Depth Imaging of Critical Normal Structures

Funded by Biden Cancer Moonshot through ARPA-H Precision Surgical Interventions

Iatrogenic injury to critical, normal anatomical structures (nerves, ureters, vessels, ducts, glands) during surgery are devastating complications, leading to substantial morbidity – sometimes mortality – in patients. Injuries to these structures often arise due to their close proximity to the surgical target. To address these morbidities, we aim to design an end-to-end solution to eliminate the impact of iatrogenic critical structure damage during robot-assisted, radical prostatectomy (RARP). We are working to develop a multimodal, minimally invasive, optical laparoscope for simultaneous imaging of two, near-infrared (NIR) fluorescent agents targeted to normal human nerve and local vasculature at depth. We aim to incorporate NIR fluorescence, multi-excitation wavelength emission ratio (MEWER) methods, and laser speckle illumination spatial frequency domain imaging (si-SFDI) into a standard surgical laparoscope that utilizes the assistant port of the da Vinci surgical robot (Intuitive Surgical). An automated and integrated interface will provide surgeons with real-time views of a depth map of the surgical field that is augmented by a priori radiological imaging data for accurate determination of critical structure dimension and location. To demonstrate the high surgical accuracy and structure localization of this methodology, we are developing: 1) novel standardization phantoms for system and depth calibration, and 2) anatomically accurate surgical phantoms that mimic prostate and colorectal surgeries.

ABY-029 Fluorescence Guided Surgery

Funded by NCI R01 CA167413 in an academic-industrial partnership with Affibody AB and LI-COR Biosciences, Inc.

ABY-029 is an anti-EGFR Affibody molecule labeled with IRDye 800CW and is approved as an exploratory investigational new drug (eIND #122681). Affibody molecules are small (~6 kDa) engineered peptides that are optimized for imaging applications and therapy. The main advantage of ABY-029 is that it has a short plasma half-life, measured in minutes, which allows administration and surgery to occur on the same day with optimal fluorescence contrast occurring within 4-8 hours. This is in stark contrast to larger imaging agents, such as antibodies, that remain in the plasma on a much longer time scale, measured in days, and require administration several days prior to surgery.

We have completed three first-in-human Phase 0 clinical trials in head and neck cancer, recurrent high-grade glioma, and soft-tissue sarcoma utilizing near-microdose administration. Successful identification of tumor tissue with sufficient fluorescence contrast correlating to EGFR expression has spurred are currently pursuing Phase 2 trials to test efficacy of detection.

Paired-Agent Imaging for Fluorescence Guided Surgery

Funded by NCI R37212187 (head and neck cancer) and the Prouty and Hopeman Pilot Funds from the Norris Cotton Cancer Center (skin squamous cell carcinomas).

While the difference in molecular expression of therapeutic targets in cancer are orders of magnitude higher than the surrounding normal tissues, fluorescence contrast using single-agent imaging is only 2-5X owing to non-specific uptake and retention of the imaging agent. To address this suboptimal contrast, we have developed paired-agent imaging (PAI) methodologies that allow quantification of true molecular differences between tissues by using a second, non-targeted imaging agent that accounts for the non-specific signal. We have demonstrated in a wide variety of preclinical xenograft tumors that PAI is equivalent to IHC, improves differentiation of tumor, decreases administration-to-imaging time, and accurately represents the heterogeneity of expression throughout a tumor as compared to ABY-029 alone. In addition, PAI appears to be especially promising for providing immunohistochemistry-like images in minutes for ex vivo fresh tissue several millimeters thick down to 7-10 m frozen sections.

PAI is being pursued as a fluorescence imaging technique for in situ fluorescence guided surgery of a variety of EGFR positive cancers using ABY-029 and IRDye 680LT carboxylate. Fluorescence imaging is rapid, requiring only seconds to capture lower resolution wide-field images and minutes to capture highly detailed scanned images.

Paired-Agent Imaging for In vivo Receptor Occupancy

Receptor occupancy is important for both drug development and individualized therapeutic plans for oncology patients. The number of receptors occupied by a therapeutic is related to both the administered dose and the induced therapeutic effect. The ability to quantitatively image receptor availability using paired-agent imaging makes it possible to determine in vivo receptor availability or therapeutic agent engagement. We can determine whether a therapeutic agent is engaged with a receptor of interest by monitoring the change in receptor availability over time. This allows us the ability to determine the drug-engagement dose and response of the therapeutic, which is especially important in cancers where drug delivery and response are highly reliant of the underlying tissue physiology.

PAI methodologies allow receptor occupancy imaging over a wide-range of times pre- and post-administration. In addition, we have recently developed methods to imaged receptor availability in real-time, allowing for receptor occupancy to be determined during the administration of a therapeutic agent.

Paired-Agent Imaging for Photodynamic Therapy Response

Photodynamic therapy (PDT) has been utilized as a therapeutic for a number of cancers (skin, bladder, head and neck, etc.) at higher doses and as a therapeutic priming methodology at low doses. In each case, an inflammatory response is induced within the tumor tissue, allowing for tumor swelling to occur. Single agent molecular imaging methodologies cannot accurately monitor the molecular changes that may be occurring after therapy due to the high permeability of treated vasculature and significant non-specific accumulation of the imaging agent. PAI is an ideal molecular imaging methodology for imaging response of tumors to PDT.