Thursday, June 16, 2016

Pre-clinical animal model of CD47-blocking immunotherapy in small-cell lung cancer

This week Journal of Clinical Investigation (JCI) published a new study examining CD47-blocking immunotherapy in small-cell lung cancer. This is a joint study by people affiliated with Forty Seven Inc. and Alexo Therapeutics Inc., two biotech companies which focus on clinical application of anti-CD47 targeting immunotherapy.

Just to remind the readers, that simply put, CD47 is an inhibitory molecule expressed on multiple cell types, including tumors, that act as a "do not eat me" signaling. It is believed that by removing this negative signaling, macrophages could phagocytose tumor cells efficiently and thus restrict tumor growth.

In this study, the authors analyzed effectiveness of blocking of CD47/SIRPĪ± pathway in NSG mouse small-cell lung cancer (SCLC) model. First, the authors showed that human small cell lung cancer cell lines or patient-derived SCLC cells express CD47 and when co-incubated with macrophage and anti-CD47 antibody, such tumor cells are efficiently phagocytosed (though there is no correlation between level of CD47 expression and phagocytosing activity).

Next, the authors showed that treatment with anti-human CD47 antibody inhibited growth of human SCLC cells implanted in immunodeficient NSG mice.

Anti-human CD47 antibody was active in PDX model as well (patient-derived xenograft tumor model in NSG mice).

Similar trend, though less potent tumor growth inhibition was observed with CD47KO SCLC cell line derived via Cas9 editing [suggesting that anti-CD47 antibody provides additional signaling beyond CD47 blocking]. 

To answer some of the criticism of earlier studies, the authors conducted CD47KO mouse tumor cell transplantation experiments in immunocompetent mice and observed similar outcome.  

In summary, this study showed that anti-CD47 therapy could be effective against CD47+ small cell lung cancer which originates from neuroendocrine cells of the lung (however keep in mind that in many models, CD47 blockade does not completely eliminate tumors). 

David Usharauli

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