Methods and materials for treating t cell cancers

Nature

Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies 1, 2, 3, 4, 5, 6, 7, 8, 9. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival 10, 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 β-chain constant region 1 (TRBC1) can kill cancerous T cells while preserving sufficient healthy T cells to maintain immunity 12, 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 cells 13, 14. Here we demonstrate that CAR T cells are lost due to killing by the patient’s normal T …

Science Translational Medicine

We previously described an approach called RealSeqS to evaluate aneuploidy in plasma cell-free DNA through the amplification of ~350,000 repeated elements with a single primer. We hypothesized that an unbiased evaluation of the large amount of sequencing data obtained with RealSeqS might reveal other differences between plasma samples from patients with and without cancer. This hypothesis was tested through the development of a machine learning approach called Alu Profile Learning Using Sequencing (A-PLUS) and its application to 7615 samples from 5178 individuals, 2073 with solid cancer and the remainder without cancer. Samples from patients with cancer and controls were prespecified into four cohorts used for model training, analyte integration, and threshold determination, validation, and reproducibility. A-PLUS alone provided a sensitivity of 40.5% across 11 different cancer types in the …

DNA containing somatic mutations is highly tumor specific and thus, in theory, can provide optimum markers. However, the number of circulating mutant gene fragments is small compared to the number of normal circulating DNA fragments, making it difficult to detect and quantify them with the sensitivity required for meaningful clinical use. We apply a highly sensitive approach to quantify circulating tumor DNA (ctDNA) in body samples of patients. Measurements of ctDNA can be used to reliably monitor tumor dynamics in subjects with cancer, especially those who are undergoing surgery or chemotherapy. This personalized genetic approach can be generally applied.

ACR Open Rheumatology

A 28-year-old woman with history of systemic lupus erythematosus (SLE) since 2014 with previous involvement including arthritis, myositis, and cutaneous small vessel vasculitis, presented with two weeks of fever and rash. There were (A) 10 cm–diameter bullae on bilateral feet dorsa and vesicles on her elbows. White blood cell count was 13,900 cells/mm3, hemoglobin was 13.4 g/dL, and platelets were 317,000 cells/mm3. Erythrocyte sedimentation rate and C-reactive protein were elevated. Renal function and complement levels were normal. Anti-RNP IgG was> 644, anti-Sm IgG was 333 (reference range< 20). Antineutrophilic cytoplasmic antibody (ANCA), rheumatoid factor, cryoglobulins, and antiphospholipid antibodies were negative. Lupus anticoagulant was positive. She developed severe sequential vision loss during hospitalization.(B) Fundoscopy and (C) retinal imaging showed bilateral diffuse vascular …

AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O ([C@ H] 1C [C@@](O)(CC= 2C (O)= C3C (= O) C= 4C= CC= C (C= 4C (= O) C3= C (O) C= 21) OC) C (= O) CO)[C@ H] 1C [C@ H](N)[C@@ H](O)[C@ H](C) O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 6GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1= C (F) C (NC (= O) OCCCCC)= NC (= O) N1 [C@ H] 1 [C@ H](O)[C@ H](O)[C@@ H](C) O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 6

12Background: Adjuvant chemotherapy (CT) following neoadjuvant chemoradiation and surgery for locally advanced rectal cancer (LARC) is widely adopted, despite uncertain survival benefit. Circulating tumor DNA (ctDNA) detection after surgery has been shown to be a strong prognostic marker in localized colorectal cancer and potentially could inform adjuvant treatment decision making. Methods: AGITG DYNAMIC-Rectal is a multi-centre randomized controlled phase II trial. Eligible patients (pts) had LARC (cT3-4 and/or cN+) treated with neoadjuvant chemoradiation, total mesorectal excision, and were fit for adjuvant CT. Pts were randomly assigned 2:1 to ctDNA-guided management or standard management (clinician decision). A tumor-informed personalized ctDNA assay was used. For the ctDNA-guided group, a positive result at 4 and/or 7 weeks after surgery prompted 4 months of oxaliplatin-based or …

The identification of mutations that are present in a small fraction of DNA templates is essential for progress in several areas of biomedical research. Though massively parallel sequencing instruments are in principle well-suited to this task, the error rates in such instruments are generally too high to allow confident identification of rare variants. We here describe an approach that can substantially increase the sensitivity of massively parallel sequencing instruments for this purpose. One example of this approach, called “Safe-SeqS” for (Safe-Sequencing System) includes (i) assignment of a unique identifier (UID) to each template molecule;(ii) amplification of each uniquely tagged template molecule to create UID-families; and (iii) redundant sequencing of the amplification products. PCR fragments with the same UID are truly mutant (“super-mutants”) if≥ 95% of them contain the identical mutation. We illustrate the …

Cancer Research

Background: Chronic systemic inflammation mediated by pro-inflammatory cytokines serves as a major mechanism by which obesity contributes to cancer development. Paradoxically, elevated body mass (BMI) has been associated with improved outcomes after treatment with immune checkpoint inhibitors (ICIs) in many tumor types. The interplay between cytokine response and obesity after ICIs is poorly understood. To characterize underlying mechanisms, we investigated cytokine profiles in relation to obesity and clinical outcomes in patients treated with ICIs. Methods: From June 2021 to October 2022, we enrolled and collected blood samples from patients with advanced or metastatic solid tumors who received ICIs as standard of care at Johns Hopkins. We calculated BMI using height and weight at treatment initiation, with BMI ≥30 obese and BMI <30 non-obese. Underweight patients (BMI <18.5) were …

A method for classifying data using non-negative matrix factorization can include receiving a population of sample data, generating a first matrix of the amplicon counts per sample data, dividing the first matrix into a product of a second matrix and a third matrix, in the second matrix, determining whether each signature is a long or short fragment per each amplicon count, in the third matrix, determining intensities of each signature per the sample data, and classifying the sample data based on the intensities of each signature. The population can include amplicon counts per sample data. The second matrix can include signatures of short and long DNA fragments and the third matrix can include intensities of each signature of the short and long DNA fragments.

This document relates to methods and materials for treating T cell cancers. For example, a composition containing one or more bispecific molecules targeting T cell receptor É chain constant region (TRBC) can be administered to a mammal having a T cell cancer to treat the mammal. For example, this document provides methods and materials for using one or more bispecific molecules to treat a mammal having a T cell cancer.

AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O ([C@ H] 1C [C@@](O)(CC= 2C (O)= C3C (= O) C= 4C= CC= C (C= 4C (= O) C3= C (O) C= 21) OC) C (= O) CO)[C@ H] 1C [C@ H](N)[C@@ H](O)[C@ H](C) O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 6GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1= C (F) C (NC (= O) OCCCCC)= NC (= O) N1 [C@ H] 1 [C@ H](O)[C@ H](O)[C@@ H](C) O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 6

Science Translational Medicine

We previously described an approach called RealSeqS to evaluate aneuploidy in plasma cell-free DNA through the amplification of ~350,000 repeated elements with a single primer. We hypothesized that an unbiased evaluation of the large amount of sequencing data obtained with RealSeqS might reveal other differences between plasma samples from patients with and without cancer. This hypothesis was tested through the development of a machine learning approach called Alu Profile Learning Using Sequencing (A-PLUS) and its application to 7615 samples from 5178 individuals, 2073 with solid cancer and the remainder without cancer. Samples from patients with cancer and controls were prespecified into four cohorts used for model training, analyte integration, and threshold determination, validation, and reproducibility. A-PLUS alone provided a sensitivity of 40.5% across 11 different cancer types in the …

Rheumatology

DEAR EDITOR, We present the case of a 62-year-oldwoman with a previous diagnosis of biopsy-proven pulmonary sarcoidosis, not on treatment, who presented with eight months of progressive upper and lower extremity weakness, gait instability, and falls. She endorsed difficulty with overhead movement, hand dexterity, and climbing stairs. She had swelling and pain in her shoulders and knees. Her strength was 2/5 at neck flexors, 4/5 at arm abductors, 4-/5 at right finger flexors and 3/5 at left, 4-/5 at hip flexors, 4/5 at right knee extensors and 4-/5 at left, and 3/5 at ankle dorsiflexors. Her gait was narrow and canedependent. Her musculoskeletal examination showed a left knee effusion, bilateral shoulder tenderness, and left wrist fracture following a fall. Lungs were clear to auscultation. Examination was otherwise unremarkable. Laboratory evaluation was notable for elevated calcium of 14mg/dl, low 25-OH vitamin …

Nature

Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies 1, 2, 3, 4, 5, 6, 7, 8, 9. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival 10, 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 β-chain constant region 1 (TRBC1) can kill cancerous T cells while preserving sufficient healthy T cells to maintain immunity 12, 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 cells 13, 14. Here we demonstrate that CAR T cells are lost due to killing by the patient’s normal T …

DNA containing somatic mutations is highly tumor specific and thus, in theory, can provide optimum markers. However, the number of circulating mutant gene fragments is small compared to the number of normal circulating DNA fragments, making it difficult to detect and quantify them with the sensitivity required for meaningful clinical use. We apply a highly sensitive approach to quantify circulating tumor DNA (ctDNA) in body samples of patients. Measurements of ctDNA can be used to reliably monitor tumor dynamics in subjects with cancer, especially those who are undergoing surgery or chemotherapy. This personalized genetic approach can be generally applied.

A method for classifying data using non-negative matrix factorization can include receiving a population of sample data, generating a first matrix of the amplicon counts per sample data, dividing the first matrix into a product of a second matrix and a third matrix, in the second matrix, determining whether each signature is a long or short fragment per each amplicon count, in the third matrix, determining intensities of each signature per the sample data, and classifying the sample data based on the intensities of each signature. The population can include amplicon counts per sample data. The second matrix can include signatures of short and long DNA fragments and the third matrix can include intensities of each signature of the short and long DNA fragments.

12Background: Adjuvant chemotherapy (CT) following neoadjuvant chemoradiation and surgery for locally advanced rectal cancer (LARC) is widely adopted, despite uncertain survival benefit. Circulating tumor DNA (ctDNA) detection after surgery has been shown to be a strong prognostic marker in localized colorectal cancer and potentially could inform adjuvant treatment decision making. Methods: AGITG DYNAMIC-Rectal is a multi-centre randomized controlled phase II trial. Eligible patients (pts) had LARC (cT3-4 and/or cN+) treated with neoadjuvant chemoradiation, total mesorectal excision, and were fit for adjuvant CT. Pts were randomly assigned 2:1 to ctDNA-guided management or standard management (clinician decision). A tumor-informed personalized ctDNA assay was used. For the ctDNA-guided group, a positive result at 4 and/or 7 weeks after surgery prompted 4 months of oxaliplatin-based or …

Advances in gene, protein and cellular engineering provide unprecedented opportunities to redirect immune cells to treat autoimmunity. In 2023, novel cellular and precision immunotherapies showed remarkable promise in the treatment of rheumatic diseases.