ABSTRACT
Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient's tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival compared with their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude that therapy matching by scFPM is clinically feasible and effective in advanced aggressive hematologic cancers. SIGNIFICANCE: This is the first precision medicine trial using a functional assay to instruct n-of-one therapies in oncology. It illustrates that for patients lacking standard therapies, high-content assay-based scFPM can have a significant value in clinical therapy guidance based on functional dependencies of each patient's cancer.See related commentary by Letai, p. 290.This article is highlighted in the In This Issue feature, p. 275.
Subject(s)
Hematologic Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Austria , Cohort Studies , Female , Hematologic Neoplasms/mortality , Humans , Male , Middle Aged , Molecular Targeted Therapy , Precision Medicine , Progression-Free Survival , Young AdultABSTRACT
Unstimulated methylcellulose cultures in 25 myelofibrosis (MF) patients were performed to better understand the role of cytokines in the proliferation of MF cells. Compared to controls MF patients show a variable but highly increased spontaneous CFU-GM formation (66 vs 4.8/10(5) PBMNC). There was a marked reduction of autonomous CFU-GM growth by the cytokine-synthesis-inhibiting molecule IL-10 as well as by antibodies against GM-CSF whereas antibodies against IL-3, G-CSF, M-CSF and IL-1ß showed heterogeneous effects. Spontaneous CFU-GM growth >100/10(5) PBMNC predicted shorter survival. Constitutive release of GM-CSF seems to contribute to proliferation of MF cells in vitro and possibly in vivo.
