LONDON—It seems that every month or so there's new research detailing yet another trick by which cancer can evade treatment—cancer cells can send out disseminated cells that hide in bone marrow and stay dormant for years; they can hijack immune checkpoints; they can mutate to develop resistance to treatment. It can seem hopeless with how slippery and mutative the disease is, but every identified defense mechanism opens up doors for new treatment targets.
And that's the case with a newly discovered evasion technique revealed by a research team from The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust. In their work, published in the Journal for ImmunoTherapy of Cancer, the researchers detail a method by which cancer cells can turn off a molecule on their surface that allows anti-cancer treatments to target them—and how these findings could be used to increase treatment effectiveness. Funding for this work came from the NIHR Biomedical Research Center at the ICR, The Royal Marsden and Cancer Research UK. The paper in question is titled “CEA expression heterogeneity and plasticity confer resistance to the CEA-targeting bispecific immunotherapy antibody cibisatamab (CEA-TCB) in patient-derived colorectal cancer organoids.”
“Cancer is very good at hiding from the body’s immune system. The latest successful immunotherapies work by acting as a matchmaker to bring the immune system together with cancer, so that it can see it and attack it,” commented study leader Dr. Marco Gerlinger, team leader in Translational Oncogenomics at the ICR, and consultant oncologist at The Royal Marsden. “Our study has found that bowel cancers have a way of dodging even the newest of immunotherapies—changing their spots by altering the levels of a key molecule on the surface of cells, so that they become harder to recognize.”
The focal point of this latest evasion strategy by cancer is a molecule known as carcinoembryonic antigen (CEA), which is found on the surface of several types of cancer cells. In working with colorectal cancer cells grown in the lab, the scientists discovered that the cells could effectively hide from cibisatamab by altering the levels of the CEA molecule expressed on their surface. Cibisatamab is an immunotherapy developed by Roche. As noted in the recent paper, “The T cell bispecific antibody cibisatamab (CEA-TCB) is a novel immunotherapy that redirects T cells independently of their T cell receptor specificity to tumor cells expressing the carcinoembryonic antigen (CEA) glycoprotein at the cell surface . A major advantage of T cell redirecting bispecific antibodies is that they mediate cancer cell recognition by T cells independently of neoantigen load.”
Biopsies were taken from eight patients with bowel cancer, which were then used to grow tumors in the lab. Looking at the generated tumor cells in terms of CEA levels revealed that cells fell into one of three categories: those with high levels of CEA, those with low levels, and those with a mix. When treated with cibisatamab, those groups saw 96 percent, 20 percent and 53 percent reduced growth, respectively, speaking cibisatamab's efficacy in targeting CEA.
Their next step consisted of isolating individual cells with either high or low levels of CEA and allowing them to grow into tumors. After a month, the CEA levels had changed in these tumors, having altered their own expression of the molecule.
Dr. Andrew Beggs, a Cancer Research UK expert on bowel cancer, said: “Mini lab-grown tumors have the potential to transform the way we test drugs before clinical trials. From a tiny biopsy, we can recreate the tumor in the lab to better reflect a patient’s cancer than with traditional ways of growing cells. This study is an example of creating mini bowel cancer tumours, known as organoids, to guide future research of an experimental immunotherapy. And we can use organoids to learn more about how cancers might respond to drugs, testing many treatments simultaneously to find potential vulnerabilities we might target.
“Organoid models are increasingly being used in this way to help researchers study, develop and refine possible treatments to test in clinical trials.”
Upon further study, the team discovered that cells that presented with low CEA levels also showed increased activity in the WNT pathway, which is known to play a role in carcinogenesis and is the target of a variety of drugs. When the lab-grown tumors were treated with such drugs—namely tankyrase inhibitors and porcupine inhibitors—the levels of CEA increased, which meant increased susceptibility to treatments such as cibisatamab.
The authors remarked that combination therapies featuring cibisatamab and WNT pathway inhibitors could be of interest in the future for the latter's ability to boost expression of CEA, but acknowledged that “[T]he WNT pathway has an essential role in the development and the homeostasis of many normal tissues in the human body. As a consequence, targeting of the WNT pathway has been challenging in preclinical models and clinical trials, particularly due to gastrointestinal toxicities.”
They also noted that “The critical role of CEA expression heterogeneity and plasticity as determinants of treatment resistance in our in vitro models may be relevant for the characterization of predictive biomarkers for CEA-targeting immunotherapies in CRC where heterogeneous CEA expression has been described. Moreover, finding strategies to increase CEA expression may increase the clinical responses of cibisatamab.”