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)

Activating phagocytosis to inhibit small cell lung carcinoma

LUNGevity Foundation

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