Discovery could lead to new treatments for cancer and tumors, but probably not to any new diagnostic assays for clinical laboratories
Researchers at the University of Texas Southwestern (UTSW) Medical Center have reported discovery of “acid walls” that appear to protect various types of cancer tumors from attack by the body’s immune system cells. Though the discovery is not directly related to a biomarker for a clinical laboratory diagnostic test, the basic research will help scientists develop ways to address the tumor’s acid wall strategy for defeating the immune system.
The UT scientists made their discovery using an internally developed imaging technique that employs nanoparticle probes to detect levels of acidity in cells. The research, they suggest, “could pave the way for new cancer treatment approaches that alter the acidic environment around tumors,” according to a UTSW press release.
“This study revealed a previously unrecognized polarized extracellular acidity that is prevalent around cancer cells,” said lead study author Jinming Gao, PhD (above), Professor in the Harold C. Simmons Comprehensive Cancer Center and head of the Gao Lab at UT Southwestern Medical Center, in a press release. Gao believes the study “will lead to several new lines of research, such as studies to better understand how cancer cells polarize their acid excretion, how those cells can withstand the acidity level that kills CD8+ T cells, and how to inhibit acid excretion to allow T cells to better kill cancer cells,” the press release notes. (Photo copyright: University of Texas.)
Developing Acid Walls
As explained in the press release, scientists have long known that cancer cells are slightly more acidic than most healthy tissue. Gao and his team designed a nanoparticle known as pegsitacianine—a pH-sensitive fluorescent nanoprobe for image-guided cancer surgery—that disassembles and lights up when exposed to the acidic conditions in tumors.
However, “it was unclear why these nanoparticles fluoresced since a tumor’s acidity was thought to be too mild to trigger their activation,” the press release note.
To learn more, they used nanoparticle probes to illuminate a variety of individual cancer cells sampled from humans and mice, including lung, breast, melanoma, and glioblastoma, as well as tumor tissue. They discovered that the cancer cells secreted lactic acid—a waste product of digested glucose—at higher levels than previously known. The cells “pumped” the acid away from their malignant neighbors to form a protective “acid wall” around the tumor, the researchers noted in Nature Biomedical Engineering.
“Samples from human tumors showed that this acid wall was practically devoid of CD8+ T cells within the tumors, an immune cell type known to fight cancer,” the press release states. “When the researchers grew cancer cells and CD8+ T cells together in petri dishes that had been acidified to a 5.3 pH, the cancer cells were spared while the CD8+ T cells perished within three hours, suggesting that this severe acidity might thwart immune cell attack without harming the cancer cells.”
Gao’s team previously discovered that sodium lactate, the “conjugate base of lactic acid” as they describe it, increases the longevity of T cells and thus enhances their cancer-fighting capabilities. The researchers described the two molecules—lactate and lactic acid—as “Dr. Jekyll and Mr. Hyde,” and suggested that future therapies could seek to convert lactic acid to lactate.
“Gao noted that this discovery will lead to several new lines of research, such as studies to better understand how cancer cells polarize their acid excretion, how those cells can withstand the acidity level that kills CD8+ T cells, and how to inhibit acid excretion to allow T cells to better kill cancer cells,” the press release states.
Commercializing the Technology
Pegsitacianine was designed to aid cancer surgeons by illuminating the edges of solid metastatic tumors in real time during surgery, a 2023 UTSW Medical Center press release explains. About 24 hours prior to surgery, nanoprobes are delivered via IV. Then, the surgeon uses a near-infrared camera to visualize the cells.
UTSW has licensed pegsitacianine to OncoNano Medicine, a Dallas-area biotech startup launched to commercialize technologies from Gao Lab. Gao and his colleague Baran Sumer, MD, Professor and Chief of the Division of Head and Neck Oncology in UT Southwestern Medical Center’s Department of Otolaryngology and co-author on the study, both sit on OncoNano’s advisory board.
In January 2023, OncoNano announced that pegsitacianine had received Breakthrough Therapy Designation for Real-Time Surgical Imaging from the US Food and Drug Administration (FDA), which will fast-track the technology for development and regulatory review.
In a Phase II clinical trial published in the Annals of Surgical Oncology, the researchers tested the technology as part of cytoreductive surgery in patients with peritoneal metastases. However, a November 2023 UTSW press release noted that the technology is “tumor-agnostic and could potentially be used in other forms of cancer.” It is currently ready for Phase 3 trials, according to the OncoNano website.
More research and studies are needed to better understand this dynamic of cancer cells. Collectively, this research into cancer by different scientific teams is adding new insights into the way tumors originate and spread. At this time, these insights are not expected to lead to any new diagnostics tests that pathologists and clinical laboratories could use to detect cancer.
Scientists reported positive Phase 1 trial results of their “intratumoral microdevice” in patients with glioma tumors
Here is an example of new microtechnology which has the potential to greatly shorten the time and improve the ability of physicians to determine which anti-cancer drug is most effective for an individual patient’s glioblastoma. As it is further developed, this technology could give anatomic pathologists and clinical laboratories an increased role in assessing the data produced by microdevices and helping physicians determine the most appropriate anti-cancer drug for specific patients.
In a news release, researchers at Brigham and Women’s Hospital (BWH) in Boston said they have developed an implantable “intratumoral microdevice” (IMD) that functions as a “lab in a patient,” capable of gauging the effectiveness of multiple drugs that target brain tumors. In a Phase 1 clinical trial, they tested the IMD on six patients with glioma tumors.
“In order to make the greatest impact on how we treat these tumors, we need to be able to understand, early on, which drug works best for any given patient,” study co-author Pier Paolo Peruzzi, MD, PhD, told the Harvard Gazette. “The problem is that the tools that are currently available to answer this question are just not good enough. So, we came up with the idea of making each patient their own lab, by using a device which can directly interrogate the living tumor and give us the information that we need.”
Peruzzi is Principal Investigator at the Harvey Cushing Neuro-Oncology Laboratories and Assistant Professor of Neurosurgery at Harvard Medical School.
“Our goal is for the placement of these devices to become an integral part of tumor surgery,” said Pier Paolo Peruzzi, MD PhD (above) of Brigham and Women’s Hospital and Harvard Medical School in an article he co-wrote for Healio. “Then, with the data that we have from these microdevices, we can choose the best systemic chemotherapy to give to that patient.” Pathologists and clinical laboratories may soon play a role in helping doctors interpret data gathered by implantable microdevices and choose the best therapies for their patients. (Photo copyright: Dana-Farber Cancer Institute.)
New Perspective on Tumor Treatments
In a news story he co-wrote for Healio, Peruzzi explained that the microdevice—about the size and shape of a grain of rice—contains up to 30 tiny reservoirs that the researchers fill with the drugs they want to test. Surgeons implant the device during a procedure to remove the tumors.
The surgery takes two to three hours to perform, and during that time, the device releases “nanodoses” of the drugs into confined areas of the tumor. Near the end of the procedure, the device is removed along with tissue specimens. The researchers can then analyze the tissue to determine the effectiveness of each drug.
“This is not in the lab, and not in a petri dish,” Peruzzi told Harvard Gazette. “It’s actually in real patients in real time, which gives us a whole new perspective on how these tumors respond to treatment.”
The Healio story notes that gliomas are “among the deadliest brain cancers and are notoriously difficult to treat.” With current approaches, testing different therapies has posed a challenge, Peruzzi wrote.
“Right now, the only way these drugs are tested in patients is through what are called window-of-opportunity studies, where we give one drug to the patient before we resect the tumor and analyze the effect of the drug,” he said. “We can only do this with one drug at a time.”
Determining Safety of Procedure
The primary goal of the Phase 1 trial was to determine the safety of the procedure, Peruzzi noted. “To be in compliance with standard clinical practice and minimize risks to the patients, we needed to integrate the placement and retrieval of the device during an otherwise standard operation.”
The trial consisted of three men and three women ranging from 27 to 86 years old, with a median age of 76. Five were diagnosed with glioblastoma and one with grade 4 astrocytoma.
“None of the six enrolled patients experienced adverse events related to the IMD, and the exposed tissue was usable for downstream analysis for 11 out of 12 retrieved specimens,” the researchers wrote in Science Translational Medicine. They noted that application of the IMD added about 32 minutes to the time required for the surgery, equating to a cost increase of $7,800.
One drug they tested was temozolomide (TMZ), “the most widely used agent in this patient population,” they wrote. “Several patients in our trial received it systemically, either before or after IMD insertion, as part of the standard of care. Thus, although our trial was not designed to choose chemotherapy agents based on IMD data, we still could compare the observed clinical-radiological response to systemic TMZ with the patient-specific response to TMZ in the IMD-exposed tissue.”
One patient, the researchers noted, had not benefited from the drug “in concordance with the poor tissue response observed in the IMD analysis.” But in another patient, a 72-year-old woman, “IMD analysis showed a marked response to TMZ,” and she survived for 20 months after receiving the treatment “with radiological evidence of tumor response. This was despite having a subtotal tumor resection, in itself an unfavorable prognostic factor. The patient expired because of an unrelated cardiovascular event, although she had remained neurologically stable.”
Drug Duration Limitation
One limitation of the study was that testing the device during the tumor removal procedure limited the duration of the drug treatments, Peruzzi said. The Harvard Gazette noted that following their initial study, the researchers were testing a variation of the procedure in which the device is implanted three days before the main surgery in a minimally invasive technique. This gives the drugs more time to work.
Cancer researchers have theorized that common treatments for tumors can impair the immune system, Peruzzi wrote in Healio. “One thing we want to look at is which drugs can kill the tumor without killing the immune system as well,” he noted.
Future studies will determine the effectiveness of implanting microdevices into tumors to test therapies in vivo. Should they become viable, clinical laboratories and anatomic pathologists will likely be involved in receiving, interpreting, storing, and transmitting the data gathered by these devices to the patient’s doctors.
Funded by both for-profit and not-for-profit organizations, this new gene sequencing center is preparing to offer its first genetic tests for use in patient care
Next-generation gene sequencing for clinical diagnostic applications is moving forward at the New York Genome Center (NYGC). Located in New York City, the center is designed to be a genetic medicine technology incubator and has funding from a number of for-profit and not-for-profit sources.
For pathologists and medical laboratory administrators, this creation and operation of this independent sequencing center is a notable development. It shows the willingness of different organizations to come together and fund a collaborative venture to advance exome sequencing and whole-genome sequencing for clinical purposes.
