CD133 auto-antibodies shine a light on early-stage small cell lung cancer

From the Dr. Paul D Lampe, Dr. Christopher Li, and Dr. A McGarry Houghton Labs, Cancer Epidemiology, Prevention and Control and Cancer Immunology Programs, Cancer Consortium.

When it comes to cancer, prevention may be the best medicine – but early detection is a close runner-up. This is especially true with highly metastatic cancers with low survivability, such as small cell lung cancer (SCLC). Unfortunately, most diagnoses of SCLC are made when it’s too late, after the cancer has metastasized from the lungs to other tissues, leading to extensive-stage SCLC with a 5-year survival rate of <3%. However, if doctors can diagnose SCLC at earlier stages, they are able to treat patients with additional therapies that improve the 5-year survival rate to nearly 50%. So, how do you detect SCLC as early as possible? That’s the question Dr. Kunihiro, Ms. Sarrett, and Dr. Lastwika sought to answer in their recent study in the Journal of Nuclear Medicine.

“This research was inspired by the lack of effective early detection methods for small cell lung cancer (SCLC), a subtype of lung cancer that rapidly progresses and is essentially incurable by the time patients may display symptoms and get diagnosed,” explained Dr. Andrew Kunihiro, a former postdoc in Dr. Paul Lampe’s lab, and one of the co-first authors of the study. “This paper builds upon prior discoveries in the Lampe lab that autoantibodies are upregulated in many different cancers, but especially SCLC, and thus may be useful as early, non-invasive detection biomarkers. We found that autoantibodies against CD133 (aka PROM1), a transmembrane glycoprotein, were upregulated in SCLC and subsequently explored the viability of targeting CD133 as an early SCLC-detection biomarker via antibody-mediated positron emission tomography (immunoPET)”. Essentially, the authors showed that CD133 mRNA and protein were highly upregulated in SCLC tumors compared to normal adjacent tissues. To see if this heightened expression was detectable with imaging-based techniques, they introduced an antibody against CD133 tagged with a fluorophore, or fluorescent chemical compound, into patient-derived xenografts in mice. This allowed them to visualize how efficiently the antibody recognized CD133, and especially CD133 in tumor cells, relative to healthy tissues. “The most exciting moment for me was seeing the near-infrared fluorescence and PET images from our mouse models showing successful localization of SCLC tumors with our anti-CD133 antibodies,” said Dr. Kunihiro.

A graphic showing that high-risk yet healthy patients have no detectable auto-antibodies against CD133, but that high-risk patients with SCLC have circulating autoantibodies against CD133 that can be detected with a blood draw.
In their recent study, Dr. Kunihiro, Dr. Sarrett, and Dr. Lastwika showed that targeting CD133 expression in tumors with antibody-based therapies could yield earlier and more accurate detection of small cell lung cancer, especially in high-risk patients.

Not only could the authors detect CD133 expression with their fluorescent antibody in known SCLC tissues, but they also showed that the presence of anti-CD133 antibodies could predict a diagnosis of SCLC in patients. These so called “auto-antibodies” are antibodies produced within a person’s body that can target and react to disease-modified epitopes in their own tissues. Often, auto-antibodies can cause autoimmune diseases, as in the case of Type-I diabetes. However, Dr. Kunihiro and his collaborators found that these anti-CD133 autoantibodies were helpful: because they circulate throughout patients’ blood, researchers can use their existence in a plasma sample to infer the presence of SCLC tumor cells in a patient’s body. In fact, anti-CD133 auto-antibodies could be detected in subjects from cohort studies up to a year before the subjects were formally diagnosed with SCLC. A year represents a huge leap forward in early detection, and a higher chance of halting SCLC progression to metastasis for patients.

This work isn’t quite ready to hit the clinic, though. One issue has to do with better definition of the epitope, or part of the protein’s surface, that is recognized by the patient-generated autoantibody. “One barrier to utilizing autoantibodies against CD133 as early detection biomarkers is the identification of the SCLC-specific autoantibody epitope(s)”, said Dr. Kunihiro. “The current paradigm we propose would detect circulating SCLC-specific autoantibodies, but then image with an off-the-shelf anti-CD133 antibody that does not necessarily recognize the same epitope(s). Successful elucidation of these epitopes, an ongoing project in the lab, will allow for the creation of antibody-based imaging agents that could detect only SCLC-specific neoepitopes”.

Nonetheless, detecting the anti-CD133 autoantibodies is a big step forward in SCLC detection. Evaluating the levels of these antibodies would require a simple blood draw, a minimally invasive procedure, but could significantly shorten the amount of time SCLC goes undetected in patients. Fred Hutchinson Cancer Center, as part of the Cancer Consortium, aims to cure cancer: early detection and prevention are two arms of that goal. Dr. Kunihiro has left Fred Hutch since this work was published, and now works at Epic Sciences in San Diego, CA. He enjoyed his time at the Hutch as a postdoc and all the resources that the Cancer Consortium provided and said he “would like to thank for jumpstarting my training in R, which I utilized in this paper to quantify expression of CD133 in publicly available RNA-seq data sets”.

AG Kunihiro, SM Sarrett, KJ Lastwika, JL Solan, T Pisarenko, O Keinanen, C Rodriguez, LR Taverne, AL Fitzpatrick, CI Li, AM Houghton, BM Zeglis, and PD Lampe. 2022. CD133 as a biomarker for an autoantibody-to-ImmunoPET paradigm for the early detection of small cell lung cancer. Journal of Nuclear Medicine. 63(8): jnumed.121.263511. DOI: 10.2967/jnumed.121.263511.

This work was funded by the National Institutes of Health and the Academy of Finland.

Cancer Consortium members Dr. A McGarry Houghton, Dr. Christopher Li, and Dr. Paul D Lampe contributed to this work.