CA | LUNGevity Foundation

Activating phagocytosis to inhibit small cell lung carcinoma

2014

Targeted Therapeutics Research Award

Julien Sage, PhD

Stanford University

Stanford

Irving Weissman, MD

Stanford University

Stanford

Drs. Sage and Weissman will test a new immunotherapy to boost the arsenal of immune cells to combat SCLC. They will work to disable a protein on the cancer cells that inhibits macrophages, a type of immune cell that can engulf and destroy cancer cells. This will boost the killing capacity of macrophages and recruit more immune cells to the area by the tumor.

Research Summary

Small cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer that kills more than 200,000 people worldwide every year and for which the survival rate has remained a dismal 5% since the 1970s. SCLC development is strongly linked to heavy cigarette smoking, and increased smoking in developing countries makes it very likely that we will observe a true SCLC epidemic this century in the world. There is a great need for the development of novel therapeutic strategies in SCLC patients. This team will use an innovative approach to tackle the challenge of identifying effective therapies against SCLC. They will focus on the development of an “immunotherapy” that promotes the anti-cancer activity of immune cells named macrophages. Macrophages are blood cells whose “job” is to engulf and digest abnormal cells, including tumor cells. Interestingly, the team earlier found that SCLC cells express at a very high level at their surface a “don’t-eat-me” signal and that expression of this protein inhibits the activity of macrophages. The team’s strategy is dual: they will block this “don’t-eat-me” signal to enhance the activity of macrophages and they will further use specific antibodies to recruit macrophages to the proximity of the tumor cells. If successful, this novel immunotherapeutic approach may be rapidly applicable to SCLC patients in the clinic.

Technical Abstract

Small cell lung carcinoma (SCLC) remains one of the most lethal human cancers. More than 25,000 patients are diagnosed with SCLC every year in the United States. Unfortunately, most patients usually survive only 6-12 months after diagnosis. Except for the combination of radiation therapy and chemotherapy, there has been no novel therapeutic approach implemented in the past 30 years. Despite a large number of clinical trials, no targeted therapy has been approved for SCLC patients, whose survival rate hovers around 5%. Previous attempts to identify therapeutic targets in SCLC patients have mostly focused on signaling networks within the tumor cells. Here we propose to test a novel immunotherapeutic approach to promote the anti-cancer activity of macrophages. Specifically, we found that SCLC cells express high levels of the CD47 antigen, a marker of self that inhibits the phagocytic activity of macrophages. Based on previous studies from the laboratories of Dr. Weissman and Dr. Garcia at Stanford, we propose to block the interaction between CD47 and SIRPa, an inhibitory receptor expressed on macrophages, to stimulate the engulfment of SCLC cells by macrophages and their eradication. Furthermore, we will identify SCLC-specific antigens and combine CD47-blocking therapies with these antibodies to enhance the recruitment and the activity of macrophages against SCLC cells. Clinical trials testing the CD47-blocking strategies are being initiated in patients with blood cancer and some solid tumors. If successful, our pre-clinical experiments may lead to the rapid implementation of this novel anti-cancer immunotherapy strategy in SCLC patients.

Key words

CD47

Immunotherapy

Small cell lung cancer (SCLC)

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In-vivo and in-vitro diagnostics to improve lung cancer care

2012

Career Development Award

Viswam S. Nair, MD

Stanford University

Stanford

Dr. Nair is developing a blood test to help determine whether a pulmonary nodule seen on a PET-scan imaging screen is cancerous. The goal of this test, which will make use of circulating molecular biomarkers, is to accurately determine which patients are most likely to have lung cancer and, therefore, should have biopsies or surgery.

Research Summary

My goal is to improve medical care for patients with a lung nodule discovered on imaging scans by fusing currently available molecular imaging techniques with circulating biomarkers that can be detected in blood during routine lab testing. Thousands of solitary pulmonary nodules (SPNs) are discovered annually in patients, many during imaging for other reasons, and many are potentially lethal. Physicians remain uneasy about this development since these nodules could be cancerous and aggressive approaches that lead to unnecessary testing, including invasive biopsies and unnecessary surgery, are common. Positron Emission Tomography (PET) imaging assesses the metabolism of lung nodules, increases the accuracy of a physician’s diagnosis and treatment strategy for the lung nodule patient and is widely used―but even PET remains imprecise. We therefore plan on investigating whether molecular biomarkers in blood can increase the utility of PET imaging in clinical practice. The concept here is “one-stop shopping,” where a patient can obtain the standard of care in molecular imaging (PET) with a routine blood test during an appointment that will increase the accuracy of a clinician’s diagnosis and facilitate the appropriate decision-making process for the patient. This could have a cost-effective impact on medical care for patients with a concerning lung nodule by not only increasing diagnostic accuracy but also by augmenting an outdated staging system used to classify lung cancer prognosis.

Technical Abstract

Better methods are required to accurately risk stratify patients with a solitary pulmonary nodule (SPN) who may undergo unnecessary procedures to exclude a cancer diagnosis. 18F-FDG Positron Emission Tomography (PET) is a widely available clinical test used to evaluate concerning SPNs and stage malignant lung nodules. It therefore facilitates clinical assessment but remains an imperfect tool for the diagnosis, localization, and prognostication of SPNs, be they infectious or malignant in nature. Furthermore, it performs well for staging lung cancer, but inaccurately categorizes patients in some cases who receive futile thoracotomies for disseminated disease, or conversely, are undertreated for localized disease. The applicant therefore plans on investigating whether circulating molecular biomarkers can increase the utility of 18F-FDG-PET imaging in clinical practice using statistical models that incorporate in vivo and in vitro diagnostics The concept here is “one-stop shopping,” where a patient can obtain routine molecular imaging and molecular diagnostics from routine blood work during an appointment that in combination increase the accuracy of a clinician’s diagnosis and facilitate the appropriate decision-making process. For this proposal we will develop a model that incorporates a circulating microRNA profile to discriminate infectious from malignant SPNs for patients along with clinical and FDG-PET data and, secondly, identify patients with malignant nodules and detectable circulating tumor cells to determine whether these cells upstage or augment clinical staging or prognosis post-operatively when compared to FDG-PET alone.

Key words

Biomarker or biomarker testing

Circulating tumor cells

Early detection

Liquid biopsy

Molecular profile or molecular testing

Non-small cell lung cancer (NSCLC)