Obtaining phenotypic information on tumor responses to drugs to enable precision medicine remains an unmet need in the treatment of gliomas. With this first-in-human pilot trial, we provide evidence of safety and feasibility for the use of intratumoral, drug-releasing microdevices as a novel approach to characterize and compare the efficacy of different pharmacologic therapies in patients with gliomas, in a personalized manner.
The main goals of this study were to demonstrate that microdevices can be easily incorporated into standard neurosurgical practice, with minimal impact to the operative protocols, no significant burden on healthcare costs, and no evidence of adverse effects, while providing valuable biological data which can be integrated with, and potentially be superior to other currently used biomarkers. The amount of information obtained with this approach, which directly integrates surgery with bioengineering, pharmacology and cancer genetics, provides a solid argument for a revisitation of surgical practice for glioma patients, where such in-situ investigational devices could become the norm in the future.
One potentially limiting aspect of this study is the relatively short indwelling time of the microdevices which was dictated by the need to minimize changes to the current standard of patient care (hereby the decision to not submit patients to an additional invasive IMD implantation procedure several days before surgery). During the available ~ 2.3h incubation period, we demonstrate the detection of early markers of drug effects by inducing cellular stress response in a drug and concentration dependent manner. We observe robust activation of early markers of DNA damage (phosphorylation of Histone Gamma), and low to moderate activation of molecular cascades which lead to cell death (cleaved caspase 3). Importantly, we find that the level of pH2AX expression in response to temozolomide treatment is congruent with molecular characterization of the patient’s tumor, and directly predicts the clinical responses observed across each of the patients which received systemic TMZ treatment. This is particularly striking in the case of patients 3 and 5, where MGMT promoter methylation status by itself was not predictive of clinical response, which was correctly identified by the IMD measurement.
Larger clinical studies will be needed to confirm the predictive capability of the IMD to identify systemic responders, and to quantitatively define exact thresholds of IMD response correlating with favorable clinical outcome. We have focused the current study on agents that are routinely used in GBM. For agents that do not penetrate the Blood Brain Barrier, IMD readouts of intratumor effect may help determine minimum effective intratumor concentrations required, and this could guide the decision to implement different delivery techniques, such as convection-enhanced or nanoparticle mediated delivery, to achieve sufficient intratumor drug levels.
While the current study focused on rapidly acting cytotoxic and targeted agents, the length of exposure is likely not enough to detect changes in adaptive immune response, which have been shown to occur over the course of two days or longer36.
Supported by the evidence of safety and non-futility provided with this first study iteration, a follow up clinical trial evaluating safety and feasibility of a two-staged procedure (insertion by a minimally invasive procedure, and retrieval 72 hours later by craniotomy) is currently underway. This will provide data to compare biological readouts between short and long exposures, and define whether a two-surgery approach is necessary to maximize data, or if the predictive values obtained with a single surgery and shorter exposure is sufficient to reliably inform therapy.
In addition to providing the ability to directly test a range of drugs in a patient, the use of IMDs in gliomas offer significant opportunities to answer questions which so far have been elusive: Firstly, this strategy allows to safely test the efficacy of drug combinations, which are commonly used in other cancers37, but only rarely in glioblastomas, despite significant preclinical evidence that different drugs acting synergistically against redundant oncogenes are more potent than single drugs38,39.
Secondly, the analysis of microdevice-exposed specimens allows a realistic vantage point into the tumor microenvironment, and particularly how drugs also affect non neoplastic cells (like immune cells, astrocytes and neurons). For example, it is still not clear how drugs modulate the anti-tumor immune response: chemotherapy is generally believed to be immunosuppressive40. However, while some have confirmed a detrimental effect of TMZ against T and B cells in mouse models of GBM, with resultant further impairment of an already weak antitumor response41, others have shown that TMZ might preferentially deplete immune-suppressive CD4 regulatory T cells (Tregs) 42,43. In theory, any drugs might display unexpected effects against non-tumor cells, which, in turn, can impact clinical outcomes.
IMDs also can address the unanswered question of how glioma cell heterogeneity influences response to each drug, characterizing how different tumor subtypes respond differently to the same drug, and how tumor heterogeneity can lead to recurrence.
Finally, by providing a measurable drug gradient within the specimen, which is easily achievable through detection by autofluorescence (Fig. 2), or using MALDI mass spectrometry44, the analysis of microdevice specimens allows quantification of tissue concentrations at which each drug is biologically effective against the tumor.
In conclusion, the direct use of IMDs in patients with gliomas represents a novel, feasible and promising approach that addresses the need to maximize efficacy of multiple pharmacotherapies, as well to understand their mechanisms of action in the most representative and predictive model.