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The findings were published in the Proceedings of the National Academy of Sciences in an article titled, “Viral nanoparticle vaccines against S100A9 reduce lung tumor seeding and metastasis.”

“Metastatic cancer accounts for 90% of all cancer-related deaths and continues to be one of the toughest challenges in cancer treatment,” wrote the researchers. “A growing body of data indicates that S100A9, a major regulator of inflammation, plays a central role in cancer progression and metastasis, particularly in the lungs, where S100A9 forms a premetastatic niche. Thus, we developed a vaccine against S100A9 derived from plant viruses and virus-like particles. Using multiple tumor mouse models, we demonstrate the effectiveness of the S100A9 vaccine candidates in preventing tumor seeding within the lungs and outgrowth of metastatic disease.”

A team led by Nicole Steinmetz, PhD, a professor of nanoengineering at the UC San Diego Jacobs School of Engineering, developed a vaccine candidate that can modulate the levels of S100A9 when it goes haywire. When injected subcutaneously, the vaccine stimulated the immune system in mice to produce antibodies against S100A9. The vaccine also increased the expression of immune-stimulating proteins with anti-tumor properties, while decreasing the levels of immune-suppressing proteins.

“S100A9 is known to form what is called a premetastatic niche within the lungs, creating an immunosuppressive environment that allows for tumor seeding and growth,” said study first author Young Hun (Eric) Chung, a UC San Diego bioengineering PhD alumnus from Steinmetz’s lab. “By reducing S100A9 levels, we can effectively counteract the formation of this premetastatic niche, leading to a reduced attraction and increased clearance of cancer cells to the lungs.”

“This is a clever, new approach to vaccination in that we are not targeting tumor cells, but rather the tumor microenvironment so that it prevents the primary tumor from making new tumors,” said Steinmetz, who is also the founding director of the UC San Diego Center for Nano-ImmunoEngineering and co-lead of the university’s Materials Research Science and Engineering Center (MRSEC). “We are essentially changing the whole immune system to be more anti-tumor.”

The vaccine consists of nanoparticles made from a bacterial virus called Q beta. The nanoparticles were grown from E. coli bacteria and isolated. Afterward, a piece of the S100A9 protein was attached to the surface.

“With this form of immunotherapy, we are not necessarily knocking out all of the protein, but we are reducing the levels everywhere,” said Steinmetz.

The vaccine was tested in metastatic mouse models of melanoma and triple-negative breast cancer. Healthy mice were first administered the vaccine, then challenged with either melanoma or triple-negative breast cancer cells through intravenous injection. Vaccinated mice exhibited a significant reduction in lung tumor growth compared to unvaccinated mice. In unvaccinated mice, the injected cancer cells circulated throughout the body and eventually homed in on the lungs to form metastatic tumors.

The researchers noted that this vaccine strategy combats tumor spread, not the primary tumor itself.

“While S100A9 does get overexpressed in certain primary tumors, it is mainly indicated in metastatic disease and progression,” said Chung. “The protein is involved in the formation of immunosuppressive tumor microenvironments. Therefore, we found that our vaccine is much more effective at reducing metastasis, and not in reducing the growth of the primary tumors.”

“These findings are the most clinically relevant, as they closely model what could happen in real-life scenarios,” said Steinmetz. “For instance, a patient diagnosed with an aggressive cancer who undergoes surgery to remove their tumor may be at risk of recurrence and metastasis to the lungs. We envision that this vaccine could be administered post-surgery to prevent such recurrence and outgrowth of metastatic disease.”

Before the vaccine can progress to human trials, more comprehensive safety studies are needed.

“S100A9 is an endogenous protein within the lungs, and there isn’t a lot of data out there that demonstrate what happens when S100A9 is abolished,” said Chung. “We know that S100A9 is important in the clearance of pathogens, and future studies should better test whether reducing S100A9 levels decreases the patient’s ability to fight infections, especially in cancer patients who may have weakened immune systems.”

Future work will also explore the vaccine’s effectiveness when combined with other cancer therapies, with the aim of improving its efficacy against hard-to-treat cancers.

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“GBM has an aggressive effect in part because of a milieu of immunosuppressive factors surrounding the tumor, which enable the tumor’s growth by preventing the immune system from entering and attacking it,” said E. Antonio Chiocca, MD, PhD, chair of the BWH Department of Neurosurgery. “This study showed that with a virus we designed, we can reshape this ‘immune desert’ into a pro-inflammatory environment.” Chiocca is corresponding author of the investigators’ published report in Nature, titled “Clinical trial links oncolytic immunoactivation to survival in glioblastoma.” In their report the team concluded, “These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumor microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy.”

Glioblastoma is an aggressive form of high-grade glioma (HGG) brain cancer that is notoriously resistant to treatment. Recurrent HGG (rHGG), including rGBM are associated with survival of less than 10 months, the authors wrote.

Immunotherapies that are designed to mobilize the body’s immune defenses against cancer have not been effective for GBM, in part because the tumor microenvironment (TME) is largely impenetrable to assaults from the body’s immune system. This immunosuppressive TME defines these tumors as “lymphocyte depleted,” the investigators stated. “For rGBMs and several other highly immunosuppressive solid cancers, there is a need to find treatment modalities that can convert the TME into one that is more amenable to immunotherapy and immune activation.”

For the reported Phase I trial, Chiocca and colleagues examined the safety of the oncolytic virus CAN-3110, which was designed and taken through preclinical testing by researchers at BWH, a founding member of the Mass General Brigham healthcare system. The cancer-attacking oncolytic herpes simplex virus is the same type of virus used in a therapy approved for the treatment of metastatic melanoma.

Unlike other clinical oHSVs, CAN-3100 includes the ICP34.5 gene, which is often excluded from clinical oHSV candidates because it causes human disease in unmodified forms of the virus. However, the researchers hypothesized that this gene may be necessary to trigger a robust, proinflammatory response necessary for attacking the tumor. For their clinical candidate they designed a version of oHSV1 that contains the ICP34.5 gene but is also genetically programmed not to attack healthy brain cells. “To take advantage of ICP34.5’s functions that enhance viral replication/persistence and minimize neurotoxicity, CAN-3110 (former designation, rQNestin34.5v.2) was engineered to express a copy of the viral ICP34.5 gene under transcriptional control of the promoter for nestin, restricting viral replication and virulence to HGG/GBM cells,” the team explained.

Overall, the trial demonstrated the safety of CAN-3110 in 41 patients with high-grade gliomas, including 32 with recurrent GBM. The most serious adverse events were seizures in two participants. Notably, GBM participants who had pre-existing antibodies to HSV1 virus (66% of the patients) had a median overall survival of 14.2 months, compared to 7.8. months for seronegative patients. In patients with pre-existing antibodies, the researchers saw markers of several changes in the tumor microenvironment associated with immune activation. They hypothesized that the presence of HSV1 antibodies resulted in a rapid immune response to the virus, which brought more immune cells to the tumor and increased the levels of inflammation in the tumor microenvironment.

The authors also observed an increase in diversity of the T cell repertoire after CAN-3110 treatment, suggesting that the virus induces a broad immune response, perhaps by eliminating tumor cells resulting in the release of cancer antigens. The immunological changes observed after treatment were also shown to be associated with improved survival. “In summary, single-timepoint intralesional injection of rHGG/rGBM with CAN-3110 enriches the tumor microenvironment with TILs [tumor infiltrating lymphocytes], inducing defined changes in peripheral and tumor T cell repertoires and tumor transcriptomic signatures,” the team commented in their discussion. “These findings therefore provide human immunological and biological evidence supporting intralesional oncolytic modalities to convert the immunosuppressive TME characteristic of many solid cancers into a TME that is more favorable to immunologic rejection of the tumor.”

Going forward, the researchers plan to complete prospective studies to further investigate the effectiveness of the oncolytic virus in patients who do and do not have antibodies to HSV1. Having demonstrated the safety of one viral injection, they are proceeding to test the safety and efficacy of up to six injections over four months, which, like multiple rounds of vaccination, may increase the effectiveness of the therapy. “We are now set to determine whether multiple-timepoint injections lead to further improvements in this therapy,” the authors confirmed.

“Almost no immunotherapies for GBM have been able to increase immune infiltration to these tumors, but the virus studied here provoked a very reactive immune response with infiltration of tumor-killing T-cells,” Chiocca said. “That’s hard to do with GBM, so our findings are exciting and give us hope for our next steps.”

Brigham and Women’s Hospital own the patents related to oHSV and CAN-3110, with Chiocca as a co-inventor. The patents have been licensed to Candel Therapeutics.

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The findings are published in eLife, in an article titled, “Identification of CD133+ intercellsomes in intercellular communication to offset intracellular signal deficit.”

“CD133 (prominin 1) is widely viewed as a cancer stem cell marker in association with drug resistance and cancer recurrence,” wrote the researchers. “Herein, we report that with impaired RTK-Shp2-Ras-Erk signaling, heterogenous hepatocytes form clusters that manage to divide during mouse liver regeneration. These hepatocytes are characterized by upregulated CD133 while negative for other progenitor cell markers.”

“Understanding cell proliferation is a fundamental issue in both cancer research and biomedical science as a whole,” said Gen-Sheng Feng, PhD, a professor of pathology at UC San Diego School of Medicine and of molecular biology at UC San Diego School of Biological Sciences. “While we studied the liver here because of its incredible regenerative potential, we’ve also found these vesicles in other types of cancer cells. We believe that this could be a universal mechanism that drives resistance to cancer therapies that target cell proliferation.”

“Cells in the liver multiply more quickly and effectively than any other cells in the body, which makes the liver the ideal place to study the biological processes that control cell division,” said Feng. “These are the same processes that go awry in cancer, and so one promising approach to treating cancer is targeting cell proliferation.”

In previous research, Feng and his team observed that a minority of liver cells in mice could still proliferate even when the cells were genetically engineered to lack a critical signaling enzyme required for cell proliferation. This enzyme, called Shp2, helps liver cells know when it’s time to divide during liver regeneration.

By clustering together and exchanging tiny, protein-wrapped packages called vesicles, liver cells are able to communicate and share the biochemical materials needed to multiply, allowing them to proliferate even without Shp2.

“We’ve known for a long time that liver cells have other ways of regenerating even when lacking Shp2, and this study shows us how they do it,” said Feng.

The researchers also uncovered evidence that cancer cells may use the same strategy to resist treatment and continue to divide.

“We believe we’ve discovered an important strategy that tumors use to resist therapy,” said Feng. “This discovery could prove to be a powerful new target for cancer treatment, particularly as part of combination therapies to mitigate treatment resistance.”

The findings suggest a new way of thinking about cancer initiation, progression, and recurrence.

“Our findings could tell us that a cancer cell’s ‘stemness,’ or ability to initiate and reinitiate tumors, isn’t a central part of its identity, but a temporary state that can be induced or possibly even turned off,” said Feng. “This could be a brand-new way of looking at tumor recurrence that could open doors for new treatments.”

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Their findings are published in Cell Chemical Biology in an article titled, “Differential network analysis of ROS1 inhibitors reveals lorlatinib polypharmacology through co-targeting PYK2.” The team also revealed the mechanisms of this inhibition.

“Drugs with polypharmacology mechanisms, meaning agents that target multiple functionally relevant proteins, may have the potential to effectively overcome drug resistance, improve anticancer activity of single-targeted inhibitors, and produce a more durable patient response and remission,” said Uwe Rix, PhD, lead study author and senior member of the department of drug discovery at Moffitt.

The team of Moffitt researchers wanted to determine whether cancer drugs that target the protein ROS1 in non-small cell lung cancer have additional hidden targets. They performed their studies in cancer models that were driven by the cancer-promoting properties of the oncogenic ROS1 protein; therefore, they needed to develop an investigative platform that would be able to identify any potential additional targets that might be hidden by the dominant properties of ROS1.

The team performed additional laboratory experiments and found that lorlatinib also targets the protein PYK2. Their findings suggested that inhibition of ROS1, PYK2, and SRC in combination would have greater anticancer effects than either agent alone.

Further studies confirmed that drug combinations targeting each protein resulted in enhanced cancer cell death and reduced cell survival than either agent alone.

The researchers hope these results and their investigative platform will lead to a better understanding of the mechanisms of action of lorlatinib and the development of drug combinations with improved clinical activity.

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Tal Danino, PhD, and Rosa L. Vincent, PhD, at Columbia University’s department of biomedical engineering, and colleagues, reported on their developments in Science, in a paper titled “Probiotic-guided CAR-T cells for solid tumor targeting,” in which they concluded, “These findings highlight the potential of the ProCAR platform to address the roadblock of identifying suitable CAR targets by providing an antigen that is orthogonal to both healthy tissue and tumor genetics … Overall, combining the advantages of tumor-homing bacteria and CAR-T cells provides a new strategy for tumor recognition and, in turn, builds the foundation for engineered communities of living therapies.”

Immunotherapies using CAR-T cells have proven successful in treating some types of blood cancers, but their efficacy against solid tumors remains elusive. A key challenge facing tumor-antigen targeting immunotherapies like CAR-T is the identification of suitable targets that are specifically and uniformly expressed on solid tumors, the authors noted. “A key challenge of antigen-targeted cell therapies relates to the expression patterns of the antigen itself, which makes the identification of optimal targets for solid tumor cell therapies an obstacle for the development of new CARs.” Solid tumors express heterogeneous and nonspecific antigens and are poorly infiltrated by T cells. As a result, the approach carries a high risk of fatal on-target, off-tumor toxicity, wherein CAR-T cells attack the targeted antigen on healthy vital tissues with potentially fatal effects. “Few tumor-associated antigens (TAAs) identified on solid tumors are tumor restricted, and thus, they carry a high risk of fatal on-target, off-tumor toxicity because of cross-reactivity against proteins found in vital tissues,” the team continued.

Previous studies have shown that, unlike CAR-T cells, which require “considerable engineering to target and infiltrate solid tumors,” some species of bacteria can selectively colonize and preferentially grow within the hostile tumor microenvironments (TMEs) of immune-privileged tumor cores, and can be engineered as antigen-independent platforms for therapeutic delivery.

In this study, Vincent, Candice Gurbatri, and colleagues combine probiotic therapy with CAR-T cell therapy to create a two-stage probiotic-guided CAR-T cell (ProCAR) platform, whereby T cells are engineered to sense and respond to synthetic CAR targets that are delivered by solid tumor-colonizing probiotic bacteria. “This approach leverages the antigen independence of tumor-seeking microbes to create a combined cell therapy platform that broadens the scope of CAR-T cell therapy to include difficult-to-target tumors,” the investigators explained.

Using synthetic gene circuit engineering on a well-characterized non-pathogenic strain of E. coli, Vincent et al. created a probiotic that could infiltrate and cyclically release synthetic CAR targets directly to the tumor core, effectively “tagging” the tumor tissue. “With this system, bacterial growth reaches a critical population density exclusively within the niche of the solid TME and subsequently triggers lysis events that cyclically release genetically encoded payloads in situ,” they further explained.

Then, CAR-T cells that were programmed to recognize the probiotic-delivered synthetic antigen tags could be generated that homed in on the tagged solid tumors, killing the tumor cells in situ. The scientists also engineered probiotics that co-released chemokines in addition to synthetic targets to further enhance CAR-T cell recruitment to the tumor, further boosting therapeutic response.

Vincent et al. tested the resulting probiotic-guided CAR-T cell platform in humanized and immunocompetent mouse models of leukemia, colorectal cancer, and breast cancer and showed that it resulted in the safe reduction of tumor volume. “Collectively, these mouse model data demonstrate the use of engineered probiotics to selectively grow within the TME niche and safely release combinations of CAR-T cell enhancing payloads in situ,” they wrote. The team acknowledged that further development of the system will be needed before it can be considered for clinical application. Nevertheless, they stated, “We have demonstrated an approach to engineering interactions between living therapies, in which tumor-colonizing probiotics have been repurposed to guide the cytotoxicity of engineered T cells.”

In a related Perspective, Eric Bressler, PhD, and Wilson Wong, PhD, at Boston University Biomedical Engineering and Biological Design Center, also noted, “Translation of the ProCAR system to the clinic will depend on scalability to larger tumors and attenuation of bacterial strains for safety.” However, they concluded, “The study of Vincent et al. is an important proof-of-concept for a potential approach to treating heterogeneous, immunologically cold, and poorly infiltrated solid tumors.”

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Bristol Myers Squibb (BMS) has agreed to acquire Mirati Therapeutics for up to $5.8 billion, the companies said, in a deal that expands the buyer’s cancer portfolio with Mirati’s marketed drug Krazati^® (adagrasib) and several pipeline candidates that have shown positive albeit early clinical data.

Krazati is an inhibitor of the RAS GTPase family that became Mirati’s first drug to generate sales after winning FDA accelerated approval last December. Krazati is indicated as a treatment for adults with KRAS^G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test—and who have received at least one prior systemic therapy. KRAS^G12C mutations account for approximately 14% of all NSCLC patients, representing one of the most frequent alterations in NSCLC.

In gaining authorization from the agency, Krazati became the first drug to challenge Amgen’s KRAS inhibitor Lumakras^® (sotorasib), which carries an identical indication and was approved by the FDA in 2021 as the first KRAS-targeted therapy authorized by the agency. Mirati said Krazati’s long half-life and ability to be combined with a PD-1 inhibitor in first-line treatment of NSCLC position the drug for greater future success.

During the first half of this year, Lumakras generated $151 million, more than half of which consisted of the $77 million collected in the second quarter.

Krazati, by contrast, generated $19.656 million in net product revenue, of which more than two-thirds (68% or $13.365 million) came in the second quarter. The Q2 number included about $11.7 million of commercial sales and $1.7 million of sales to a third-party commercial customer for its clinical trials, Mirati said in August.

“Uptake in 2L+ [second and subsequent line] NSCLC has been slow for both MRTX and AMGN,” Jefferies analyst Maury Raycroft, PhD, and colleagues observed in a research note. “However, we believe MRTX’s drug could be best-in-class w/ better CNS penetration and combinability w/ IO agents, which could support 1L [first line] use w/ access to a much larger mkt oppty [market opportunity].”

Did Amgen setback trigger deal?

Raycroft and colleagues questioned whether BMS moved to buy Mirati because of a setback to Amgen’s quest to expand the FDA’s accelerated approval for Lumakras into full approval.

Earlier this month, the FDA’s Oncologic Drugs Advisory Committee recommended against the expansion 10–2 by concluding that it could not reliably interpret Amgen’s progression-free survival data from the Phase III CodeBreaK 200 confirmatory study (NCT04303780) comparing Lumakras with docetaxel in NSCLC patients with a KRAS p. G12c mutation. The panel cited factors ranging from potential bias from investigators to the trial patient population, and a high number of patients dropping out of the study.

The FDA’s PDUFA target decision date on full approval is December 24.

BMS agreed to $58 a share for Mirati—approximately $4.8 billion—representing a 52% premium to the 30-day volume-weighted average price as of Wednesday, before speculation arose about a Mirati buyout, plus an additional contingent value right (CVR) of $1 per share upon FDA acceptance of a new drug application for MRTX1719 to treat either locally advanced or metastatic NSCLC in patients who have received up to two prior lines of systemic therapy within seven years after the closing of the acquisition deal.

While the $58-per-share price is 4% below Mirati’s Friday closing price of $60.20, it is fair because oncology drug companies have sold for about 3.5 to 4 times peak sales, Raycroft and colleagues added.

Jefferies forecasts peak year worldwide sales in 2032 of $1.4 billion for Krazati just on its current indication—with peak year sales growing by an additional $420 million should it add an indication for KRAS^G12C-mutated colorectal cancer (CRC), where Mirati is expected to file a supplemental NDA for third-line and beyond CRC treatment by year’s end.

Buyout speculation

Speculation about a buyout of Mirati emerged in August, after CEO David Meek stepped down as CEO and a board member after just two years in the position. He and Mirati “mutually agreed” on Meek’s departure, the company announced at the time.

Meek succeeded founder Charles M. Baum, MD, PhD, who became Mirati’s president. When Meek left, Mirati returned Baum to the helm as interim CEO, but retained Meek as a consultant through October 15.

Krazti’s revenues could grow if BMS can fulfill Mirati’s quest of adding indications for the drug—both as a monotherapy and in combination with PD-1 inhibitors. Mirati said has begun working with regulators to expand the use of adagrasib based on it having shown central nervous system (CNS) penetration and intracranial responses in patients with active and untreated brain metastases.

The drug has also demonstrated efficacy as a second- and third-line treatment for colorectal cancer in combination with Eli Lilly’s Erbitux^® (cetuximab), and as a monotherapy in previously treated pancreatic ductal adenocarcinoma.

Also in Mirati’s pipeline:

• MRTX1719, a Phase I MTA-cooperative PRMT5 inhibitor that has shown positive early efficacy data across several tumor types with MTAP deletion, including NSCLC, bile duct cancer, and melanoma. MRTX1719 is designed to target MTAP-deleted tumors that comprise approximately 10% of all cancers. MRTX1719 is expected to enter Phase II clinical study in the first half of 2024.

• MRTX0902, a Phase I SOS1 inhibitor that has shown the potential for combination use with other agents targeting the MAPK/RAS pathway, including Krazati.
• MRTX1133, which targets the KRAS^G12D mutation implicated in pancreatic cancer, NSCLC—and colorectal cancer, in which the KRAS^G12D mutation is implicated in over 30% of patients.

“With a strong strategic fit, great science, and clear value creation opportunities for our shareholders, the Mirati transaction is aligned with our business development goals,” BMS CEO and Board Chair Giovanni Caforio said in a statement. “By leveraging our skills and capabilities, including our global commercial infrastructure, we will ensure patients globally can benefit from Mirati’s portfolio of innovative medicines.”

BMS acknowledged the deal would reduce its non-GAAP earnings per share by approximately 35 cents per share in the first 12 months after the transaction closes.

BMS said it expects to use a combination of cash and debt to finance its buyout of Mirati, which has been unanimously approved by the boards of both companies. The deal is expected to close by the first half of 2024, subject to fulfillment of customary closing conditions, including approval by Mirati stockholders and regulatory approvals.

Alex Philippidis is senior business editor of GEN.

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“There is an unmet clinical need to implement real-time, minimally invasive molecular analyses to understand patients’ responses to cancer treatments and guide clinical decision-making,” said lead study author Valsamo “Elsa” Anagnostou, MD, PhD, director of the thoracic oncology biorepository at Johns Hopkins, leader of Precision Oncology Analytics, co-leader of the Johns Hopkins Molecular Tumor Board, and co-director of the Lung Cancer Precision Medicine Center of Excellence. “Our study demonstrates that ctDNA response correlated with tumor size seen on imaging, which is the gold standard for monitoring response to cancer treatments and seemed to be better correlated with survival. This suggests ctDNA could be used as a strategy to identify patients at high risk of disease progression who could benefit from a switch in their therapeutic regimen.”

The results from this first, independent observational stage of the BR.36 study were reported in Nature Medicine, in a paper titled “ctDNA response after pembrolizumab in non-small cell lung cancer: phase 2 adaptive trial results.” In their paper, the team concluded, “Overall, our findings support the implementation of liquid biopsies in interventional IO clinical trials and further advance the evidentiary roadmap toward integration of ctDNA molecular responses in clinical decision-making for the increasing number of patients receiving immunotherapy.”

Immunotherapies are designed to unleash the power of the immune system against cancers, but despite their success in improving survival for some patients, they pose a challenge to the standard use of imaging to determine treatment response, because changes in imaging may not always reflect how well immunotherapy is working. “… we face emerging challenges related to heterogeneity in clinical responses and insufficiency of imaging to rapidly and accurately capture therapeutic response,” the authors noted.

Liquid biopsies may offer another way to help determine which patients are benefiting from available immunotherapies, and could represent a new endpoint for clinical trials that are testing these treatments. “Liquid biopsies are gaining momentum in immuno-oncology (IO) as they can be used to rapidly and accurately determine clinical response, especially in the metastatic setting,” the team noted. “Liquid biopsy analyses of circulating cell-free tumor DNA (ctDNA) have shown promise in capturing tumor burden dynamics during immune checkpoint blockade, allowing patients with primary resistance to be rapidly identified and redirected to receive alternative therapies.” But while initial reports are promising, the authors pointed out that “… several outstanding urgent questions need to be answered before implementation of liquid biopsy-guided ctDNA molecular responses in clinical decision-making.”

The BR.36 clinical trial (NCT04093167) is designed to establish the role of ctDNA as an early measurement of immunotherapy response by first defining ctDNA response, its timing and how it compares with the gold standard of imaging tests, and then by using ctDNA response to guide treatment for patients with advanced NSCLC.

The first stage of the trial enrolled patients with advanced/metastatic NSCLC who were eligible for standard-care immunotherapy using single-agent pembrolizumab. The aim was to evaluate, through serial liquid biopsy analyses, “ … the optimal definition, timing, and concordance of ctDNA molecular response with radiographic response.”

The investigators hypothesized that liquid biopsies would rapidly and accurately predict outcomes for patients. For this observational stage of the BR.36 study, they enrolled 50 patients with advanced or metastatic non-small cell lung cancer at six medical centers in the United States and Canada, between May 2020 and September 2022. Nearly all patients had been smokers, and 92% received no prior therapies. The group was 82% white, 52% female, and 56% age 65 years or older. The goals were to identify the optimal timepoint for ctDNA molecular response and to see how well molecular response correlated to response evaluation criteria in solid tumors (RECIST), the standard for measuring response to cancer treatment by monitoring changes in tumor size as seen on imaging.

Patients received the immunotherapy drug pembrolizumab based on standard of care, at a 200 mg or 2 mg/kg infusion every three weeks. After the first three cycles, investigators could switch to a 400 mg or 4 mg/kg infusion every six weeks. Patients remained in the trial until they received 24 months of therapy, had unacceptable drug toxicity, or imaging tests revealed progression of disease.

Investigators performed RECIST response assessments every six weeks until week twelve, and at longer intervals thereafter. They also collected blood samples from patients prior to treatment administration on the first day of the first cycle (baseline), the first day of the second cycle (three weeks into treatment), and the first day of the third cycle (six weeks) of treatment. These were used to conduct a ctDNA response assessment at these timepoints and to define molecular response as ctDNA clearance on the first day of the third cycle of treatment with pembrolizumab.

Analyses of molecular response were assessed using the Personal Genome Diagnostics (PGDx) elio liquid biopsy platform, which “represents an exciting opportunity for tailoring immunotherapy to enhance the interpretation of patterns of tumor response and progression during treatment,” stated study co-author Mark Sausen, PhD, executive director and head of technology innovation, PGDx, Labcorp.

The reported results indicated found that serial testing ctDNA using next-generation sequencing allowed early detection of immunotherapy responses, within an average of eight weeks after treatment started. A ctDNA response (ctDNA no longer detected in the blood) reflected tumor shrinkage by imaging. However, there were notable exceptions that indicated the ctDNA response may capture survival more accurately, especially for patients with stable disease on imaging.

Compared to patients who did not have a ctDNA response, patients with a ctDNA response had a longer progression-free survival, with a difference of 2.6 months versus 5.03 months respectively. In addition, patients with a ctDNA response had a longer overall survival (OS), with median survival not reached at the time of analysis, compared with 7.23 months. “ … ctDNA molecular response, defined as complete clearance of circulating tumor load after two cycles of pembrolizumab, was largely concordant with radiographic response assessments but, notably, was more informative in predicting OS,” the scientists stated.

“ctDNA response is particularly informative to understand the complexity of stable disease on imaging, which represents a sizable fraction of patients in whom imaging fails to timely and accurately detect the magnitude of therapeutic response,” Anagnostou said.

The study investigators will incorporate their findings into the second stage of the BR.36 trial, which will evaluate the potential clinical benefit of tailoring treatment for patients with lung cancer based on their ctDNA responses after two cycles of pembrolizumab treatment. ctDNA response will be used to identify patients with lung cancer at high risk for disease progression, who will be subsequently randomized to treatment intensification with pembrolizumab and chemotherapy, versus continuation of pembrolizumab.

“Taken together, we show that ctDNA molecular response can identify patients with metastatic NSCLC less likely to attain favorable clinical outcomes with single-agent anti-PD-1 therapy, and this opens a therapeutic window of opportunity for treatment intensification for patients with molecular disease progression,” the team noted in their published paper.

Co-corresponding study author Janet Dancey, MD, director of the Canadian Cancer Trials Group, further stated, “ctDNA has the potential to improve our ability to advise patients on the best treatment options for them. It may be better than traditional imaging in determining changes to treatments or providing assurance that patients should continue their current treatment. Our initial study indicates promising results, and we will move forward with a larger trial to clearly show whether ctDNA monitoring provides useful information based on treatment recommendations.”

“The Cancer Research Institute (CRI) is pleased to invest in Stage 2 of this clinical trial,” said Jay Campbell, managing director of the CRI Anna-Maria Kellen Clinical Accelerator. “This is being designed as a registrational study, meaning if the study meets its primary endpoint, the ctDNA detection assay used in the BR.36 study could be approved. This could lead to molecular assessment by liquid biopsies becoming the standard means of assessing whether first-line patients with non-small cell lung cancer are responding to cancer immunotherapies, compared to conventional radiographical assessment of response.”

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The findings are published in Cell in an article titled, “Arginine reprograms metabolism in liver cancer via RBM39.”

“Metabolic reprogramming is a hallmark of cancer. However, mechanisms underlying metabolic reprogramming and how altered metabolism in turn enhances tumorigenicity are poorly understood. Here, we report that arginine levels are elevated in murine and patient hepatocellular carcinoma (HCC), despite reduced expression of arginine synthesis genes. Tumor cells accumulate high levels of arginine due to increased uptake and reduced arginine-to-polyamine conversion.”

“We investigated liver tumor samples from mice and patients and found elevated levels of arginine, although cancer cells produce less or none of this amino acid. The tumor cells accumulate high levels of arginine by increasing its uptake and suppressing its consumption,” explained lead author Dirk Mossmann, PhD, a postdoctoral researcher at the University of Basel. “Furthermore, we found that the high levels of arginine are necessary for tumor development, independently of the amino acid’s role in protein synthesis. This then begged the question, how does arginine lead to tumorigenicity?”

At high concentrations, arginine binds to a specific factor, which triggers metabolic reprogramming and promotes tumor growth by regulating the expression of metabolic genes. As a consequence, tumor cells revert back to an undifferentiated embryonic cell state, in which they can divide indefinitely. Interestingly, tumor cells also benefit in another way from increasing the uptake of arginine. “Our immune cells depend on arginine to function properly,” said Mossmann. “Therefore, depleting arginine in the tumor environment helps the tumor cells escape the immune system.”

The scientists propose to target the specific arginine-binding factor rather than depleting arginine. “When treating liver tumors with the anticancer drug indisulam, we induce the degradation of this factor and thus prevent metabolic reprogramming,” added Mossmann. “Via this route, one can avoid unwanted side effects of reducing overall arginine levels, like harming immune cells that need arginine to work properly.” Furthermore, metabolic changes such as increased arginine levels may serve as biomarkers for detecting cancer at an early stage, which is crucial for successful cancer treatment and patient survival.

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Their findings are published in Science in an article titled, “PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection,” and led by Eva Frickel, PhD, senior Wellcome Trust fellow at the University of Birmingham.

The research reveals how GBP1 is controlled through a process called phosphorylation, a process in which a phosphate group is added to a protein by enzymes called protein kinases. The kinase targeting GBP1 is called PIM1 and can also become activated during inflammation. Phosphorylated GBP1 in turn is bound to a scaffold protein, which keeps uninfected bystander cells safe from uncontrolled GBP1 membrane attack and cell death.

The mechanism blocks GPB1 from attacking cell membranes indiscriminately, creating a guard mechanism that is sensitive to disruption by the actions of pathogens inside the cells. The new discovery was made by Daniel Fisch, a former PhD student in the Frickel lab working on the study.

“This discovery is significant for several reasons, said Frickel. “Firstly, guard mechanisms such as the one that controls GBP1 were known to exist in plant biology, but less so in mammals. Think of it as a lock and key system. GPB1 wants to go out and attack cellular membranes, but PIM1 is the key meaning GPB1 is locked safely away.”

“The second reason is that this discovery could have multiple therapeutic applications. Now we know how GBP1 is controlled, we can explore ways to switch this function on and off at will, using it to kill pathogens.”

Frickel and her team conducted this initial research on Toxoplasma gondii, a single-celled parasite that is common in cats. While Toxoplasma infections in Europe and Western countries are unlikely to cause serious illness, in South American countries it can cause reoccurring eye infections and blindness and is particularly dangerous for pregnant women.

The researchers found that Toxoplasma blocks inflammatory signaling within cells, preventing PIM1 from being produced, meaning that the “lock and key” system disappears, liberating GBP1 to attack the parasite. Switching PIM1 “off’ with an inhibitor or by manipulating the cell’s genome also resulted in GPB1 attacking Toxoplasma and removing the infected cells.

Frickel continued: “This mechanism could also work on other pathogens, such as Chlamydia, Mycobacterium tuberculosis, and Staphylococcus all major disease-causing pathogens which are increasingly becoming more resistant to antibiotics. By controlling the guard mechanism, we could use the attack protein to eliminate the pathogens in the body. We have already begun looking at this opportunity to see if we are able to replicate what we saw in our Toxoplasma experiments. We are also incredibly excited about how this could be used to kill cancer cells.”

PIM1 is a key molecule in the survival of cancer cells, while GPB1 is activated by the inflammatory effect of cancer. The researchers think that by blocking the interaction between PIM1 and GPB1 they could specifically eliminate cancer cells.

Frickel said: “The implication for cancer treatment is huge. We think this guard mechanism is active in cancer cells, so the next step is to explore this and see if we can block the guard and selectively eliminate cancer cells. There is an inhibitor on the market which we used to disrupt PIM1 and GPB1 interaction. So, if this works, you could use this drug to unlock GPB1 and attack the cancer cells. There is still a very long way to go, but the discovery of the PIM1 guard mechanism could be a massive first step in finding new ways to treat cancer and increasingly antibiotic-resistant pathogens.”

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