Evaluation of an implantable microdevice for rapid cancer drug screening directly in T cell lymphoma patients

Brigham And Women'S Hospital, Boston MA

Investigators

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Abstract

Project Summary/Abstract: Advanced cutaneous T cell lymphoma (CTCL) and peripheral T cell lymphoma (PTCL) have very poor survival due to limited effective treatments. Three fundamental barriers have stalled drug development: 1) the low incidence of each T--cell lymphoma (TCL) subtype, which limits sample availability and clinical trial enrollment; 2) heterogeneity across subtypes, which further complicates biologic interrogation; and 3) a lack of faithful model systems for in vitro and in vivo studies, which also cannot adequately assess immunotherapies. Thus, there is a major scientific gap to direct rational clinical trial efforts for novel therapeutic regimens. Here, we propose the use of an innovative implantable microdevice (MD) for in situ drug screening in patients to identify the most effective cancer drugs and novel agents to direct future personalized treatment of TCL. Our MD delivers up to 20 drugs of any class into spatially distinct regions of a tumor. It is delivered percutaneously and retrieved 72 hours later by excising the device along with surrounding tissue with a standard skin biopsy tool. This device allows testing of a range of relevant drugs directly inside the living tumor, thereby preserving the native tumor physiology and, importantly, avoiding systemic toxicities. Drug sensitivity is determined by histologic assessment of the tumor surrounding the drug chambers with immunohistochemistry (IHC). The MD and the method for processing and analyzing tissue has been validated across multiple cancer types in murine models and is being employed in an ongoing pilot study in breast cancer. The specific aims of these studies will be to: i) determine the safety and feasibility implanting and retrieving the MD in skin lesions of TCL; ii) assess local responsiveness of TCL to cancer treatments delivered via the MD through IHC and use highly multiplexed cyclic immunofluorescence, a novel platform, to characterize changes in the native immune microenvironment following drug treatment, and iii) correlate genomic features of TCL with drug response to nominate potential therapeutic biomarkers and to correlate these responses with a patient’s clinical and molecular response to systemically administered treatment. We hypothesize that in situ pharmacological profiling of drugs in TCL has the ability to predict systemic responses to standard of care therapies and therefore can serve as a rapid screen for multiple investigational single or combination treatments. Additionally, genomic and immunophenotypic analysis of tumors may assist in identification of predictive biomarkers of treatment. The results of our studies will direct clinical trial efforts evaluating the most promising treatment strategies and usher in the era of precision medicine in TCL.