On June 22, 2020 Targovax ASA (OSE: TRVX), a clinical stage immuno-oncology company developing oncolytic viruses to target hard-to-treat solid tumors, reported 12-month efficacy and immunological data from the randomized phase I/II trial of ONCOS-102 in combination with standard of care chemotherapy in malignant pleural mesothelioma (MPM) (Press release, Targovax, JUN 22, 2020, View Source [SID1234564002]).

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The trial is an open label, exploratory phase I/II trial adding ONCOS-102 to standard of care (SoC) chemotherapy (pemetrexed/cisplatin) in first and second (and later) line MPM to assess safety, immune activation and clinical efficacy vs SoC only. In total, 31 patients have been treated in the trial, with 20 patients in the experimental group receiving the ONCOS-102 and SoC combination, and 11 patients in a control group receiving SoC only. The 31 patients have now completed the 12-month follow-up. The first set of data was reported in January 2020, see press release here, with an update in May 2020, see press release here.

The median Progression Free Survival (mPFS) for ONCOS-102 treated first line patients remains at 8.9 months, which is identical to the previously reported early data. mPFS for the control group first line patients treated with SoC chemotherapy only is 7.6 months. The first line mPFS data continues to compare favorably to SoC historical controls, which have shown mPFS of 5.7-7.3 months[1]. As there is now longer follow-up and few censored patients left in the PFS analysis, the updated figures can be considered close to final.

The 12-month survival rate was 64% in the first line ONCOS-102 treated patients, compared to 50% in the first line control group treated with SoC chemotherapy only (median Overall Survival is too early to report). The patients continue to be followed and updated Overall Survival (OS) figures will be published as they mature. This 64% 12-month survival rate is encouraging compared to the control group, but there are few historical control reference points. Recently, at ASCO (Free ASCO Whitepaper) 2020, results from a first line mesothelioma trial assessing SoC chemotherapy in combination with the anti-PD-L1 checkpoint inhibitor durvalumab showed a 70% 12-month survival rate. This suggests that ONCOS-102 alone plus SoC chemotherapy may already achieve a level of benefit close to that observed with checkpoint inhibition plus SoC chemotherapy. It is expected that addition of checkpoint inhibition to ONCOS-102 and Soc will provide even further clinical benefit due to engagement of distinct and complementary biological mechanisms. As such, Targovax’s future clinical development of ONCOS-102 will focus on first line mesothelioma with the triple combination of a checkpoint inhibitor, ONCOS-102 and SoC. A randomized phase II trial is currently being planned in collaboration with a pharma partner.

Tumor biopsy immunohistochemistry and gene expression analyses from the present trial confirm the predicted mode of action of ONCOS-102. Importantly, profound innate and adaptive immune activation is observed in the ONCOS-102 treated patients compared to the control group, and this immune activation is associated with better clinical outcome. The immune activation is hallmarked by an increase in intra-tumoral cytotoxic T-cells and upregulation of adaptive immunity and cytotoxicity related gene expression, in parallel with polarization from M2 to M1 macrophage phenotype and upregulation of PD-L1 expression, indicating that ONCOS-102 is driving a favorable remodeling of the tumor microenvironment. This powerfully demonstrates the immune activation potential of ONCOS-102 far beyond what is achieved by chemotherapy alone and suggests that patients may be effectively sensitized to treatment with an anti-PD1/L1 antagonist, thereby providing strong scientific rationale for the combination of ONCOS-102 and checkpoint inhibition in first line mesothelioma.

Dr. Magnus Jäderberg, Chief Medical Officer of Targovax, said: "We are very pleased to see the encouraging first line PFS data holding up in the 12-month analysis, with early signs of positive survival outcomes. We are particularly excited to observe a broad and profound immune activation in the ONCOS-102 treated patients, which confirms the proposed mode of action. ONCOS-102 treatment clearly drives a favorable remodeling of the tumor microenvironment, and this remodeling is linked to better clinical outcomes. This immune activated tumor micro-environment provides the key scientific rationale and an ideal backdrop for combination treatment with a checkpoint inhibitor. These data set us up perfectly to move forward with a trial combining ONCOS-102 and a checkpoint inhibitor, which we believe will release the full potential of immunotherapy in this hard-to-treat patient population".

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.