UCLA Oncologist Pursues Promise of CSF1R Inhibitor Combos

Zev Wainberg, MD

Wainberg, an associate professor of medicine and co-director of the gastrointestinal (GI) oncology program at UCLA Medical Center in Santa Monica, California, focuses on the molecular classification of GI malignancies and the development of novel therapeutics.

What is the function of CSF1R in normal cells, and how is it involved in promoting cancer?

How is CSF1R being targeted for anticancer therapy, and what is your interest in that?

He has been involved in the development of CSF1R inhibitors pexidartinib and cabiralizumab and is serving as the lead investigator for a clinical trial evaluating cabiralizumab in combination with nivolumab (Opdivo) in patients with pancreatic cancer. Wainberg presented data from the pancreatic cancer cohort of this trial at the 2017 Annual Meeting of the Society for Immunotherapy of Cancer (NCT02526017).In a normal cell, it’s not entirely clear what the role is of CSF1R. It does help to stimulate macrophage growth, and it does help on some level to ensure that certain macrophages continue to grow and function. In cancer cells, it serves the same purpose. The problem is that in this setting it’s generally a driver for tumor-associated macrophages [TAMs]—those that are more inclined to be critical for tumor development.The concept of targeting CSF1R stems from the notion, made clear in several scientific publications, that blockage of CSF1R will destabilize TAMs and perhaps even convert them to more functional macrophages—those that really serve a useful purpose. By blocking the primary growth stimulator of those macrophages, which is the CSF1R, the concept has been put forward that it will deplete those TAMs and lead to less growth potential of the tumors themselves.

In your opinion, which are the most promising drugs in this class?

Where do you see the development of CSF1R inhibitors heading?

Conceptually, that was put forward a number of years ago. A single avenue of blockade is insufficient, for the most, to adequately shrink the tumors, because the tumors simply don’t have enough immune cell infiltrates or immunedriven components to kill them off. My interest, along with several others, has been to combine blockade of the CSF1R, and therefore TAMs, along with stimulating increased availability of T cells through checkpoint inhibitors, thus allowing those T cells to better penetrate into the tumor. It’s hoped that the combination will have a better chance of antitumor activity.Our data [on] the CSF1R monoclonal antibody, cabiralizumab, [is] probably some of the most robust data presented to date in the field. But there are also several kinase inhibitors, which come with several pros and cons, and some antibodies that block the ligand. As with many targets in oncology, there are a few ways to skin this cat. The approach that we selected was with an antibody that blocks the receptor directly, primarily because CSF1R is the main driver. So combining it with checkpoint inhibitors particularly makes sense.Across oncology, these inhibitors are being studied in many cancer types, not just pancreatic cancer. But in pancreatic cancer, perhaps, as we demonstrated in our trials, there were responses in some patients who would otherwise not be expected to respond to immunotherapy. We were compelled enough by those results to add another 30 patients to our cohort, which is now nearly completed and will include a total of 60 patients. Beyond that, there is a second trial that has been launched, which is in pancreatic cancer as well but with a strategy that combines these antibodies with chemotherapy, which may ultimately be the best approach. That is one approach that is moving its way forward as we speak.

Are there concerns about added toxicity with the immune combination?

If we can identify which patients are responding and who gets benefit from this combination treatment strategy, then it will be easier to develop these drugs, with chemotherapy in particular. While we did see some responses, certainly there weren’t enough, so we want to develop this drug for a broader range of patients, and that involves finding perhaps a chemotherapy combination that is effective and developing biomarkers. There are biomarkers that are being developed as we speak and hopefully one of them will be clinically validated.Whenever you do double immune blockade, you are, of course, increasing toxicity. Some of them are acceptable toxicities that are not going to lead to significant deterioration in quality of life. For example, the most common one we probably see in our trial is fatigue, which is generally tolerable. Additionally, in our trial and several other trials of CSF1R inhibitors, you do see some very classical increases in certain blood tests that don’t really have any clinical consequences.

Wainberg ZA, Piha-Paul S, Luke J, et al. First-in-human phase 1 dose-escalation and expansion of a novel combination, anti-CSF-1 receptor (cabiralizumab) plus anti-PD-1 (nivolumab), in patients with advanced solid tumors. Presented at: 2017 Annual Meeting of the Society for Immunotherapy of Cancer; November 8-12, 2017; National Harbor, MD. Abstract O42. jitc.biomedcentral.com/articles/10.1186/s40425-017-0297-3.

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The future of anticancer strategies aimed at colony stimulating factor 1 receptor (CSF1R) most likely lies in combinations that include immune checkpoint therapies and chemotherapy, according to Zev A. Wainberg, MD.