TNF Protein and Immune Response in Prostate Cancer

How a Particular Protein (Tumor Necrosis Factor) Might Control the Immune Response in Prostate Cancer” Brad Power and Kristen Warren October 30, 2024 “Blocking TNF with existing, approved FDA drugs may enhance immunotherapy efficacy in prostate cancer by reprogramming the tumor microenvironment to promote a more robust anti- tumor immune response.” – Ida Deichaite, PhD

Advanced prostate cancer patients are always searching for more treatment options, especially since each therapy eventually fails. Immunotherapies for cancer are very attractive since they can result in a more durable response, and the side effects can be less severe. Prostate cancer has been considered a harder cancer type to apply immunotherapies to, yet research continues on new approaches.

One of these is using a particular protein, the Tumor Necrosis Factor, to control the immune response. The translational goal is to make prostate cancer respond to immunotherapies.

Ida Deichaite, PhD, Assistant Adjunct Professor, Radiation Medicine and Applied Science, at the University of California, San Diego, is uniquely qualified to describe the state of research into therapies using the Tumor Necrosis Factor to modulate the immune response in prostate cancer. Dr. Dechaite's background is in virology and molecular biology. She is conducting genomics analysis to identify susceptibility targets for aggressive cancers.

The overarching goal of her research program is to identify and validate actionable targets and new targetable mechanisms for oncology diagnostic and therapeutic development. Her bench-to-bedside approach to studying real-world genomics paired with clinical data facilitates rapid translation into the clinic and access to patients. What should you know about this novel immunotherapy approach?

This is a hypothesis, like many, of a possible avenue for controlling cancer, in this case focused on prostate cancer. The hypothesis is that blocking a particular protein (Tumor Necrosis Factor) with existing drugs approved by the FDA that may enhance immunotherapy efficacy in prostate cancer by reprogramming the tumor microenvironment to promote a more robust anti-tumor immune response.

It is in a research phase and will have to go through clinical trials, which are being developed, before it will be accessible to patients. The opportunity is to launch an exploratory clinical study to test the hypothesis of using TNF inhibitors in combination with checkpoint inhibitors. The study would involve pre-treating patients with TNF inhibitors and analyzing biomarkers of immunosuppression post-treatment. How can you learn more about this?

Brian McCloskey: We are very happy to have Dr. Ida Deichaite from UC San Diego join us. Ida is an assistant Adjunct Professor of radiation medicine and applied science at UC San Diego. She's a molecular biologist by training, and she's been doing significant research on tumor necrosis factor, TNF, and its relationship to immune response in prostate cancer. Beyond that, she is the director of industry relations at Moores Cancer Center.

Ida and I go back to, I think 2017, when she boldly asked me to present some hair brain idea that I had about how medicine should be approached, and we've been fast friends ever since then. She and her teams have been very helpful in terms of looking at my genomic and multiomic data to identify potential treatment options. She’s an amazing friend, and we are looking forward to having her talk.

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Ida Deichaite: I focus more on the patient group here, because I figured that if we want to get deeper into science, we can just connect with the researchers here. I just wanted to bring everybody on the same page and think about the research we're doing, or specifically by my team, and how we can think about it in terms of translational approaches (bringing research from the lab to patients), and how we can take it to patients.

“How a Particular Protein (Tumor Necrosis Factor) Might Control the Immune Response in Prostate Cancer” The title, which I discussed with Brad, focuses on TNF – how a particular protein, in this case, tumor necrosis factor, might control the immune response in prostate cancer. We'll just organize ourselves around this.

I will start with the hypothesis, because we'll repeat the hypothesis several times as we get to know a little bit more about the data. As you can see it's clearly stated, we think that blocking TNF with existing, approved FDA drugs may enhance immunotherapy efficacy in prostate cancer by reprogramming the tumor microenvironment to promote a more robust anti tumor immune response.

And we really are thinking about checkpoint inhibitors, which are widely available and FDA approved. And this really comes from the clearly unmet need we are wanting to understand, how can we improve the efficacy of checkpoint inhibitors in prostate cancer? And we'd try to understand what makes prostate cancer cold. So the hypothesis is really to address this unmet need.

“How a Particular Protein (Tumor Necrosis Factor) Might Control the Immune Response in Prostate Cancer” So just to bring everybody on the same page by refreshing our understanding of TNFs function in inflammation. Inflammatory processes are complex, and TNF plays multiple roles within them. It acts on various pathways initiating and regulating the body's response. So let's explore these effects in more detail.

TNF is implicated in the inflammatory response. TNF appears to be sort of at the head of the inflammatory cascade, and it initiates a lot of a signaling that eventually becomes kind of a chain effect and accomplishes what needs to be done to address pathogens or any sort of cell problems that need to be removed from the system. So that includes initiating the inflammatory response just like I said.

What's interesting is it’s heavily involved in activating endothelial cells, helping the peripheral immune cells reach their targeted tissue size. So it helps to localize the immune cells to the actual tissue where pathogens took over, or there is any other reason to remove infection in those tissues. So it also increases vascular permeability, further enabling the reach of peripheral immune cells into the affected areas.

It turns out that TNF may also be involved in clearing the inflammatory response, and that's another effect that TNF has. When TNF is over expressed for a period of time. It often leads to autoimmune diseases, and that's kind of a place where TNF has been targeted successfully.

“How a Particular Protein (Tumor Necrosis Factor) Might Control the Immune Response in Prostate Cancer” We know today that there are many TNF inhibitors which are widely used in clinics in autoimmune diseases. So HUMIRA is one of the key biologics that are used widely, but the first approvals came in as early as 1998 and obviously these are widely used drugs. They capture a huge market share, 15 billion globally.

Today, we already have biosimilars coming along, such as Amjevita and Cyltezo, so access to these drugs is pretty well addressed. And what we know from using those drugs or those drugs being in the clinic from 1998 is that they have a well established safety profile, and they're considered to be generally safe. While there are some risks, they can be managed with regular monitoring.

“How a Particular Protein (Tumor Necrosis Factor) Might Control the Immune Response in Prostate Cancer” So what's interesting to me, and where I'm focusing, is that it turns out that at some point the inflammatory response needs to be resolved to allow tissue healing. Currently, it's a very hot field of research, and the mechanisms driving this transition from inflammation to healing are being studied.

However, what's really interesting to me is that TNF may play a role in this process too, and so TNF has a dual function, it has an inflammatory function that's very well understood, but it may also have an immunosuppressive function that is less understood. Lately I see more and more literature on that, and more and more research on that.

So what we are thinking, based on our genomic study, is that in prostate cancer, the prostate exploits TNF or hijacks TNF driven immunosuppressive mechanisms, and that contributes to cold tumor microenvironment and reduced response to checkpoint inhibitors.