TRBC1-targeting antibody-drug conjugates for the treatment of T cell cancers.

Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies1-9. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival10,11 and lack such targeted therapies. Thus, T cell cancers particularly warrant the development of CAR T cells and antibodies to improve patient outcomes. Preclinical studies showed that targeting T cell receptor ß-chain constant region 1 (TRBC1) can kill cancerous T cells while preserving sufficient healthy T cells to maintain immunity12, making TRBC1 an attractive target to treat T cell cancers. However, the first-in-human clinical trial of anti-TRBC1 CAR T cells reported a low response rate and unexplained loss of anti-TRBC1 CAR T cells13,14. Here we demonstrate that CAR T cells are lost due to killing by the patient's normal T cells, reducing their efficacy. To circumvent this issue, we developed an antibody-drug conjugate that could kill TRBC1+ cancer cells in vitro and cure human T cell cancers in mouse models. The anti-TRBC1 antibody-drug conjugate may provide an optimal format for TRBC1 targeting and produce superior responses in patients with T cell cancers.

Mortality Rate and Outcomes of Omicron Variant Positive Patients with Osteoporotic Fractures: A Retrospective Study.

BACKGROUND: During the lockdown period associated with the coronavirus disease 2019 (COVID-19) pandemic, increased mortality rates among patients with COVID-19 have been reported. This study aimed to analyze the mortality rate of osteoporotic hip fractures in patients who were COVID-19-positive after the lockdown during the Omicron period. METHODS: A retrospective study was performed with 194 patients who were aged 70 years or more and diagnosed with osteoporotic hip fracture. The patients were divided into two groups according to their COVID-19 diagnoses. Surgery was performed within 10 days of diagnosis. Age, sex, past medical history, time until surgery, postoperative complications, and the primary outcome of mortality rate at 30 and 90 days were analyzed. RESULTS: Among the 194 patients, 13 and 181 were in the COVID-19-positive and negative group, respectively. The total, 30-day, and 90-day mortality rates in the control and COVID-positive group were 11% and 0% (P=0.368), 1.7% and 0% (P=1.000), and 5.0% and 0% (P=1.000), respectively. No significant differences were observed in age, sex, history, time to surgery, postoperative complications, or postoperative mortality. In 1:1 propensity score matching, the time to surgery was 5.34 days in patients who were COVID-19-positive, and 3.00 days in patients who were COVID-19 negative, with no statistical significance (P=0.09). Age, sex, medical history, postoperative complications, and postoperative mortality were not significantly different between the groups. CONCLUSIONS: Regardless of the COVID-19 diagnosis, surgical treatment without delay is believed to result in positive outcomes in older patients with osteoporotic hip fractures, as no significant differences in mortality rate and respiratory complications were observed between patients who were COVID-19-positive and those who were COVID-19 negative.

Comparative analysis of superior capsule reconstruction between long head of biceps tendon autograft and human dermis allograft.

BACKGROUND: Although many superior capsule reconstruction (SCR) techniques are currently practiced in clinical settings, guidelines for choosing the appropriate graft material are lacking. Therefore, at most times, the surgeon's personal preference becomes the deciding factor. This study compared 2 fairly recent SCR techniques-SCR with biceps tendon (BT) autograft and SCR with human dermis (HD) allograft-by evaluating clinical and radiologic outcomes to aid the surgeon's decision in choosing the appropriate graft. METHODS: Thirty-one patients underwent SCR using BT autograft (SCR BT), and 22 underwent SCR using HD allograft (SCR HD). SCR BT was selected for patients with a partial BT tear <20%, no severe inflammation signs, and favorable anchor conditions. SCR HD was performed in patients with a BT tear >20%, a superior labrum anterior-posterior (SLAP) lesion, severe inflammation, or subluxation. Range of motion (ROM), strength and shoulder function scoring, plain radiography, and magnetic resonance imaging were evaluated before and after surgery at regular intervals. RESULTS: In the SCR BT group, forward flexion ROM increased from 122° ± 43° to 149° ± 18° at 2 years postoperatively, whereas in the SCR HD group, forward flexion ROM improved from 129° ± 28° to 149° ± 18°. In the SCR BT group, internal rotation (IR) ROM increased from 5 ± 3 to 6 ± 2 at 2 years postoperatively, whereas in the SCR HD group, IR ROM improved from 5 ± 3 to 6 ± 1. Although ROM, strength, visual analog scale score, American Shoulder and Elbow Surgeons score, and Constant score all improved 2 years after surgery, no statistically significant differences were found. Six months after surgery, graft thickness was 3.58 ± 0.384 mm in the SCR BT group and 2.49 ± 0.326 mm in the SCR HD group (P < .001). At 2 years postoperatively, graft thickness was 3.54 ± 0.399 mm in the SCR BT group and 2.49 ± 0.306 mm in the SCR HD group (P < .001). The SCR HD group showed a negative correlation of -0.475 between graft thickness and IR ROM (P = .026). In the SCR BT group, a negative correlation of -0.466 was found between graft thickness and IR ROM (P = .008). A positive correlation of 0.363 was found between IR ROM and the acromiohumeral distance when the results were compared before and 2 years after surgery (P = .045). CONCLUSION: Both SCR using BT autograft and SCR using HD allograft tissue showed favorable results, and no significant difference was noted between the 2 techniques. Given that the 2 techniques show equally favorable results, the surgeon's personal preference in choosing the SCR technique appears to be acceptable. Understanding the costs and patient's characteristics may aid the surgeon in deciding on the graft material.

Identification of nonsense-mediated decay inhibitors that alter the tumor immune landscape.

Despite exciting developments in cancer immunotherapy, its broad application is limited by the paucity of targetable antigens on the tumor cell surface. As an intrinsic cellular pathway, nonsense- mediated decay (NMD) conceals neoantigens through the destruction of the RNA products from genes harboring truncating mutations. We developed and conducted a high throughput screen, based on the ratiometric analysis of transcripts, to identify critical mediators of NMD. This screen revealed disruption of kinase SMG1's phosphorylation of UPF1 as a potent disruptor of NMD. This led us to design a novel SMG1 inhibitor, KVS0001, that elevates the expression of transcripts and proteins resulting from truncating mutations in vivo and in vitro . Most importantly, KVS0001 concomitantly increased the presentation of immune-targetable HLA class I-associated peptides from NMD-downregulated proteins on the surface of cancer cells. KVS0001 provides new opportunities for studying NMD and the diseases in which NMD plays a role, including cancer and inherited diseases. One Sentence Summary: Disruption of the nonsense-mediated decay pathway with a newly developed SMG1 inhibitor with in-vivo activity increases the expression of T-cell targetable cancer neoantigens resulting from truncating mutations.