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.

Allogeneic Blood or Marrow Transplantation with Post-Transplantation Cyclophosphamide for Peripheral T Cell Lymphoma: The Importance of Graft Source.

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus host-disease (GVHD) prophylaxis has revolutionized allogeneic blood or marrow transplantation (alloBMT), but there is limited published experience in peripheral T cell lymphoma (PTCL). We sought to assess outcomes in patients with PTCL who underwent alloBMT with PTCy. We reviewed the charts of all adult patients age ≥18 years who underwent alloBMT with nonmyeloablative conditioning and PTCy-based GVHD prophylaxis at the Sidney Kimmel Comprehensive Cancer Center between January 2004 and December 2020. Sixty-five patients were identified. The median age was 59 years (range, 24 to 75 years). Lymphoma histology included PTCL not otherwise specified (n = 24), anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (n = 14), angioimmunoblastic T cell lymphoma (n = 7), enteropathy-associated T cell lymphoma (n = 6), hepatosplenic T cell lymphoma (n = 4), and others (n = 10). Eleven patients were in first complete remission (17%); the remaining patients were in first partial remission or underwent salvage therapy to at least PR prior to transplantation. Forty-eight patients underwent alloBMT from a haploidentical related donor (74%), 10 from a fully matched donor (15%), and 7 from a mismatched unrelated donor (11%). All patients received fludarabine, cyclophosphamide, and total body irradiation (TBI). The graft source was bone marrow (BM) in 46 patients (71%) and peripheral blood (PB) in 19 patients (29%); all patients in the BM cohort received 200 cGy TBI, and most patients in the PB cohort (15 of 19) received 400 cGy TBI. GVHD prophylaxis comprised PTCy, mycophenolate mofetil, and a calcineurin inhibitor or sirolimus. With a median follow-up of 2.8 years (range, 290 days to 14.2 years), the 2-year progression-free survival (PFS) for the entire cohort was 49% (95% confidence interval [CI], 38% to 64%), and the 2-year overall survival (OS) was 55% (95% CI, 44% to 69%). Outcomes were significantly improved in those receiving PB compared to those receiving BM, including a 2-year PFS of 79% (95% CI 63% to 100%) versus 39% (95% CI, 27% to 56%), 2-year OS of 84% (95% CI, 69% to 100%) versus 46% (95% CI, 33% to 63%), and 1-year cumulative incidence of relapse of 5% (95% CI, 0 to 16%) versus 33% (95% CI, 19% to 46%), with no difference in GVHD and nonrelapse mortality. AlloBMT with PTCy is safe and well-tolerated in patients with PTCL. Our data suggest that increasing the TBI dose to 400 cGy and using PB allografts may offer improved disease control and better survival outcomes, though additional studies are needed to confirm these findings.

Allogeneic haematopoietic cell transplant in patients with relapsed/refractory anaplastic large cell lymphoma.

The prognosis of relapsed/refractory (R/R) anaplastic large cell lymphoma (ALCL) is poor. Large studies evaluating outcomes of allogeneic haematopoietic cell transplantation (allo-HCT) in systemic R/R ALCL are not available. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we evaluated outcomes of 182 adults (aged ≥18 years) with R/R ALCL undergoing allo-HCT between 2008 and 2019. Non-relapse mortality (NRM), disease relapse/progression (REL), progression-free survival (PFS), and overall survival (OS) were modelled using Cox proportional hazards models. The median (range) follow-up of survivors was 62 (3-148) months. The 1-year NRM was 18%. The 5-year REL, PFS and OS were 32%, 41% and 56% respectively. On multivariable regression analysis African American race (hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.6-4.8; p < 0.001) and refractory disease at allo-HCT (HR 3.2, 95% CI 1.6-6.2; p < 0.001) were predictive of inferior OS. Similarly, African-American race (HR 2.1, 95% CI 1.3-3.4; p = 0.003), other minority race (HR 2.5, 95% CI 1.2-5.3; p = 0.02) and refractory disease (HR 2.2, 95% CI 1.2-4.3; p = 0.01) were predictive of inferior PFS. These data, demonstrate that allo-HCT can result in durable disease control in a sizable proportion of patients with R/R ALCL. Refractory disease and racial minority status predicted inferior allo-HCT outcomes. Whether the inferior outcomes of racial minorities with R/R ALCL after allo-HCT are driven by differences in disease biology or disparities in post allo-HCT care, or both, requires further investigation.

Allogeneic Blood or Marrow Transplantation with Nonmyeloablative Conditioning and High-Dose Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis for Secondary Central Nervous System Lymphoma.

Secondary central nervous system (CNS) lymphoma is a rare and often fatal complication of non-Hodgkin lymphoma (NHL). Treatment options include radiation therapy, high-dose systemic chemotherapy, intrathecal chemotherapy, and high-dose chemotherapy with autologous stem cell rescue, but outcomes remain poor. Allogeneic blood or marrow transplantation (alloBMT) is widely used in patients with relapsed/refractory systemic NHL. We sought to understand whether a graft-versus-lymphoma effect could maintain remission in CNS disease. We reviewed outcomes in 20 consecutive patients with secondary CNS lymphoma who underwent alloBMT with nonmyeloablative conditioning using fludarabine, cyclophosphamide, and 200 cGy total body irradiation. For graft-versus-host disease prophylaxis, all patients received post-transplantation cyclophosphamide, mycophenolate mofetil, and a calcineurin inhibitor. With a median follow up of 4.1 years, the median overall survival for the entire cohort was not reached. Median progression-free survival was 3.8 years (95% confidence interval [CI], 5.3 months to not reached). The cumulative incidence of relapse was 25% (95% CI, 5% to 45%), and nonrelapse mortality was 30% (95% CI, 5% to 54%) at 4 years. Of the 5 patients who relapsed, 2 were CNS only, 1 was systemic only, and 2 were combined CNS/systemic. The use of alloBMT in CNS lymphoma merits further investigation.

Harnessing the immune system after allogeneic stem cell transplant in acute myeloid leukemia.

Allogeneic stem cell transplantation (allo-SCT) is the most successful and widely used immunotherapy for the treatment of acute myeloid leukemia (AML), as a result of its anti-leukemic properties driven by T cells and natural killer (NK) cells, leading to a graft-vs-leukemia (GVL) effect. Despite its essential role in AML treatment, relapse after allo-SCT is common and associated with a poor prognosis. There is longstanding interest in developing immunologic strategies to augment the GVL effect post-transplant to prevent relapse and improve outcomes. In addition to prophylactic maintenance strategies, the GVL effect can also be used in relapsed patients to reinduce remission. While immune checkpoint inhibitors and other novel immune-targeted agents have been successfully used in the post-transplant setting to augment the GVL effect and induce remission in small clinical trials of relapsed patients, exacerbations of graft-vs-host disease (GVHD) have limited their broader use. Here we review advances in three areas of immunotherapy that have been studied in post-transplant AML: donor lymphocyte infusion (DLI), immune checkpoint inhibitors, and other monoclonal antibodies (mAbs), including antibody-drug conjugates (ADCs) and ligand receptor antagonists. We also discuss additional therapies with proposed immunologic mechanisms, such as hypomethylating agents, histone deacetylase inhibitors, and the FLT3 inhibitor sorafenib.

Endoscopic Endonasal Approach to Mesencephalic Cavernous Malformations.

BACKGROUND: Symptomatic cavernous malformations involving the brainstem are difficult to access by conventional approaches, which often require dramatic brain retraction to gain adequate operative corridor. Here, we present a successful endoscopic endonasal transclival approach for resection of a hemorrhagic, symptomatic mesencephalic cavernous malformation. CASE DESCRIPTION: A 20-year-old woman presented with acute onset of headache, nausea, and vomiting. Computed tomography scan revealed a ventral midbrain hemorrhage. On day 3 of admission, the patient developed left-sided hemiparesis, restriction of medial and lateral left-eye movements, and loss of left pupillary light reflex. Subsequent magnetic resonance imaging demonstrated an increase of the midbrain lesion to 1.2 cm × 1.7 cm. Diffusion tensor imaging showed compression and lateral displacement of the right corticospinal tract near the thalamus and cerebral peduncle. Given the patient's clinical presentation and the findings on imaging, we suspected a mesencephalic cavernous malformation. CONCLUSIONS: The patient underwent an endoscopic endonasal transclival resection of a ventral midline mesencephalon cavernous malformation. A dark red lesion was directly visualized under the endoscope. After a small cortiectomy, the pial and perforator vessels were dissected, and dark-brown blood was drained from the cavernoma cavity. Using a biopsy forceps and with careful attention to the cavernoma borders, the lesion was removed and hemostasis was achieved. Pathologic examination confirmed cavernous malformation. One week after the operation, magnetic resonance imaging demonstrated total resection of the lesion. A 3-month follow-up revealed improved neurologic symptoms with minimal surgical morbidity.

(1) H-NMR quantification of major saccharides in açaí raw materials: a comparison of the internal standard methodology with the absolute intensity qNMR method.

INTRODUCTION: While the use of internal standard methodology for qNMR is a proven and reliable form of quantification, simplified alternative approaches are needed. Agilent's absolute intensity qNMR utility software is a valuable alternative that has not yet been subjected to validation in the peer-reviewed literature. OBJECTIVE: To provide validation of Agilent's absolute intensity qNMR method with a specific application to natural product quantification by measuring saccharide content in açaí materials. METHODS: In order to validate the method, calibration test samples of ibuprofen were prepared in DMSO-d6 at nine different concentrations and measured with (1) H-NMR. A minimum of 40 spectra were collected for each sample, and the absolute intensity utility was used for quantification. The same methodology was then applied to the açaí materials, creating triplicates for each of the materials and using 3-(trimethylsilyl)-1-propanesulphonic acid sodium salt in water-d2 as both the solvent and internal standard. (1) H-NMR spectra were collected, and the amounts of glucose, sucrose and fructose were determined using both the internal standard approach and the absolute intensity qNMR method. RESULTS: Applying the absolute intensity utility to the ibuprofen samples demonstrated a linear response (R(2) = 0.99943). For the açaí investigations, results obtained from the absolute intensity method were comparable to those obtained from the internal standard approach, with percentage differences ranging from 0.5-6.2%. CONCLUSION: This study demonstrates the accuracy, precision and reliability of Agilent's absolute intensity qNMR method. In addition, practical information is provided for assessing the saccharide contents of açaí materials.