Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematologic Cancers and Identifies Exceptional Responders

Abstract

We thank the patients and their families for their trust in taking part in this study. The study was academically funded and supported by the Medical University Vienna, the General Hospital Vienna, and the Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences. We gratefully acknowledge funding from the Vienna Science and Technology Fund (LS16-034 to GSF and UJ), the Austrian Science Fund (F4704-B20 to PV, F4711-B20 to GSF, and P27132-B20 to PBS), and the European Molecular Biology Organization Long Term Fellowship (1543-2012 to GIV, 733-2016 to TP). BS acknowledges

Multiplexed high-throughput immune cell imaging reveals molecular health-associated phenotypes

“…To be able to comprehensively measure immune cell phenotypes, we developed a multiplexed immunofluorescence approach for peripheral blood mononuclear cells (PBMCs) that extends our previously developed protocol for high-throughput image-based screening in human biopsies compatible with mixed non-adherent cells (Vladimer et al 2017;Snijder et al 2017;Kornauth et al 2021) (Figure 1). In contrast to previously reported cyclical multiplexed immunofluorescence protocols (J.-R. Lin, Fallahi-Sichani, and Sorger 2015;Gerdes et al 2013;Gut, Herrmann, and Pelkmans 2018), we stain once with a comprehensive immune cell marker panel that multiplexes 8 surface markers and a nuclear dye, which is imaged by automated confocal microscopy and brightfield imaging in a single run (Figure 1i and Supplementary Table 1).…”

“…In the future, repeated profiling of individual donors will allow to further stratify temporally stable from dynamic immune cell phenotypes. Furthermore, comparative studies across larger patient and donor cohorts, and identifying clinically relevant cell morphologies in the context of personalized treatment identification for hematological malignancies (Snijder et al 2017;Kornauth et al 2021), will be additionally attractive avenues of study. This will inevitably define the boundaries of the personal health information reflected by immune cell phenotypes.…”

Mcl‐1 and Bcl‐xL levels predict responsiveness to dual MEK/Bcl‐2 inhibition in B‐cell malignancies

“…Direct drug testing of a patient’s tumor cells can identify effective therapies, including novel agents and combinations [ 4 ]. The feasibility of this approach has been demonstrated for aggressive hematological malignancies in the EXALT study (NCT03096821), in which integration of sensitivity testing in treatment decisions improved the treatment outcome [ 5 ]. The follow‐up study, EXALT‐2 (NCT04470947), is a randomized, three‐arm study, which compares treatment decisions guided by drug screening, genomic profiling, and physician’s choice.…”

Functional testing of relapsed chronic lymphocytic leukemia guides precision medicine and maps response and resistance mechanisms. An index case

“…Immunotherapies such as CAR T-cell therapy or bispecific antibodies may be efficacious in this setting, but are not readily available to patients outside clinical trials 3 . Direct drug testing on tumor cells can indicate treatment vulnerabilities 4 , and implementation of this approach in treatment decisions for aggressive refractory hematological malignancies led to improved treatment 5 . Elucidation of treatment sensitivities in multi-drug refractory CLL may thus inform novel therapeutic concepts for this patient group.…”