On June 22, 2020 BioNTech reported that A phase 1b trial of a personalized cancer vaccine in development at Roche has chalked up a "low" response rate (Press release, BioNTech, JUN 22, 2020, View Source [SID1234561516]). Nine of the 108 evaluable solid tumor patients responded when given the vaccine in combination with Tecentriq, although researchers pointed to immune response results to support continued study in other populations.

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Roche’s Genentech paid BioNTech $310 million in upfront and near-term milestones in 2016 to gain access to mRNA-based personalized cancer vaccines. The collaboration gave rise to RO7198457, a drug that targets up to 20 tumor-associated antigens (TAAs) expressed by a patient’s cancer. By giving patients mRNA corresponding to TAAs, Roche and BioNTech hope to rally cytotoxic T-lymphocyte and memory T-cell-dependent immune responses against tumors.

Researchers are using this week’s virtual American Association for Cancer Research (AACR) (Free AACR Whitepaper) event to share an early look at whether RO7198457, also known as BNT122, works as hoped. The results contain plenty of ammunition for anyone who is skeptical about the likelihood of Roche and BioNTech ending the long losing streak of cancer vaccines.

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Evaluations of 108 patients who received RO7198457 and checkpoint inhibitor Tecentriq identified nine responses, including one complete response. The figures translate into a response rate of 8%. It is unclear whether those subjects would have responded to Tecentriq given as a monotherapy. A smaller assessment of RO7198457 as a monotherapy linked the cancer vaccine to a 4% response rate.

Juanita Lopez, Ph.D., consultant medical oncologist at The Royal Marsden and co-author of the RO7198457 abstract, said the "clinical response rate overall was low" in a statement about the trial. Despite that, Lopez sees positives in the results, noting that "we were able to generate tumor-specific immune responses in the majority of evaluable patients."

An analysis of peripheral blood taken from 49 patients found evidence of neoantigen-specific T cell responses in 77% of samples. Viewed alongside the efficacy data, the analysis suggests RO7198457 reliably elicits specific immune responses that rarely translate into reductions in tumor size.

Lopez thinks the health status of participants at baseline may explain why immune activity is failing to translate into partial and complete responses. Participants in the combination trial had received a median of three prior therapies. Almost 40% of subjects had previously received immunotherapy. It is unclear if any of the nine patients who responded to the combination had previously received an immunotherapy.

The debate over whether RO7198457 is a dud or a good drug given to the wrong patients will remain inconclusive until data from other populations are available. Roche and BioNTech began gathering such data last year by initiating a phase 2 trial of RO7198457 in combination with Merck’s Keytruda. The trial is randomizing previously untreated advanced melanoma patients to receive Keytruda as a single agent or in combination with RO7198457.

That design positions the trial to clear up questions raised by the Tecentriq combination study about what RO7198457 contributes to checkpoint inhibitor cocktails and whether it works better earlier in the treatment pathway. Lopez said work to assess RO7198457 in post-surgery early-stage non-small cell lung cancer patients is also underway.

On June 22, 2020 Dana-Farber Cancer Institute reported that a novel liquid biopsy method can detect kidney cancers with high accuracy, including small, localized tumors which are often curable but for which no early detection method exists (Press release, Dana-Farber Cancer Institute, JUN 22, 2020, View Source [SID1234561515]).

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The report in Nature Medicine suggests that if validated in larger trials and applied widely, the non-invasive test could find more early kidney cancers when they haven’t spread, thus reducing the mortality of the disease. "Hopefully we can scale this to a much larger level and detect cancer earlier so we can act earlier," said Toni Choueiri, MD, a co-senior author of the study. He is the director of the Lank Center for Genitourinary Oncology at Dana-Farber.

It’s estimated that 73,750 new kidney cancer cases will be diagnosed in 2020, and about 14,830 will die of the disease. About 35 percent of cancers are diagnosed only after they have spread beyond the kidney and are more difficult to treat. Small, early kidney tumors usually cause no symptoms, and increasingly are found incidentally in scans of the abdomen performed for another purpose. However, there is no imaging or other screening test recommended for the general population to look for early kidney cancers. Initially, a test based on the method described in the new report might be used to screen people with a family history of kidney cancer, or who had a previous kidney cancer, said Choueiri. "We need to be specific first, before making it totally mainstream," he said.

Non-invasive liquid biopsies, which search for cancer-related DNA shed by tumors into blood or other body fluids, are moving rapidly toward clinical use as a means of early detection for some kinds of tumors. However, "kidney cancer is one of the hardest tumors to detect, because it doesn’t shed as much DNA as other tumors," said Matthew Freedman, MD, a medical oncologist at Dana-Farber and co-senior author of the report. "That’s where this test performs really well" because it can identify abnormal patterns in small amounts of tumor-shed DNA. "And it’s a proof of principle that early stage disease is detectable."

The test was nearly 100 percent accurate when used with blood samples to distinguish patients with kidney cancer from those known to be free of kidney cancer. The method achieves less accuracy in testing urine samples, but the researchers believe that performance can be improved. If the test is validated in larger trials and becomes widely applicable clinically, a urine sample would be even less-invasive than a blood draw.

The technical name for the testing method is cfMeDIP-seq, which stands for cell-free methylated DNA immunoprecipitation and high-throughput sequencing. Where other liquid biopsy methods search for mutations in tumor-shed DNA that reveal the type and location of cancer, cfMeDIP-seq detects abnormal methylation – the addition of chemical tags to DNA, which doesn’t alter their genetic code but can affect their function.

The method was tested on samples from 99 patients with early and advanced kidney cancer, 15 patients with stage IV urothelial bladder cancer, and 28 healthy, cancer-free control subjects. In analyzing blood serum with the test, the study reported "near-perfect" classification of patients across all stages of kidney cancer. While urine-based classification was not as accurate, "we believe that performance can ben improved through technical and computational optimization," the authors wrote.

Co-first authors of the report are Pier Vitale Nuzzo, Jacob E. Berchuck, Keegan Korthauer, and Sandor Spisak.

This study was conducted with support from Rebecca and Nathan Milikowsky, the Claudia Adams Barr Program for Innovative Cancer Research, the H.L. Snyder Medical Research Foundation, the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute.

On June 22, 2020 A new program called PATRIOT, developed by the Translational Genomics Research Institute (TGen), an affiliate of City of Hope,reported that it is using organoids — laboratory cultures derived from samples of patient tumors — to provide a whole new level of accuracy in prescribing anti-cancer treatments (Press release, TGen, JUN 22, 2020, View Source [SID1234561511]).

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PATRIOT builds on other precision medicine programs devised by Ashion Analytics, a TGen clinical laboratory, which uses its GEM ExTra proprietary test to match each patient’s unique cancer to the best available cancer treatments.

PATRIOT, which stands for PAThway based RNA and DNA Integration with tumor Organoid Testing for clinical therapeutics, will be showcased in a study presentation June 22-24 at the second 2020 virtual annual meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

"Cancer tumors are complicated," said Dr. Sunil Sharma, Deputy Director of TGen Clinical Sciences and Chief of Translational Oncology and Drug Development at the HonorHealth Research Institute. "PATRIOT is a very powerful platform that will make GEM ExTra even more powerful. This will expand the use of RNA analysis in a way that has never been used before."

In this system, organoids — which can mimic the reactions of solid tumors in patients’ bodies —are grown in a laboratory and then used to test different anti-cancer therapies.

"It’s a way of conducting clinical trials on a laboratory plate," said Dr. Sharma, who also is a Professor and Director of TGen’s Applied Cancer Research and Drug Discovery Division.

The study being presented at AACR (Free AACR Whitepaper) shows how Dr. Sharma’s TGen lab, using melanoma tumor samples provided by HonorHealth, used the new PATRIOT system to identify potential therapeutic targets by focusing on molecular pathways within tumor cells, a level of analysis that goes beyond searching for mutations in DNA, and even builds on top of the intricate analysis of RNA-expression provided by Ashion’s GEM ExTra.

"These druggable targets were validated on the tumor organoids," said Dr. Sharma, who hails the system as a whole new way to provide therapeutic benefit to patients. "This allows for a holistic assessment of a patient’s tumor for improving therapy recommendations and expanding personalized therapy options."

In addition, he said, PATRIOT analysis of organoids gives investigators the ability to test immunotherapy options in the laboratory.

Ashion’s GEM ExTra platform already has expanded the therapeutic potential of genomic sequencing by using RNA sequencing to identify novel fusions and alternate transcripts, providing additional tumor profiling data in addition to that identified by DNA sequencing.

Unlike many other genomic sequencing tests, which use panels of dozens or even hundreds of known cancer-causing genomic variants, Ashion’s GEM ExTra screens cancer patients for all of the nearly 3 billion nucleotides, or letters, in human DNA, which includes more than 19,000 genes.

The next step, Dr. Sharma said, is to test the predictions from PATRIOT and GEM ExTra analysis of patient organoids in the laboratory to see if they might work in a larger clinical trial.

This study was supported by funding from Flinn Foundation grant #2193.

On June 22, 2020 Celsion Corporation (NASDAQ: CLSN), an oncology drug-development company, reported that affirmed that the independent Data Monitoring Committee (iDMC) is scheduled to meet during the first half of July to conduct the second pre-planned interim safety and efficacy analysis of the Phase III OPTIMA Study with ThermoDox plus RFA (radiofrequency ablation) in patients with hepatocellular carcinoma (HCC), or primary liver cancer (Press release, Celsion, JUN 22, 2020, View Source [SID1234561482]). Members of the iDMC represent the global market for HCC and are based in the U.S., Canada and Europe, and Celsion believes that any logistical challenges to the Committee’s performing its work presented by the global COVID-19 pandemic have been addressed. Celsion expects to announce the iDMC’s recommendations and Company next steps soon after the meeting concludes.

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Data lock for the second pre-specified interim analysis occurred during April 2020 after the prescribed minimum number of events of 158 patient deaths was reached.

As previously announced, the hazard ratio for success at 158 deaths is 0.70, which represents a 30% reduction in the risk of death compared with RFA alone. The p-Value required is 0.022. Both compare favorably with the hazard ratio of 0.65 and p-Value = 0.02 observed in the prospective HEAT Study subgroup upon which the OPTIMA Study is based.

Michael H. Tardugno, Celsion’s chairman, president and chief executive officer, said, "The iDMC meeting is expected to take place as planned and we look forward to receiving their recommendation. While we are hopeful for a positive outcome, it is not a binary event for the OPTIMA Study. Should the data not reach the threshold for success, we believe the OPTIMA Study is ultimately well-positioned for success at the final analysis, if necessary. The final analysis would be based on 197 patient deaths where the hazard ratio for success is 0.75 or a 25% reduction in the risk of death, with a p-Value = 0.042. We believe that a successful study has blockbuster revenue potential and, more importantly, will be globally transformational for patients with HCC, the largest unmet need in oncology with more than 750,000 cases annually."

About the OPTIMA Study

The Phase III OPTIMA Study enrolled 556 patients at 65 clinical sites in North America, Europe, China and Asia Pacific. The Study is evaluating ThermoDox in combination with optimized RFA, which will be standardized to a minimum of 45 minutes across all investigators and clinical sites for treating lesions 3-7 cm in size, versus optimized RFA alone. The primary endpoint for the trial is Overall Survival, which is supported by post-hoc analyses of data from the Company’s 701-patient HEAT Study, where optimized RFA demonstrated the potential to significantly improve survival when combined with ThermoDox. The statistical plan calls for two interim efficacy analyses by an independent Data Monitoring Committee.

About ThermoDox

Celsion’s most advanced program is a heat-mediated drug delivery technology that employs a novel heat-sensitive liposome engineered to address a range of difficult-to-treat cancers. The first application of this platform is ThermoDox, a lyso-thermosensitive liposomal doxorubicin (LTLD) whose novel mechanism of action delivers high concentrations of doxorubicin to a region targeted with the application of localized heat at 40°C, just above body temperature. ThermoDox is positioned for use with multiple heating technologies and has the potential to treat of a broad range of cancers including metastatic liver, recurrent chest wall breast cancer and non-muscle invading bladder cancers.

Celsion’s LTLD technology leverages two mechanisms of tumor biology to deliver higher concentrations of drug directly to the tumor site. In the first mechanism, rapidly growing tumors have leaky vasculature, which is permeable to liposomes and enables their accumulation within tumors. Leaky vasculature influences a number of factors within the tumor, including the access of therapeutic agents to tumor cells. Administered intravenously, ThermoDox is engineered with a half-life to allow significant accumulation of liposomes at the tumor site as these liposomes recirculate in the blood stream.

In the second mechanism, when an external heating device heats tumor tissue to a temperature of 40°C or greater, the heat-sensitive liposome rapidly changes structure and the liposomal membrane selectively dissolves, creating openings that can release a chemotherapeutic agent directly into the tumor and the surrounding vasculature. Drug concentration increases as a function of the accumulation of liposomes at the tumor site, but only where the heat is present. This method damages only the tumor and the area subject to tumor invasion, supporting more precise drug targeting.

On June 22, 2020 Chimerix (NASDAQ:CMRX), a biopharmaceutical company focused on accelerating the development of medicines to treat cancer and other serious diseases, reported the appointment of Allen Melemed, M.D., M.B.A., as Chief Medical Officer (Press release, Chimerix, JUN 22, 2020, View Source [SID1234561433]).

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"We are delighted to welcome Dr. Melemed as a key member of our management team. We look forward to leveraging his considerable clinical and regulatory experience as a distinguished pharmaceutical executive. His vast experience bringing oncology therapeutics through development and approval across multiple modalities will be invaluable as we initiate our dociparstat sodium (DSTAT) Phase 3 trial in first line acute myeloid leukemia (AML), our ongoing Phase 2/3 trial to combat acute lung injury (ALI) in COVID-19 patients, and finalize our rolling New Drug Application (NDA) for brincidofovir (BCV) as a medical countermeasure for smallpox," said Mike Sherman, Chief Executive Officer of Chimerix.

"I am particularly pleased to be joining Chimerix at such an important juncture in its growth trajectory. DSTAT’s potential to improve survival in newly-diagnosed AML patients is critically important in a disease where five-year survival rates remain far too low, particularly in older populations. Furthermore, DSTAT’s broad mechanism to manage inflammation and hematologic disorders offers promise to treat ALI in COVID-19 patients and underpins its mechanism of action in ALI beyond the current pandemic. I look forward to working with the team to advance our pipeline of important therapies and to bringing these life-saving treatments to patients in need," said Dr. Melemed.

Dr. Melemed joins Chimerix from Eli Lilly and Company, where he spent more than 20 years dedicated to the clinical development and approval of oncology medicines across a broad range of tumor types including VERZENIO, CYRAMZA, LARTRUVO , ALIMTA and RETEVMO among others. Most recently, he served as a Distinguished Medical Fellow and Senior Director of Regulatory Affairs Oncology, North America. In addition to his role at Eli Lilly, Dr. Melemed was an attending physician in pediatric oncology at Indiana University (IU) School of Medicine, Riley Children’s Hospital from 1996 to 2012.

Dr. Melemed holds a B.S. in Genetics and Cell Biology from the University of Minnesota and a M.D. from the University of Minnesota School of Medicine. In addition, he completed his residency in pediatrics at the University of Wisconsin, Madison and fellowship in pediatric hematology/oncology at IU School of Medicine. He earned an M.B.A. from the University of Chicago Booth School of Business. Dr. Melemed has authored dozens of scientific and clinical publications.