of PTDM after HCT.