With David Cheresh, PHD, Distinguished Professor & Vice Chair of Pathology at Moores Cancer Center, University of California, San Diego
By Sarah DiGiulio
A new therapeutic approach to killing cancer cells has researchers excited. A study identified an antigen that arises on the surface of drug-resistant tumors and showed this antigen can be targeted by a therapeutic antibody (Cancer Res 2019; doi: 10.1158/0008-5472.CAN-19-1246). Additionally, the research revealed the antibody utilizes tumor-associated macrophages (which typically promote tumor cell growth) to actually destroy these drug resistant tumor cells. In the presence of the therapeutic antibody, these tumor-associated macrophages become armed to recognize and eliminate cancer cells in mouse models.
"This antibody is designed to seek and destroy the most stem-like, drug-resistant, aggressive tumor cells. It does this by building a bridge between tumor-associated macrophages and these highly aggressive tumor cells," stated David Cheresh, PhD, Distinguished Professor and Vice Chair of Pathology at Moores Cancer Center at University of California, San Diego.
In this trial, researchers did not observe tumor growth or drug resistance in the mouse models treated with this antibody, whereas the tumors in the untreated mice did grow and metastasize. For this study, the therapy was tested in pancreatic and lung cancer cells, but the researchers have designed a new humanized version of this antibody they expect to work similarly in patients in combination with other cancer drugs. Cheresh told Oncology Times about the new therapeutic approach and promising findings.
1. What are the key findings in this paper—and how are they different from other research on tumor-associated macrophages?
"Tumor-associated macrophages typically promote the growth and metastasis of cancer. They do this by releasing cytokines and factors that enhance tumor cell growth, invasion, and survival. They also promote angiogenesis and immune suppression of the cancer by preventing T cells from entering the tumor. This results in a tumor that is not well-recognized by the immune response. So, in essence, tumor-associated macrophages contribute to the progression of cancer in multiple ways.
"While tumor-associated macrophages typically act to promote tumor growth, we discovered that a particular antibody that targets a human tumor cell antigen avb3 simultaneously interacts with a receptor on tumor-associated macrophages enabling [those macrophages] to come in contact with the tumor cells—and in so doing promotes tumor cell death. This occurs through a process referred to as 'antibody-dependent cellular cytotoxicity.'
"So, while tumor-associated macrophages contribute to the tumor growth and progression, when armed with our therapeutic antibody their role becomes reversed, such that these tumor-associated macrophages are recruited to actually destroy the tumor cells.
"It is also important to point out that the tumor cell target avb3 of this antibody is expressed on cancer stem cells, which are among the most drug-resistant cells within the tumor. So the antibody is being used to recruit tumor-associated macrophages to eliminate the drug-resistant tumor cells, and we have found this dramatically prolongs the tumor response to standard of care."
2. If this type of therapeutic approach was used in patients with cancer, how would it work?
"We have now designed a new humanized antibody that has both the avb3 binding properties, along with the highly specific macrophage recruitment capacity of the murine monoclonal antibody. A first generation of this antibody was clinically evaluated years ago, but at that time we did not appreciate the requirement for the macrophage binding activity. The original humanized antibody does not have this property, but our new antibody has been re-engineered with this in mind. Our goal is to advance this newly designed humanized antibody into the clinic by the end of next year. Based on the first version of this antibody tested in man, we expect it to be safe—but we also hope to see improved efficacy based on our new design parameters.
"It is important to note that our approach allows us to destroy tumors that express high levels of the 'don't eat me' molecule, CD47, since our antibody induces antibody-dependent cellular cytotoxicity-mediating killing, and does not induce macrophage-mediated phagocytosis."
3. What is the bottom-line message about your work and the next steps of translating this technology into clinical therapies?
"We have now re-engineered a human antibody that we hope will do in man what our murine antibody does in the mouse—arm and recruit tumor-associated macrophages to destroy the tumor. We have a good idea what in vitro parameters are required to select the optimally designed antibody. Once this is done, we plan to initiate IND enabling studies early next year with the hope that phase I trials will begin by early 2021.
"Ultimately, we hope to test this antibody in patients with advanced lung cancer and other epithelial cancers that have developed resistance to standard of care since those tumors express high levels of the antigen avb3 and also contain a large number of tumor-associated macrophages, which are the two requirements needed for this therapy to succeed.
"We believe this is a whole new way of exploiting the immune system to gain a therapeutic benefit to attack cancer. Our goal is to develop antibodies that now only hit an appropriate target at a particular stage of tumor progression and do so in the context of the appropriate effector cell. In this case, we are exploiting the tumor-associated macrophages. Normally, [these macrophages] contribute to tumor progression; however, in the presence of our antibody, we have reversed this effect by activating these macrophages to attack some of the most aggressive drug resistant cells in the tumor."