Welche Chancen bietet die Immunonkologie für ein indikationsübergreifendes Langzeitüberleben?

Tumore nutzen verschiedene Escape-Mechanismen, um das körpereigene Immunsystem zu überlisten und sich gegenüber der Tumor-Immunabwehr durchzusetzen: Die Erkenntnis, dass sie immunregulative Moleküle wie z.B. CTLA-4 (Cytotoxic T Lymphocyte Antigen 4) oder PD-1 (programmed cell death 1) sowie deren Liganden PD-L1/PD-L2 instrumentalisieren können, um der Immunüberwachung zu entkommen (immune escape), hat einen vollständig neuen Therapiezugang für die Onkologie eröffnet..

Dual targeting of CD19 and CD22 with Bicistronic CAR-T cells in Patients with Relapsed/Refractory Large B Cell Lymphoma

Relapse following CD19-directed chimeric antigen receptor T-cells (CAR-T) for relapsed/refractory large B-cell lymphoma (r/r LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multi-antigen targeting and PD-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in r/r LBCL as inpatient or outpatient therapy (NCT03289455, https://clinicaltrials.gov/ct2/show/NCT03289455). Endpoints include toxicity (primary) and response rates (secondary). AUTO3 was manufactured for 62 patients using autologous leukapheresis, modified with a bicistronic transgene. 52 patients received AUTO3 (7/52,50x106; 45/52,150-450x106) and 48/52 received pembrolizumab. Median age was 59 years (range,27-83) and 46/52 had stage III/IV disease. Median follow-up was 21.6 months (range,15.1-51.3) at last data cut (Feb 28, 2022). AUTO3 was safe: grade 1-2 and grade 3 CRS affected 18/52 (34.6%) and 1/52 (1.9%) patients, neurotoxicity arose in 4 patients (2/4, grade 3-4), HLH affected 2 patients, and no Pembrolizumab-associated autoimmune sequalae were observed. On this basis, outpatient administration was tested in 20 patients, saving a median of 14 hospital days/patient. AUTO3 was effective: overall response rates were 66% (48.9%, CR; 17%, PR). For patients with CR, median DOR was not reached, with 54.4% (CI: 32.8, 71.7) projected to remain progression-free beyond 12 months after onset of remission. DOR for all responding patients was 8.3 months (95% CI: 3.0, NE) with 42.6% projected to remain progression-free beyond 12 months after onset of remission. Overall, AUTO3 +/- pembrolizumab for r/r LBCL was safe, lending itself to outpatient administration, and delivered durable remissions in 54.4% of complete responders, associated with robust CAR-T expansion. Neither dual-targeting CAR-T nor pembrolizumab prevented relapse in a significant proportion of patients, and future developments include next-generation-AUTO3, engineered for superior expansion/persistence in vivo, and selection of CAR binders active at low antigen densities

The effects of feeding varying concentrations of phosphorus and zinc to laying hens on the apparent ileal and total tract digestibility of phosphorus and zinc

extended abstract

Evaluation of EGFR protein expression by immunohistochemistry using H-score and the magnification rule: Re-analysis of the SATURN study

AbstractIntroductionThe phase III SATURN study demonstrated that first-line maintenance erlotinib extended progression-free survival (PFS) and overall survival (OS) versus placebo in patients with advanced non-small cell lung cancer (NSCLC). Analysis of epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC) found no significant interaction between EGFR IHC status and PFS (p=0.63) or OS (p=0.52). The FLEX study of first-line cetuximab plus chemotherapy demonstrated that EGFR IHC expression was predictive of improved OS with cetuximab when assessed by H-score with a magnification rule. This novel method was used to reassess samples from SATURN.MethodsThe H-score method assigned a score of 0–300 to each patient, based on the percentage of cells stained at different intensities viewed at various magnifications. The discriminatory threshold was set at 200, per the FLEX study, and existing samples were re-read and classed as low (H-score<200) or high (≥200) EGFR expression. PFS and OS were re-analyzed based on these new classifications.ResultsIn the overall and EGFR wild-type populations, erlotinib provided a consistent survival benefit versus placebo. Hazard ratios (HRs) in the overall population were similar between EGFR IHC-positive and -negative patients for median PFS (HR 0.68 [95% confidence interval (CI) 0.53–0.86] and 0.76 [95% CI 0.62–0.93], respectively) and OS (HR 0.80 [95% CI 0.62–1.05] and 0.80 [95% CI 0.64–1.01] for IHC-positive and IHC-negative, respectively). In the EGFR wild-type population, HRs were again similar between EGFR IHC-positive and -negative subpopulations for PFS (HR 0.69 [95% CI 0.51–0.95] and 0.84 [95% CI 0.63–1.12], respectively) and OS (HR 0.78 [95% CI 0.55–1.10] and 0.76 [95% CI 0.55–1.05], respectively).ConclusionsThese data suggest that EGFR IHC does not have value as a marker to predict erlotinib benefit in the first-line maintenance setting for advanced NSCLC

Optimal use of bendamustine in hematologic disorders: Treatment recommendations from an international consensus panel - an update

Bendamustine has achieved widespread international regulatory approval and is a standard agent for the treatment for chronic lymphocytic leukemia (CLL), indolent non-Hodgkin lymphoma and multiple myeloma. Since approval, the number of indications for bendamustine has expanded to include aggressive non-Hodgkin lymphoma and Hodgkin lymphoma and novel targeted therapies, based on new bendamustine regimens/combinations, are being developed against CLL and lymphomas. In 2010, an international panel of bendamustine experts met and published a set of recommendations on the safe and effective use of bendamustine in patients suffering from hematologic disorders. In 2014, this panel met again to update these recommendations since the clarification of issues including optimal dosing and management of bendamustine-related toxicities. The aim of this report is to communicate the latest consensus on the use of bendamustine, permitting the expansion of its safe and effective administration, particularly in new combination therapies