Our last speaker is Dr. Pakhawat. I'm sorry, I'm going to mispronounce your last name. I'm very sensitive to that. The title of the discussion is Symphony, a novel synergistic nanotechnology-based platform for the improvement of laser interstitial therapy. Okay, last one, please bear with me. Good afternoon, everybody. My name is Pakhawat Jongsathit Kiat. I'm a second year PhD student working in the lab of Dr. Peter Fetchy. We are part of the Brain Tumor Immunotherapy Program, Duke Neurosurgery. I have no actual or potential conflict of interest to declare here. So I'm going to start my talk with this slide. Intracranial tumor has a unique therapeutic challenge, and these brain tumors include the primary American tumors such as glioblastoma or GBM. It also includes brain metastases from metastatic cancer from the systemic other cancers. So this group of brain tumor have poor prognosis. The conventional treatment including surgical rejection, chemotherapy, and radiations has shown limited efficacy. Not only these treatment not effective, but they also has side effect on their normal brain tissue surrounding them. So immunotherapy emerged as promising novel treatment modality for this cancer, given that their ability to distinguish cell from non-cells. So we owe into its specificity, this immunotherapy will only cure the tumor cell, but spare the normal brain cells. However, immunotherapy for brain tumor is not without limitations. One of the biggest limitation for immunotherapy is the access to the CNS as imposed by brain barrier. Before we move on, let's get to know this new term. The laser-induced interstitial thermotherapy, or LIT, has emerged as the new modality of minimally invasive treatment that used to do the ablation of lesion in the brain. So therefore, it's promote using of this new technology in different intercranial lesions. So let's get to know a little bit more about LIT. So LIT is a minimally invasive tool for lesion ablation, as I mentioned before. And the size of incision is normally less than one centimeter. It's stereotactic introduction of catheter with laser diode into a lesion. And with using robotic control of depth and directionalities, conducting intraoperative or a de-exnoted MRI suite with real-time MRI tomography, used to cook the lesion from inside out. And the most important thing is there's a computer software that we can use to calculate their zone of killing based on the MRI imaging data that we get. And typically, the patient will go home the next day. So as I mentioned before, the LIT technology has three main components. They are laser probe. Right now, there are two competing companies out there. So it just are the variety of options that is available in the market. The second component is the robotic control that use... the surgeon can use this platform to control the system from the control room. And the last thing would be the MRI tomography that use their computer software based on the equations to calculate the zone of temperature and the zone of killing. The next thing that I would like to emphasize over here is their mechanism of killing is not the light. Because as you can see over here, the laser light penetration into the tissue is only about two millimeters. But the zone of killing expanding to 1.5 centimeter in radius or 3 centimeter in diameter. So it's the heat that induced the irreversible tissue destruction and protein denaturation. So the cell death is the function of the temperature and the time of exposure. I'm not going to go too much into detail about LIT. But now I'm going to just link the thing that we talk about together. So if you know this person, his name is William Coley. And then he is recognized as the father of immunotherapy. In the late 19th century, he administered what is called the colitoxin, which is the mixed bacterial vaccine for cancer treatment. And he has shown that patients that develop higher fever after vaccine administration have better outcome. So what I'm trying to say here is that the origin of the hyperthermia and immunotherapy for cancer treatment, they actually share the same origin. Also, there's a lot of study out there that has shown the mechanism behind that how hyperthermia treatment can enhance the cancer immunotherapy, including increased T cell and NK cell markers on the tumor, heat shock protein, tumor exosome release, and also direct activation of the infiltrating immune cells. And one of the things that is very important over here is that it also has been shown to increase perfusion and vascular permeability. And as I mentioned before, that the bad brain barrier is kind of a problem over here because it limits access of immunotherapy to the tumor. Come back to immunotherapy, one of the most promising immunotherapy among all of them is the immune checkpoint blockade that has been shown efficacy in various types of cancer. One of the well-known immune checkpoint blockade has something to do with the PD-1, PD-L1 axis, and these molecule, the PD-1 normally expressed on T cell and PD-L1 normally expressed on tumor cell or other cell like dendritic cell. So these serve as the natural mechanism to prevent autoimmunity or prevent T cell from being too active. But in the setting of tumor, we want this system to be more active because we want T cell to do their job and kill the tumor. So right now, we introduced two modality of the novel cancer treatment, which immunotherapy that I talk about the limitation of being limited access to the CNS and also poor local activations. And also the laser, although laser seemed to address those limitations that imposed by immunotherapy, it still has the limitation of the range of delivery and also the lack of specificity. So maybe we need a third helper over here. So on your left-hand side, what you can appreciate is the electron microscopic picture of the metallic nanoparticle. This one is called nanostar because it's shaped like star. And it's something we call plasmonic nanoparticle. So what it can do is it can absorb the light, for example, when we deliver the laser and amplify the signal and convert it into heat. So it acts like a lightning rod that absorbs the light and then converts the heat to the place that we deliver it to. One of the best things about this gold nanostar that we developed is that we have shown that it specifically accumulated within the tumor lesions. So with that being said, when we combine the laser together with nanostar, we would be able to obviate one of the limitations of the laser, which is non-specific treatment boundary. Combined with immunotherapy, which is anti-PD-1 over here, we hope to activate the immune system and develop a long-term memory of the immunotherapy. So we come up with this cool term, which is SYMPHONY. So it stands for synergistic merging of photothermal therapy and nanotechnology. So it's laser plus nanotechnology and immunotherapy. And here are some of our preliminary data. So in this experiment, we used the subcutaneous model of malignant glioma. You can appreciate that the group that has gold nanostar plus laser plus the with or without anti-PD-1 has the lowest tumor volume compared to other groups. Only these two groups also has long-term survivor, which has a tumor-free survivor. And we also re-challenged the long-term survivor with tumor cells on the contralateral site subcutaneously. And our data demonstrate that only the group with anti-PD-1 has the lowest tumor volume. And the group with high PD-L1 reject the tumor re-challenge, implying that this group of mice develop long-term immunologic memory to prevent the recurrence of the tumor. And we move on from subcutaneous model into intracranial model of mouse model of malignant glioma. So in this picture, what you can appreciate is we use the 700 micron microfiber to deliver the laser into the intracranial compartment of our mouse model. And on your right-hand side is the T2 MRI imaging, showing that only the group that get the gold nanostar together with laser develop their cytotoxic edema compared to the group that only get laser. So our next step would be moving into larger animal models that we can manipulate more. And hopefully, this will turn into something that can be translatable to the clinics very rapidly. With that being said, I would like to thank all the members of FETCHI lab, the Duke Brain Tumor Inner Therapy, and our collaborators, WODi lab, COD lab, and Laskala lab. And thank you very much.

Dr. Pakhawat Jongsathit Kiat

Symphony

nanotechnology-based platform

laser interstitial therapy

brain tumor treatment