SBIR-STTR Award

Lung cancer remains the leading cause of cancer-related deaths worldwide. Surgical removal of the tumor is the best therapeutic option for patients with non-small cell lung cancer, yet up to 20% of patients still leave the operating room with deposits of cancer left behind. Advances in CAT and PET scans have provided surgeons with helpful radiographic imaging information prior to surgery, but have limited specificity for nodules less than 5-7mm in diameter. Subsequent pathological analysis confirms/refutes what a surgeon has resected. However, both of these procedures require additional time and occur outside of the operating room, providing little real- time support during the surgery. The applicant has developed a novel cocktail that combines two ligands targeted specifically to lung tumor tissue tagged with near infrared (NIR) dyes. The fluorescent cocktail containing ligands targeted to both folate receptor and the CCK2 receptor will essentially identify tumor populations that overexpress either or both of these cell surface receptors. Real-time visualization not only of the complete tumor margins but also potentially other malignant sites outside the primary tumor area will enable more complete surgical removal of primary and other tumor tissue. Moreover, fluorescence imaging could aid in the surgical decision to conserve lung function by removing only the diseased tumor tissue rather than lobectomy or pneumonectomy. The significance of this tumor-targeted fluorescent cocktail is that it will provide real-time visualization of tumor tissue during surgery - a valuable tool to differentiate tumor from healthy tissue. In this Phase I SBIR proposal, the applicant will demonstrate the feasibility of co-stainin with the cocktail in cell culture and human lung carcinoma tissue samples. Studies in mice implanted with tumor cells will demonstrate specificity and sensitivity of the levels of detection n vivo. Our commercialization efforts will be aimed at the development of the cocktail for intraoperative use in lung cancer resection surgery. The immediate objective of this work is to provide proof of concept for the NIR-ligand cocktail both in vitro and in vivo. The ultimate goal i to introduce a commercially viable product that will enable more complete tumor removal and a reduction in the recurrence rate of pulmonary cancer and its associated morbidity, mortality, and expense.

Public Health Relevance Statement:


Public Health Relevance:
Lung cancer remains a leading cause of cancer-related deaths worldwide. Surgical resection is the best therapeutic option for patients with non-small lung cell cancer. However, survival rates are directly affected by incomplete removal of the primary tumor and other malignant sites that cannot be identified. The applicant is developing a cocktail of two fluorescent ligands that will be specifically targeted to tumor surface receptors that will visualize and enable image-guided resection of lung cancer, representing a significant advancement over current surgical limitations in pulmonary resection.

Project Terms:
Address; Affect; Affinity; Animal Model; Animals; Area; Binding (Molecular Function); Biodistribution; Biological Markers; Caliber; cancer cell; Cancer Etiology; Canis familiaris; Cell Culture Techniques; Cell surface; Cell Surface Receptors; Cells; Cessation of life; Cholecystokinin B Receptor; Clinical; commercial application; commercialization; cost; Data; Deposition; Detection; Development; Disseminated Malignant Neoplasm; Drug Kinetics; Dyes; efficacy testing; Excision; FDA approved; Fluorescence; fluorescence imaging; folate-binding protein; Funding; Goals; Grant; Hour; Human; Image; Imagery; Implant; In Vitro; in vivo; Individual; intraoperative imaging; Investigational Drugs; Investigational New Drug Application; Laboratories; Lead; Left; Ligands; Lobectomy; Lung; lung Carcinoma; Lung Neoplasms; lymph nodes; Malignant - descriptor; Malignant neoplasm of lung; Malignant Neoplasms; Medical; Morbidity - disease rate; Mortality Vital Statistics; Mus; Nature; neoplastic cell; Nodule; Noise; Non-Small-Cell Lung Carcinoma; novel; Operating Rooms; Operative Surgical Procedures; Outcome; overexpression; Patients; Phase; phase 2 study; Phase I Clinical Trials; Pneumonectomy; Population; Positron-Emission Tomography; pre-clinical; Primary Neoplasm; Procedures; public health relevance; Rattus; receptor; Recurrence; Resected; Respiratory physiology; Safety; Sensitivity and Specificity; Signal Transduction; Site; Small Business Innovation Research Grant; Specificity; Surface; Surgeon; Survival Rate; System; Techniques; Therapeutic; Time; Tissue Sample; Tissues; tool; Toxic effect; Toxicology; tumor; Tumor Debulking; Tumor Tissue; uptake; whole body imaging; Work; X-Ray Computed Tomography

Lung cancer remains the leading cause of cancer-related deaths worldwide. Surgical removal of the tumor is the best therapeutic options for patients with non-small cell lung cancer, yet up to 20% of patients still leave the operating room with deposits of cancer left behind. Advances in CAT and PET scans have provided surgeons with helpful radiographic imaging information prior to surgery, but have limited specificity for nodules less than 5-7mm in diameter. Subsequent pathological analysis confirms/refutes what a surgeon has resected. However, both of these procedures require additional time and occur outside of the operating room, providing little real-time support during the surgery. The applicant has developed a novel cocktail (OTL489) that combines two ligands targeted specifically to lung tumor tissue tagged with a near infrared (NIR) dye (OTL38+OTL338). The fluorescent cocktail containing ligands targeted to both folate and the CA IX receptors will essentially identify tumor populations that overexpress either or both of these cell surface receptors. Real-time visualization not only of the complete tumor margins but also potentially other malignant sites outside the primary tumor area will enable complete surgical removal of primary and other tumor tissues. Moreover, fluorescence imaging could aid in the surgical decision to conserve lung function by removing only the diseased tumor tissue rather than lobectomy or pneumonectomy. During Phase II, OTL will perform a critical proof of concept study that will extend prior studies using components of the cocktail, alone and in combination, and validate continued development toward an Investigational New Drug (IND) application. First, OTL will optimize the manufacturing of OTL338. Pre- pharmacological studies will then be conducted in small animals to determine the optimum dose, imaging time, tumor-to-background ratio, etc. of OTL338 to be used in the IND-enabling studies. OTL will manufacture OTL338 (non-GMP), 13C-OTL338, and 13C-OTL38 in-house for the IND-enabling safety and pharmacology toxicity studies that will be conducted at Charles River Laboratories (CRL). Similarly, following the optimization of formulation and drug-drug interaction and pre-pharmacological studies of the cocktail (OTL489), IND-enabling bridging toxicity studies for the cocktail will be conducted in rodent and non-rodent species at CRL. The ultimate goal will be to finish non-GMP manufacturing and IND-enabling studies to file the IND application for the Phase 1 first in human study of the cocktail. Commercialization efforts will be aimed at the development of the cocktail for intraoperative use in lung cancer resection surgery that will enable more complete tumor removal and a reduction in the recurrence rate of pulmonary cancer and its associated morbidity, mortality, and expense.

Public Health Relevance Statement:
Project Narrative Lung cancer remains a leading cause of cancer-related deaths worldwide. Surgical resection is the best therapeutic option for patients with non-small cell lung cancer (NSCLC). However, survival rates are directly affected by incomplete removal of the primary tumor and other malignant sites that cannot be identified. The applicant is developing a cocktail of two ligands attached to a fluorescent dye that will be specifically targeted to tumor surface receptors that will visualize and enable image-guided resection of NSCLC, representing a significant advancement over current surgical limitations in pulmonary resection.

Project Terms:
Address; Affect; Affinity; analog; analytical method; Animal Model; Animals; Area; Binding; Biodistribution; Biological Markers; Caliber; cancer cell; Cancer Etiology; Cancer Patient; Canis familiaris; carbonate dehydratase; Cell surface; Cell Surface Receptors; Cessation of life; Clinical; Clinical Treatment; Clinical Trials; commercialization; cost; Deposition; deprivation; Detection; Development; Diagnostic radiologic examination; Disease; Disseminated Malignant Neoplasm; Dose; Drug Interactions; Dyes; Excision; fluorescence imaging; Fluorescent Dyes; folate-binding protein; Folic Acid; Formulation; Funding; Generations; Goals; healthy volunteer; Hour; Howard Temin Award; Human; human study; Hypoxia; Image; image guided; Imagery; imaging agent; In Vitro; in vivo; Individual; Intravenous; Investigational Drugs; Investigational New Drug Application; Laboratories; Lead; Left; Lesion; Ligands; Literature; Lobectomy; Lung; Lung Neoplasms; lymph nodes; Malignant - descriptor; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant Neoplasms; Medical; method development; Methods; Microscopic; Morbidity - disease rate; mortality; Mus; Nature; neoplastic cell; Nodule; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; novel; novel therapeutics; Nude Mice; Operating Rooms; Operative Surgical Procedures; Outcome; overexpression; Oxygen; Pathologic; patient population; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Phase; phase I trial; Phase II Clinical Trials; Phase III Clinical Trials; Pneumonectomy; Population; Positron-Emission Tomography; Preparation; Primary Neoplasm; Procedures; Process; Rattus; receptor; Recurrence; Reference Standards; Resected; Respiratory physiology; Rivers; Rodent; Safety; scale up; Schedule; Site; Small Business Innovation Research Grant; Specificity; Surface; Surgeon; Survival Rate; targeted imaging; Techniques; Therapeutic; Time; Tissue Sample; Toxic effect; tumor; Tumor Debulking; Tumor Tissue; uptake; Validation; whole body imaging; X-Ray Computed Tomography