In this monologue Dr. Dino Prado (founder of Envita Medical Center) critiques the limited and often transient efficacy of PD‑1/PD‑L1 checkpoint inhibitors, noting that only about 19% of patients achieve a response that typically lasts around 10 months. He explains that resistance arises from tumor antigen loss, immune exhaustion, and a suppressive tumor microenvironment (TME) populated by regulatory T cells, myeloid suppressor cells, and additional checkpoints such as TIM‑3, LAG‑3, and TIGIT. Prado argues that a one‑size‑fits‑all PD‑1 strategy is insufficient and advocates for precision, n‑of‑1 immunotherapy guided by spatial biology, deep immunoprofiling, and genomics. By mapping each patient’s tumor ecosystem—identifying cold vs. hot regions, cellular neighborhoods, and checkpoint expression—clinicians can design tailored therapies, including engineered natural killer (NK) cells and dendritic cell vaccines, oncolytic viruses, and agents that remodel the TME (e.g., vascular normalization, checkpoint blockade beyond PD‑1). He cites his decade‑long clinical experience, claiming that combining these approaches can raise response rates from ~19% to 85‑95% and achieve durable, long‑term remissions. The talk concludes with a hopeful call for patients to seek precision oncology rather than rely on standard PD‑1 monotherapy.
Chapters
Most people think immunotherapy is a silver bullet. The truth only about 1 in 5 patients actually get strong responses with things like PD1 inhibitors. Long term, it's actually less than that. And even then, it often fades. That's not failure, it's a signal. We need precision immunotherapy, personalized to each patient's tumor biology. I'm Dr. Dino Prado, founder of Envita Medical Center. For the last several decades, I've seen patients that have tried everything and tried different immunotherapies, whether conventional, integrative and. Today we're going to take a look at the real data, why these treatments fail. We've been using PD1 inhibitors for longer than a decade, on and off label. And I can tell you they don't work as people expect them to. Often we'll talk about why they fail and why n of 1 planning. With immunotherapy, immunoprofiling and spatial biology can really turn a tumor that's cold, hot, and finally help response. This is really the important piece. So let's take a look at the big picture. Across cancers, we have these PD1, PD L1 drugs which have really exploded the world of immunotherapies. These are called checkpoint inhibitors. You hear about them and on average response rates are about probably 19. According to Frontier oncology, the mean benefit may last maybe around 10 months. But some cancers do better, like melanoma, lung cancer. These cancers that respond well to immunotherapy, but many do worse. Even when patients respond, resistance often develops. Sometimes the tumor itself changes, loses its ability to present these antigens because as you can see, a tumor on the outside of it. Think of it like a snake that sheds its skin. It's its antigen, and that antigen needs to be released so the immune system can recognize it. With dendritic cell, move it to the natural killer cells so it can kill cancer. Oftentimes this just doesn't work, or you get immune exhaustion where the natural killer cells are run down, exhausted and not operating well. And the immune system environment really just shuts down these T cells. Because if you look at the neighborhoods of cells outside the tumors, called the tumor microenvironment, it's blocking the T cells from responding, things like FoxP3T regulatory cells and others that are just blocking the immune system from doing its work. So what does this mean? Immunotherapy works powerfully when it's targeted, get the right treatment, the right durable results, because they don't have the right immunotherapy. So basically, if you're just doing an immunotherapy that's a PD1 inhibitor, likelihood is it isn't going to work long term and you're going to need more targeting. It's not the end of the story. So immunotherapy can stall these checkpoint drugs, release breaks that allow t to attack the tumor. But what those T cells are exhausted, too far gone to bounce back. And others are blocked by additional checkpoints like TIM3, LAG3, or TIGIT and others. But the important thing to remember here is that immune exhaustions can also occur by chemotherapy and radiation and other treatments that our patients are getting, which is actually weakening their immune system because it's not targeted and it's a too high of a dose. So this is the important thing. When we're looking at a cancer and we're looking at immunotherapy, we have to understand tumor microenvironment. That's the environment around the tumor. Some tumors are cold. That means they hardly have any good T cells to kill the tumor. They're being blocked by dense stromal barriers. They're sending signals to shut down. Or there's other cells in those neighborhoods that are blocking those cells, those natural killer cells, those immune cell. And if you don't know why the tumor is cold and not responding, you can't design a plan to make it work. Remember, the immune system is the first and last defense against cancer. And if your immune system was working correctly in the first place, it gets rid of early mutations. It does it every day. About 10,000 early mutations are removed by a healthy immune system. But when that's not happening, the cancer cell can expand and grow. So in this case, we have cancer that is growing with an immune system that's being evaded. So that's why standard PD1 therapies often fail. It's not just the wrong tool, it's just incomplete. For most patients, the end one mapping is really the difference here. So n of one is where we mapping the tumor and the immunotherapy on you, the patient, on your specific tumor. So how do we fix what's going on today? We take the guesswork out. We use spatial biology and lets us look at the tumor. T cells, myeloid suppressive cells, all the neighborhood of cells, FoxP3 and other cells that are blocking it, checkpoints, cytokines, which are these, you know, immune modulatory signaling agents and allows us to look at it in a holistic way and then sit down and re engineer care to turn that on. And this makes a difference. And one of the most advanced forms of immunoath is where we take natural killer cells out. Dendritic cells target them to damps, which are essentially antigens and information in your blood and in your body that tells us about the tumor. And then these cells are returned, usually into the billions, with high cytotoxic activity to go after and kill cancer cells. But it's typed after your cancer. Now the natural killer cells and your dendritic cells can see the cancer because it has the right antigens and the right information that's been mapped. So the mapping is critical. For example, if you have suppressive macrophages of one type of macrophage versus another, an M2 to an M1 sitting right next to tumor cells, then, you know, these cells are stuck. They're not able to work. These patterns can predict better response to the PD L1. They can predict whether it's going to work or not. We can do that with precision medicine, and we can change that behavior by introducing the correct agents to help change that environment. Recent studies have shown when we combine spatial biology with genomics and immunoprofiling, we can predict response dramatically. Precision immunotherapy isn't just giving a PD1 and hoping for the best, which is what's going on. It's designing a plan around unique ecosystems for each tumor. I can tell you because for like I said, over about a decade now, We've been using PD1s on and off label, and we knew their limitations. But when you combined with other immunotherapies, you can get better responses. And that's what we've seen clinical with precision oncology. So here's a simplified way for you to see this, because I might have gotten into too much medical language or scientific language, But I want you to understand this. Increasing tumor visibility is critical. Your tumor is hiding from your immune system. We need to turn that on. So we can use tools like oncolytic viruses. We can use tools like antigen presenting, building and stabilizing the immune system targeted therapies. We can use genomics, transcriptomics, and other tools to help. We can help your immune system see the cancer improve T cell integrity. In fact, we can help reduce the blood vessels to the tumors while increasing the T cell activity to the tumor. We can guide the T cells right to the tumor so they can kill them. We can block some of these things that are suppressing it, like other markers that are occurring, like Lag3 or Tim3. And myeloid suppressive cells. We can change these things because we know they're there and we can have the targeted agents to aff patient because each patient is different. So instead of seeing the T cells shut down, we can turn them on and get them to work. The PD1 drugs alone don't do all of this. So we need to keep the T cells fit, we need to keep them oriented and we need the tools in precision medicine to know exactly where we're going. So we get good cell based therapy to prevent re exhaustion of the cells and to also help the cells attack the tumor. Every tumor playbook is going to be different. That's why n of 1 is essential. So this is when we say n of 1, it's customly built for you and with the aim of durability in care isn't magic, it's mechanics, it's data. Keep the tumor visible, keep the T cells working to kill the cancer, keep the cells from getting exhausted and your immune system is going to do the job because it's so powerful. The average response today may be around 10 months if you're fortunate. But that's a baseline, not the ceiling. With precision immunotherapy, we can aim for long term remissions, longer term responses. And going at this from a much more comprehensive, holistic approach to the immune system. Immunotherapy changes oncology forever. But the don't save individuals. So it's important that you get precision oncology to really understand what's the best immunotherapy for you. How to take a tumor that's cold, make it hot. We need to move away from just a standard PD1 therapy. That may not be enough. So the answer in my clinical experience and our work is precision treatment. N of 1 targeting guided by spatial biology, deep immune mapping, deep learning of the immune system, immune profiling, that's how we move beyond this 19% average response of the PD1 inhibitor and get a much higher response, maybe closer to 85 or 95, 90% responses because we are custom building it for the patient. That's the goal, that's what we want. Durable remissions. So this is why immunotherapy works so well for some patients, but fails for most. It's exactly what we just went over. People aren't getting precision targeting, they're just getting a one size fits all model that isn't working. I hope this was helpful. So don't lose Hope if your PD1 inhibitor isn't doing what you hope it would do. Because it usually doesn't. For most patients, you need the right targets for you. And that's what we're here to do. That's what the promise I believe, of precision oncology offers us in the future is to help people live longer, with a better quality of life and dare to say, reach long term remissions. May the Lord bless you on your journey to healing.
