On February 6, 2020 On Target Laboratories Inc., a privately held biotechnology company developing the use of Purdue University-discovered fluorescent markers to target and illuminate cancer during surgery, reported that it has announced the results of a multi-institutional Phase 2 clinical trial in which outcomes were improved for 26% of patients undergoing pulmonary resection for non-small-cell lung cancer (NSCLC) (Press release, On Target Laboratories, FEB 6, 2020, View Source,-improve-outcomes,-receives-fda-fast-track-as-phase-3-clinical-trials-begin.html [SID1234553942]).

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The results of the treatment, called OTL38, were presented at the 56th annual Meeting of the Society of Thoracic Surgeons (STS), held last month in New Orleans, and were featured in a plenary session as a J. Maxwell Chamberlain Memorial Paper for General Thoracic Surgery, considered to be among the top-rated abstracts at STS. The treatment was developed in the Purdue laboratory of Philip Low in the Purdue Institute of Drug Discovery. Low is the Presidential Scholar for Drug Discovery and Ralph C. Corley Distinguished Professor of Chemistry-Biochemistry in the Department of Chemistry. Currently, there are 288 clinical trials performed or in process using Purdue-developed medical treatments at 4,841 sites across the globe.

"Our goal is to provide surgeons with new technology to help them provide a more complete resection to more patients. This gives patients the best chance of improved outcomes after surgery," said Christopher Barys, president and CEO of On Target Laboratories.

Lung cancer is the leading cause of cancer-related deaths in the United States. Pulmonary resection, either a wedge resection, segmentectomy, or lobectomy, is recommended for most patients who have operable stage I-II non-small cell lung cancer. Intraoperative molecular imaging (IMI) — also referred to as fluorescence-guided surgery — may increase the likelihood of a more complete surgical resection, which could translate into increased survival for patients and reduced re-operations or adjuvant treatment for hospitals.

Conducted over 18 months, the study included 92 patients eligible for analysis. There were no drug-related serious adverse events and 24 patients, or 26%, were impacted during pulmonary resection, with 8% of patients having a change in their stage due to the use of IMI.

The study showed that IMI improved localization of small and peripheral lesions, which can be difficult for surgeons to identify visually or through manual palpitation, and enabled localization of otherwise unlocalizable lesions in 11 patients, or 12%. Further, 10 additional cancers were found in seven patients, or 8%. During the Specimen Check Phase, when the surgeon confirms that the nodule is in the specimen and analyzes the margins, surgeons thought all margins were adequate, yet back-table inspection using IMI revealed inadequate margins in eight patients, or 9%.

"OTL38 is the first technique that is specific to imaging adenocarcinomas of the lung, which is one of the most common types of invasive lung cancer," said Dr. Inderpal (Netu) S. Sarkaria of the Department of Cardiothoracic Surgery at the University of Pittsburgh Medical Center. "Near-infrared imaging with OTL38 may be a powerful tool to help surgeons significantly improve the quality of lung cancer surgery by more clearly identifying tumors and allowing the surgeon to better see and completely remove them — one of the most vital components in the overall care of patients with this disease."

OTL38 is under development in two Phase 3 clinical trials for lung and ovarian cancer indications. Both trials are being conducted under a special protocol agreement with the U.S. Food and Drug Administration. OTL38 also has received a fast-track designation for both the lung and ovarian cancer indications and an orphan designation for ovarian cancer from the FDA.

Low is a co-founder of On Target and the technology is licensed through the Purdue Research Foundation Office of Technology of Commercialization. The Purdue Institute of Drug Discovery is situated near Discovery Park District, a $1 billion-plus long-term enterprise to support a transformational center of innovation on the western edge of the Purdue University campus. The district includes the Convergence Center for Innovation and Collaboration, where startups, entrepreneurs, innovators and companies can collaborate with Purdue to address global challenges in health, sustainability, IT and space. The district already includes a public airport with a 7,000-foot runway, and partnerships with international companies including Rolls-Royce, Schweitzer Engineering Laboratories and Saab. Visit Discovery Park District.

About Intraoperative Molecular Imaging

To date, there have been limited ways for surgeons to confidently assess the location and full extent of cancerous tissue while operating. On Target Laboratories’ fluorescent markers are composed of a near-infrared dye and a targeting molecule, or ligand, that binds to receptors overexpressed on cancer cells. These markers illuminate the cancerous lesions, lighting the way for the resection of malignant tissue and enabling surgeons to see and remove more diseased tissue. On Target’s first novel compound, OTL38, targets folate receptors commonly found on many cancers, including lung and ovarian cancers. A small single dose of the compound is administered via IV infusion one to 24 hours before surgery, allowing the surgeon to identify malignant tissue during the procedure using the near-infrared camera.

On February 6, 2020 University of Pennsylvania reported Genetically-edited immune cells can persist, thrive, and function months after a cancer patient receives them, according to new data published by researchers (Press release, University of Pennsylvania, FEB 6, 2020, View Source [SID1234553941]). The team showed cells removed from patients and brought back into the lab setting were able to kill cancer months after their original manufacturing and infusion. Further analysis of these cells confirmed they were successfully edited in three specific ways, marking the first-ever sanctioned investigational use of multiple edits to the human genome. This is the first U.S. clinical trial to test the gene editing approach in humans, and the publication of this new data today in Science follows on the initial report last year that researchers were able to use CRISPR/Cas9 technology to successfully edit three cancer patients’ immune cells. Penn is conducting the ongoing study in cooperation with the Parker Institute for Cancer Immunotherapy and Tmunity Therapeutics.

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"Our data from the first three patients enrolled in this clinical trial demonstrate two important things that, to our knowledge, no one has ever shown before. First, we can successfully perform multiple edits with precision during manufacturing, with the resulting cells surviving longer in the human body than any previously published data have shown. Second, thus far, these cells have shown a sustained ability to attack and kill tumors," said Carl June, MD, the Richard W. Vague Professor in Immunotherapy and director of the Center for Cellular Immunotherapies in the Abramson Cancer Center and director of the Parker Institute for Cancer Immunotherapy at the Perelman School of Medicine at the University of Pennsylvania and the study’s senior author.

The findings are the latest milestone in Penn’s history as cellular and gene therapy pioneers, including development of the first FDA-approved CAR T cell therapy, Kymriah, for pediatric and adult blood cancer patients.

Patients on this trial were treated by Edward A. Stadtmauer, MD, section chief of Hematologic Malignancies at Penn, who is the co-lead author on the study along with Joseph A. Fraietta, PhD, an assistant professor of Microbiology at Penn. The co-senior author is Simon F. Lacey, PhD, director of the Translational and Correlative Studies Laboratory in the Center for Cellular Immunotherapies.

The approach in this study is closely related to CAR T cell therapy, in which patient immune cells are engineered to fight cancer, but it has some key differences. Just like CAR T, researchers in this study began by collecting a patient’s T cells from blood. However, instead of arming these cells with a receptor against a protein such as CD19, the team first used CRISPR/Cas9 editing to remove three genes. The first two edits removed a T cell’s natural receptors so they can be reprogrammed to express a synthetic T cell receptor, allowing these cells to seek out and destroy tumors. The third edit removed PD-1, a natural checkpoint that sometimes blocks T cells from doing their job.

"This new analysis of the three patients has confirmed that the manufactured cells contained all three edits, providing proof of concept for this approach. This is the first confirmation of the ability of CRISPR/Cas9 technology to target multiple genes at the same time in humans and illustrates the potential of this technology to treat many diseases that were previously not able to be treated or cured," June said.

Once the three genes are knocked out, a fourth genetic modification was accomplished using a lentivirus to insert the cancer-specific synthetic T cell receptor, which tells the edited T cells to target an antigen called NY-ESO-1. Previously published data show these cells typically survive for less than a week, but this new analysis shows the edited cells used in this study persisted, with the longest follow up at nine months.

Several months after the infusion, researchers drew more blood and isolated the CRISPR-edited cells for study. When brought back into the lab setting, the cells were still able to kill tumors.

"Previous studies have shown these cells lose function within days, so the fact that the CRISPR-edited cells in this study retained anti-tumor function for a significantly longer period of time after a single infusion is very encouraging," June said.

The CRISPR-edited T cells used in this study are not active on their own like CAR T cells. Instead, they require the cooperation of a molecule known as HLA-A*02:01, which is only expressed in a subset of patients. This means that patients had to be screened ahead of time to make sure they were a match for the approach. Participants who met the requirements received other clinically-indicated therapy as needed while they waited for their cells to be manufactured. Once that process was completed, all three patients received the gene-edited cells in a single infusion after a short course of chemotherapy. Analysis of blood samples revealed that all three participants had the CRISPR-edited T cells take root and thrive in the patients. While none responded to the therapy, there were no treatment-related serious adverse events.

CRISPR technology has not previously been tested in humans in the U.S. Investigators at Penn have pioneered a number of other "first uses" of engineered T cells over the past decade. Even with that experience, moving this work into the clinic while ensuring appropriate patient safeguards meant the research team had to move through a comprehensive and rigorous series of institutional and federal regulatory approval steps, including approval by the National Institutes of Health’s Recombinant DNA Research Advisory Committee and review by the U.S. Food and Drug Administration, as well as Penn’s institutional review board and institutional biosafety committee. The entire process required more than two years. Researchers say these new data will open the door to later stage studies to investigate and extend this approach to a broader field beyond cancer, several of which are already planned at Penn.

On February 6, 2020 Oncotarget Volume reported in this study, locally advanced head and neck cancer patients undergoing definitive chemoradiation were randomly allocated to weekly cisplatin – radiation {CRT arm} or nimotuzumab -weekly cisplatin -radiation {NCRT arm} (Press release, Oncotarget, FEB 6, 2020, View Source [SID1234553940]).

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An interaction test was performed between the study arms and HPV status prior to doing any HPV specific analysis for each of the studied outcomes.

We had 187 HPV negative oropharyngeal cancers, 91 in the CRT arm and 96 in NCRT arm.

The addition of nimotuzumab to weekly cisplatin-radiation improves outcomes inclusive of OS in HPV negative oropharyngeal cancers.

Dr. Kumar Prabhash from the Department of Medical Oncology at the Tata Memorial Hospital, HBNI in Mumbai India said in their Oncotarget research article, "Locally advanced oropharyngeal cancers possess a unique challenge."

Patients with HPV positive disease have a favorable prognosis as opposed to HPV negative disease.

They had hypothesized that an improvement in outcomes in our study was seen due to the differential patient population in our study when compared to the RTOG 0552 study.

Another phase 3 study, exploring the role of cetuximab along with carboplatin -5 FU with radiation, reported improvement in outcomes with the addition of cetuximab.

Taking this into consideration, the authors decided to perform a subgroup analysis of the HPV negative oropharyngeal cancer cohort, to study the absolute improvement in 2-year outcomes with the addition of nimotuzumab.

The Prabhash Research Team concluded in their Oncotarget article that an interaction test was performed prior to doing the subgroup analysis, to determine whether nimotuzumab had a differential impact or not.

On February 6, 2020 eFFECTOR Therapeutics, Inc., a leader in the development of selective translation regulators (STRs) for the treatment of cancer, reported that Steve Worland, Ph.D., president and chief executive officer of eFFECTOR, will present a company overview during the BIO CEO & Investor Conference on Tuesday, February 11 at 2:00 p.m. ET (Press release, eFFECTOR Therapeutics, FEB 6, 2020, View Source [SID1234553938]). The conference will take place February 10-11, in New York, N.Y.

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On February 6, 2020 Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, reported that it has entered into an amendment of its collaboration, license and option agreement with Aurigene Discovery Technologies, Ltd. (Aurigene) (Press release, Curis, FEB 6, 2020, View Source [SID1234553937]). Under the terms of the amended agreement, Aurigene will fund and conduct a Phase 2b/3 randomized study evaluating CA-170, an orally available, dual inhibitor of VISTA and PDL1, in combination with chemoradiation, in approximately 240 patients with non-squamous non-small cell lung cancer (nsNSCLC). In turn, Aurigene receives rights to develop and commercialize CA-170 in Asia, in addition to its existing rights in India and Russia, based on the terms of the original agreement. Curis retains U.S., E.U., and rest of world rights to CA-170, and is entitled to receive royalty payments on potential future sales of CA-170 in Asia.

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In 2019, Aurigene presented clinical data from a Phase 2a basket study of CA-170 in patients with multiple tumor types, including those with nsNSCLC. In the study, CA-170 demonstrated promising signs of safety and efficacy in nsNSCLC patients compared to various anti-PD-1/PD-L1 antibodies.

"We are pleased to announce this amendment which leverages our partner Aurigene’s expertise and resources to support the clinical advancement of CA-170, as well as maintain our rights to CA-170 outside of Asia," said James Dentzer, President and Chief Executive Officer of Curis. "Phase 2a data presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) conference last fall supported the potential for CA-170 to serve as a therapeutic option for patients with nsNSCLC. We look forward to working with our partner Aurigene to further explore this opportunity."

"Despite recent advancements, patients with localized unresectable NSCLC struggle with high rates of recurrence and need for expensive intravenous biologics. The CA-170 data presented at ESMO (Free ESMO Whitepaper) 2019 from Aurigene’s Phase 2 ASIAD trial showed encouraging results in Clinical Benefit Rate and Prolonged PFS and support its potential to provide clinically meaningful benefit to Stage III and IVa nsNSCLC patients, in combination with chemoradiation and as oral maintenance" said Kumar Prabhash, MD, Professor of Medical Oncology at Tata Memorial Hospital, Mumbai, India.

Murali Ramachandra, PhD, Chief Executive Officer of Aurigene, commented, "Development of CA-170, with its unique dual inhibition of PD-L1 and VISTA, is the result of years of hard-work and commitment by many people, including the patients who participated in the trials, caregivers and physicians, along with the talented teams at Aurigene and Curis. We look forward to further developing CA-170 in nsNSCLC."