Harvard Catalyst Profiles

Project 1: Modulation and real time monitoring of immune responses induced by photodynamic therapy. (Faculty Mentor: Prof. Tayyaba Hasan, WCP) Immunotherapy using immune checkpoint blocking antibodies such as PD-1/PD-L1 has produced impressive results in a wide range of cancers. However, the response remains heterogeneous among patients. This is also attributed to lack of robust methods to stratify patients into responders/non-responders and identify treatment outcomes in real-time that help to distinguish success or failure of a therapeutic approach during the course of treatment. The primary focus of this project is to evaluate immune responses (both systemic and local) in pre-clinical pancreatic cancer models, post-photodynamic therapy, and develop strategies to enhance response of immune checkpoint inhibitors in pancreatic cancers. Photodynamic therapy (PDT) is a photochemistry-based treatment modality involving the administration of a photosensitizer (PS) followed by light activation and is being clinically evaluated in pancreatic cancers. Fellows will be provided with an opportunity to learn and perform experiments using orthotopic/sub-cutaneous syngeneic mouse models and evaluate immune responses through flow cytometry and immunofluorescence. This project also involves the use of a hyperspectral fluorescence microendoscope (in collaboration with Dr. Bryan Spring at Northeastern University) for online multi-molecular imaging to quantify tumor cell phenotypes and their spatio-temporal location during PDT and immunotherapy in mouse cancer models. This information will be used to rationally design and optimize new combination treatments. The goal is to determine both the key time points and spatial localizations of immune responses for guiding the administration of immune check-point inhibitors. Fellows will participate in molecular imaging using the hyperspectral fluorescence microendoscope, including GPU programming, video-rate image analysis, and ex vivo histopathological validation. Substantial image analysis will be involved in the project. The anticipated outcome of these studies is a clear understanding of mechanisms that ensue after therapy administration and image guided treatments. The project also involves ex vivo culturing tumor tissues, as organoids or in heterocellular 3D in vitro models, to integrate stromal cells, extracellular matrix and the complex immune microenvironment. These models will be established for studying complex biological responses, as observed in pancreatic cancers, and evaluate drug delivery strategies employing rationally designed combination treatments, including photodynamic therapy, immunotherapy, chemotherapy, etc. using multi-agent nanocarrier-based treatments. The outcome of these studies will assist in developing biologically relevant models and a platform for rapid screening of therapeutic agents. Fellows will be provided with an opportunity to learn and perform immune organoid cultures along with developing nanoplatforms for co-delivery of multiple therapeutic agents. Project 2: Development and evaluation of an integrated imaging and treatment device for image-guided photodynamic therapy of oral cancer. (Faculty Mentor: Prof. Tayyaba Hasan, WCP) Of the 300,000 to 700,000 new cases of oral cancer that occur globally each year, about two thirds are in low to middle-income countries (LMICs). The detrimental effects of this public health crisis are exacerbated by lack of medical infrastructure, especially in rural areas. Even when early cancer or high-grade dysplasia (HGD) and oral potentially malignant lesions (OPML) are detected, insufficient access to clinical centers providing surgical oncology or radiation therapy will ultimately often lead to disease progression and death. Photodynamic therapy (PDT), a photochemistry-based treatment modality involves the administration of a photosensitizer (PS) and light activation, has previously demonstrated promise for oral malignancy, though a lack of robust affordable enabling technology has limited broader adoption. To address this, we developed a low-cost, portable platform for ergonomic intraoral PDT for use with 5-aminolevulinic acid (ALA)-photosensitization. The current NCI funded project is aimed at developing low-cost technology (developed at University of Arizona), for imaging and treatment of oral cancers in low resource settings. The integrated “Screen, Image and Treat Optical System” (SITOS) will utilize an FDA approved pro-drug (5-ALA) that is preferentially converted into a fluorophore/photosensitizer, Protoporphyrin-IX (PpIX) in malignant cells. The integrated platform enables the use of the same hardware for initial imaging, and a single theranostic molecule for image-guided PDT and online monitoring during therapy. Fellows will be provided with an opportunity to learn and perform experiments involving preliminarily validation of the device on optical phantoms, in vitro 3D tumor models and orthotopic/sub-cutaneous mouse syngeneic models. Project 3: Dual function theranostic constructs for photoacoustic guided surgery and photodynamic therapy. (Faculty Mentor: Prof. Tayyaba Hasan, WCP) Survival rates in patients with oral cavity tumors (e.g., tongue cancers) have remained nearly stagnant in the past decade with exceptional morbidity. The goal of this project is to develop, for the first time, a single theranostic agent namely targeted Dual Function Antibody Conjugate (DFAC) enabling deep tissue photoacoustic imaging (PAI) with targeted photodynamic therapy (PDT), and an integrated PAI-ultrasound imaging (US) module (developed at Dr. Mallidi’s group at Tufts University) for surgery guidance such that the two main barriers (imaging tumor margins and residual microscopic disease) to oral cancer treatment outcomes are overcome. The project has 2 parts that will enable deep tissue image-guided surgery and treat residual disease in one intraoperative setting. 1. Synthesis of DFAC, that enables both imaging and therapy by targeting Epidermal growth factor receptor (EGFR), as an established biomarker in oral cavity tumors. 2. Targeted PDT, also referred to as photoimmunotherapy. DFAC is composed of cetuximab, an FDA-approved EGFR targeting antibody, conjugated to a new near-infrared (>850 nm) naphthalocyanine dye for deep-tissue PAI and an FDA-approved photosensitizer Benzoporphyrin Derivative (BPD). We postulate that DFAC-enabled deep-tissue PAI-guided surgery and intraoperative PDT of residual disease will achieve local tumor control. Fellows will be provided exposure to chemistry/biology training during synthesis of DFACs, in vitro testing (imaging and therapy on tumor phantoms), in vivo testing (on small animal models of oral cancer), and patient sample evaluation.