On July 27, 2020 AstraZeneca’s Imfinzi (durvalumab) reported that it has been recommended for marketing authorisation in the European Union (EU) for the 1st-line treatment of adults with extensive-stage small cell lung cancer (ES-SCLC) in combination with a choice of chemotherapies, etoposide plus either carboplatin or cisplatin. SCLC is a highly aggressive, fast-growing form of lung cancer that typically recurs and progresses rapidly despite initial response to chemotherapy.1,2 (Press release, AstraZeneca, JUL 27, 2020, View Source [SID1234562385])

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The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency based its positive opinion on results from the Phase III CASPIAN trial for Imfinzi plus chemotherapy, which have also been published in The Lancet.3

The trial showed that Imfinzi plus chemotherapy demonstrated a statistically significant and clinically meaningful overall survival (OS) benefit for the 1st-line treatment of patients with ES-SCLC, reducing the risk of death by 27% versus chemotherapy alone (based on a hazard ratio [HR] of 0.73; 95% confidence interval [CI] 0.59-0.91; p=0.0047). Results also showed an increased confirmed objective response rate in the Imfinzi plus chemotherapy arm (68% versus 58% for chemotherapy alone) and that Imfinzi added to chemotherapy delayed the time it took for lung cancer-related symptoms to worsen.4

An updated analysis recently showed sustained efficacy for Imfinzi plus chemotherapy after a median follow up of more than two years (OS HR: 0.75; 95% CI 0.62-0.91; nominal p=0.0032). The safety and tolerability for Imfinzi plus chemotherapy were consistent with the known safety profile of these medicines. No patients tested positive for treatment-emergent anti-drug antibodies to Imfinzi.

Luis Paz-Ares MD, Ph.D., Chair, Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid, Spain and principal investigator in the Phase III CASPIAN trial said: "The CASPIAN trial shows that Imfinzi plus a choice of platinum-etoposide chemotherapies offers an important new 1st-line treatment option for extensive-stage small cell lung cancer, providing a sustained survival benefit with a well-tolerated treatment. For many physicians in Europe, cisplatin is a preferred chemotherapy in this setting, and this recommendation is a vital step toward bringing an immunotherapy combination with cisplatin to these patients in Europe for the first time."

José Baselga, Executive Vice President, Oncology R&D, said: "Imfinzi has the potential to address a critical unmet need for patients with extensive-stage small cell lung cancer in Europe who have few options to treat this aggressive and devastating disease. We look forward to delivering a new standard of care that significantly improves survival with a choice of chemotherapies and convenient dosing every four weeks during maintenance."

The CHMP recommendation is for Imfinzi in combination with etoposide and either carboplatin or cisplatin for the 1st-line treatment of adults with ES-SCLC. The CASPIAN trial used a fixed dose of Imfinzi (1500mg) administered every three weeks for four cycles while in combination with chemotherapy and then every four weeks until disease progression.

Imfinzi in combination with etoposide and either carboplatin or cisplatin is approved in the US and several other countries around the world for the treatment of ES-SCLC in the 1st-line setting and is currently under regulatory review in Japan and other countries.

Small cell lung cancer

Lung cancer is the leading cause of cancer death among both men and women and accounts for about one fifth of all cancer deaths.5 Lung cancer is broadly split into non-small cell lung cancer (NSCLC) and SCLC, with about 15% classified as SCLC.6 About two thirds of SCLC patients are diagnosed with extensive-stage disease, in which the cancer has spread widely through the lung or to other parts of the body.7 Prognosis is particularly poor, as only 6% of all SCLC patients will be alive five years after diagnosis.7

CASPIAN

CASPIAN was a randomised, open-label, multi-centre, global, Phase III trial in the 1st-line treatment of 805 patients with ES-SCLC. The trial compared Imfinzi in combination with etoposide and either carboplatin or cisplatin chemotherapy, or Imfinzi and chemotherapy with the addition of a second immunotherapy, tremelimumab, versus chemotherapy alone. In the experimental arms, patients were treated with four cycles of chemotherapy. In comparison, the control arm allowed up to six cycles of chemotherapy and optional prophylactic cranial irradiation. The trial was conducted in more than 200 centres across 23 countries, including the US, in Europe, South America, Asia and the Middle East. The primary endpoint was OS in each of the two experimental arms. In June 2019, the CASPIAN trial met one primary endpoint of demonstrating OS for Imfinzi plus chemotherapy at a planned interim analysis. In March 2020, the second experimental arm with tremelimumab did not meet its primary endpoint of OS.

Imfinzi

Imfinzi (durvalumab) is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is approved in the curative-intent setting of unresectable, Stage III NSCLC after chemoradiation therapy in the US, Japan, China, across the EU and in many other countries, based on the Phase III PACIFIC trial. Imfinzi is also approved for previously treated patients with advanced bladder cancer in the US and a small number of other countries.

As part of a broad development programme, Imfinzi is also being tested as a monotherapy and in combinations including with tremelimumab, an anti-CTLA4 monoclonal antibody and potential new medicine, as a treatment for patients with NSCLC, SCLC, bladder cancer, head and neck cancer, liver cancer, biliary tract cancer, cervical cancer, ovarian cancer, endometrial cancer and other solid tumours.

AstraZeneca in lung cancer

AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage development for the treatment of different forms of lung cancer spanning different histologies, several stages of disease, lines of therapy and modes of action. AstraZeneca aims to address the unmet needs of patients with EGFR-mutated tumours as a genetic driver of disease, which occur in 10-15% of NSCLC patients in the US and EU and 30-40% of NSCLC patients in Asia, with the approved medicines Iressa (gefitinib) and Tagrisso (osimertinib) and its ongoing Phase III trials LAURA, NeoADAURA and FLAURA2.8-10

AstraZeneca is committed to addressing tumour mechanisms of resistance through the ongoing Phase II trials SAVANNAH and ORCHARD which test Tagrisso in combination with savolitinib, a selective inhibitor of c-MET receptor tyrosine kinase, along with other potential new medicines. Enhertu (trastuzumab deruxtecan), a HER2-directed antibody drug conjugate, is in development for metastatic non-squamous HER2-overexpressing or HER2-mutated NSCLC including trials in combination with other anticancer treatments.

An extensive Immuno-Oncology development programme focuses on lung cancer patients without a targetable genetic mutation which represents up to three-quarters of all patients with lung cancer.11 Imfinzi, an anti-PDL1 antibody, is in development for patients with advanced disease (Phase III trials POSEIDON and PEARL) and for patients in earlier stages of disease including potentially-curative settings (Phase III trials MERMAID-1, AEGEAN, ADJUVANT BR.31, PACIFIC-2, PACIFIC-4, PACIFIC-5, and ADRIATIC) both as monotherapy and in combination with tremelimumab and/or chemotherapy. Imfinzi is also in development in the Phase II trials NeoCOAST, COAST and HUDSON in combination with potential new medicines from the early-stage pipeline including Enhertu.

AstraZeneca’s approach to Immuno-Oncology

Immuno-oncology (IO) is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. The Company’s IO portfolio is anchored by immunotherapies that have been designed to overcome anti-tumour immune suppression. AstraZeneca is invested in using IO approaches that deliver long-term survival for new groups of patients across tumour types.

The Company is pursuing a comprehensive clinical-trial programme that includes Imfinzi as a monotherapy and in combination with tremelimumab in multiple tumour types, stages of disease, and lines of therapy, and where relevant using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient. In addition, the ability to combine the IO portfolio with radiation, chemotherapy, small targeted molecules from across AstraZeneca’s Oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumours.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With seven new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investment that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

On July 27, 2020 Sysmex Corporation (HQ: Kobe, Japan; Chairman and CEO: Hisashi Ietsugu) reported the July 2020 launch of its OncoGuideTM NET1 expert panel support system (the "System"), which enhances the administrative efficiency of expert panels2 in cancer genome profiling (Press release, Sysmex, JUL 27, 2020, View Source [SID1234562369]). The OncoGuideTM NET allows for the sharing of information needed for discussions by expert panels, which consist of experts in various disciplines from multiple medical institutions, and arrangement of session schedules. When connected to the OncoGuideTM Portal, 3 the System retrieves test results. With these functions being managed under an information security environment complying with the Three Guidelines from Three Ministries (3G3M),4 the System supports the establishment of an efficient framework for cancer genomic medicine.

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Sysmex received manufacturing and marketing approval in Japan for the first time and then approval for insurance coverage for its OncoGuideTM NCC Oncopanel System to be used in cancer genome profiling, making the system readily available to medical institutions. At the same time, we have implemented a complete domestic testing service, with comprehensive support that includes an assay service by RIKEN GENESIS. 5

One of the challenges of spreading cancer genomic medicine at an accelerated pace in Japan’s healthcare setting is how they can go about increasing the efficiency of expert panels, in which medical professionals from multiple institutions participate. In response to the expectations of such medical professionals, in July 2020, we will start providing the System to cancer genomic medicine core hospitals, hub hospitals, and liaison hospitals that organize expert panels.

The System allows for the sharing of patient information and analysis results, which are necessary for discussions by expert panels, a process with a particularly demanding workload, and efficient arrangement of session schedules. When connected to the OncoGuideTM Portal, the System performs automatic input of IDs and other data and retrieves test results. The System is managed under an advanced information security environment complying with the Three Guidelines from Three Ministries (3G3M) by the Ministry of Health, Labour and Welfare, the Ministry of Economy, Trade and Industry, and the Ministry of Internal Affairs and Communications of Japan.

Going forward, Sysmex aims to contribute to the clinical implementation of genomic medicine in Japan by providing high-value-added information useful in the diagnosis and treatment of cancer and the selection of anti-cancer drugs. To this end, we will expand the functions of the System, such as linking case information files of the Center for Cancer Genomics and Advanced Therapeutics (CCAT)6 and analyzing the activities by previous expert panels, in addition to enhancing the efficiency of expert panels. By delivering the OncoGuideTM NET, together with the cancer genome profiling system, Sysmex will lead the efforts towards realizing personalized medicine, so that we can reduce the workload of medical professionals, improve patients’ quality of life (QOL), and contribute to the advancement and progress of healthcare.

References
"Sysmex Receives Manufacturing and Marketing Approval to Use the OncoGuideTM NCC Oncopanel System in Cancer Genome Profiling," released on December 25, 2018 View Source

"Commencement of Assay Service Using the OncoGuideTM NCC Oncopanel System in Cancer Genome Profiling," released on February 21, 2019 View Source

"The OncoGuideTM NCC Oncopanel System Receives Insurance Coverage for Use in Cancer Genome Profiling," released on May 31, 2019 View Source

Terminology

1 OncoGuideTM NET: NET is short for Network for Expert Panel Team.

2 Expert panel: A committee comprised of experts from diverse fields, including cancer medication, medical genetics, genetic counseling, pathology, molecular genetics, and cancer genomic medicine, from multiple medical institutions, as well as the attending physician. Determines implications of analysis results of cancer genome profiling and suggests therapies optimized for individual patients.

3 OncoGuideTM Portal: Monitors progress in testing at providers of lab-assay services using the OncoGuideTM NCC Oncopanel System and retrieves electronic files of test reports.

4 Three Guidelines from Three Ministries (3G3M): Refers collectively to the three separate guidelines drawn up by the Ministry of Health, Labour and Welfare, Ministry of Economy, Trade and Industry, and Ministry of Internal Affairs and Communications of Japan in line with the roadmap for the development of medical information safety management guidelines for reasons of security, etc. of electronic medical information.

5 RIKEN GENESIS Co., Ltd.: A subsidiary of Sysmex Corporation that provides lab-assay services for genetic testing.

6 Center for Cancer Genomics and Advanced Therapeutics (C-CAT): A platform for constructing a "cancer genomics information repository," a master database of sequence information and clinical information obtained from genomic analyses conducted by hospitals implementing cancer genomic medicine and elsewhere, and for building a cancer genome knowledge database for interpreting and determining the clinical implications of genome analysis results.

On July 27, 2020 AstraZeneca reported that it has entered into a new global development and commercialisation agreement with Daiichi Sankyo Company, Limited (Daiichi Sankyo) for DS-1062, Daiichi Sankyo’s proprietary trophoblast cell-surface antigen 2 (TROP2)-directed antibody drug conjugate (ADC) and potential new medicine for the treatment of multiple tumour types (Press release, AstraZeneca, JUL 27, 2020, https://www.astrazeneca.com/media-centre/press-releases/2020/astrazeneca-and-daiichi-sankyo-enter-collaboration-to-develop-and-commercialise-new-antibody-drug-conjugate.html [SID1234562368]).

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DS-1062 is currently in development for the treatment of multiple tumours that commonly express the cell-surface glycoprotein TROP2. Among them, TROP2 is overexpressed in the majority of non-small cell lung cancers1 and breast cancers,2,3 tumour types that have long been a strategic focus for AstraZeneca. This collaboration reflects AstraZeneca’s strategy to invest in antibody drug conjugates as a class, the innovative nature of the technology and the successful existing collaboration with Daiichi Sankyo.

Pascal Soriot, Chief Executive Officer, said: "We see significant potential in this antibody drug conjugate in lung as well as in breast and other cancers that commonly express TROP2. We are delighted to enter this new collaboration with Daiichi Sankyo and to build on the successful launch of Enhertu to further expand our pipeline and leadership in Oncology. We now have six potential blockbusters in Oncology with more to come in our early and late pipelines."

Sunao Manabe, Representative Director, President and CEO of Daiichi Sankyo, said: "DS-1062, one of our lead DXd ADCs that will form a pillar of our next mid-term business plan, has the potential to become a best-in-class TROP2 ADC in multiple tumours, including lung and breast cancers. This new strategic collaboration with AstraZeneca, a company with extensive experience and significant expertise in the global oncology business, will enable us to deliver DS-1062 to more patients around the world as quickly as possible. As we have done with Enhertu, we will jointly design and implement strategies to maximise the value of DS-1062."

Using Daiichi Sankyo’s proprietary DXd ADC technology, DS-1062 is designed to deliver chemotherapy selectively to cancer cells and to reduce systemic exposure. A comprehensive development programme with DS-1062 is planned globally.

Financial considerations

AstraZeneca will pay Daiichi Sankyo an upfront payment of $1bn in staged payments: $350m is due upon completion, with $325m after 12 months and $325m after 24 months from the effective date of the agreement.

AstraZeneca will pay additional conditional amounts of up to $1bn for the successful achievement of regulatory approvals and up to $4bn for sales-related milestones.

The transaction will be accounted for as an intangible asset acquisition, recognised initially at the present value of non-contingent consideration, with any potential future milestone payments capitalised into the intangible asset as they are recognised.

The companies will jointly develop and commercialise DS-1062 worldwide, except in Japan where Daiichi Sankyo will maintain exclusive rights. AstraZeneca and Daiichi Sankyo will share equally development and commercialisation expenses as well as profits relating to DS-1062 worldwide, except for Japan where Daiichi Sankyo will be responsible for such costs and will pay AstraZeneca mid single-digit royalties. Daiichi Sankyo will record sales in the US, certain countries in Europe and certain other countries where Daiichi Sankyo has affiliates. Profits shared with AstraZeneca from those countries will be recorded as Collaboration Revenue by AstraZeneca. AstraZeneca will record Product Sales in other countries worldwide, for which profits shared with Daiichi Sankyo will be recorded within Cost of Sales. Daiichi Sankyo will manufacture and supply DS-1062.

There are no closing conditions to the transaction. The collaboration agreement became effective on 27 July 2020. The transaction does not impact the Company’s financial guidance for 2020.

TROP2

TROP2 is a transmembrane glycoprotein that is overexpressed in many cancers including up to 80% of patients with triple-negative breast cancer.2,3 High TROP2 expression also has been identified in a majority of non-small cell lung cancers.1 Research indicates that high TROP2 expression is associated with cancer cell growth and proliferation.4 TROP2 is recognised as a promising molecular target for therapeutic development in various cancers.4

DS-1062

DS-1062 is a TROP2-directed ADC. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy (‘payload’) via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, DS-1062 is comprised of a humanised anti-TROP2 monoclonal antibody attached to a topoisomerase I inhibitor payload by a tetrapeptide-based linker. DS-1062 is a potential new medicine that has not been approved for any indication in any country. Safety and efficacy have not been established.

Collaboration between AstraZeneca and Daiichi Sankyo in Oncology

In March 2019, AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise Enhertu (HER2-directed ADC) worldwide, except in Japan, where Daiichi Sankyo maintains exclusive rights.

AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With six new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

On July 26, 2020 TCR2 Therapeutics Inc. (Nasdaq: TCRR), a clinical-stage immunotherapy company with a pipeline of novel T cell therapies for patients suffering from cancer, reported positive interim data from the first five patients treated in the Phase 1 portion of the TC-210 Phase 1/2 clinical trial for mesothelin-expressing solid tumors (Press release, TCR2 Therapeutics, JUL 26, 2020, View Source [SID1234562396]). All five patients showed tumor regression including two RECIST unconfirmed partial responses (one of which remains subject to independent central review) and two patients with stable disease through six months. Translational data further demonstrated TRuC-T cell expansion and activation. A manageable toxicity profile was observed with only one patient exhibiting TC-210-related non-hematologic grade >2 toxicity and no evidence of neurotoxicity or on-target, off-tumor toxicity.

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"We are delighted that our very first dose of TC-210 induced consistent tumor regression and clinical benefit in heavily pre-treated cancer patients," said Garry Menzel, Ph.D., President and Chief Executive Officer of TCR2 Therapeutics. "There are very few options for patients with solid tumors and those expressing mesothelin represent a significant frontier of unmet medical need. While these are early data requiring further study, we are encouraged by the potential of our TRuC-T cells as we continue to enroll and treat patients with the goal of quickly finding a recommended Phase 2 dose for TC-210."

"Based on my prior experience working with both TCR-T and CAR-T cells, including the FDA approval of Kymriah, observing consistent clinical benefit in patients at presumably suboptimal T cell doses is quite meaningful," said Alfonso Quintás-Cardama, M.D., Chief Medical Officer of TCR2 Therapeutics. "These early TC-210 data suggest our approach may overcome the challenges faced by many T cell therapies in the hostile solid tumor microenvironment. Our enrolled patients have failed multiple lines of therapy, including standard chemotherapy, checkpoint inhibitors and in some cases other mesothelin-directed approaches, in indications where survival has been historically shorter than six months."

The primary objectives of the Phase 1 portion of the study are to define the safety profile of TC-210 in patients whose tumors overexpress mesothelin and to determine the recommended Phase 2 dose (RP2D). Secondary objectives include overall response rate (ORR) and disease control rate (DCR). Exploratory objectives include the assessment of expansion, tumor infiltration, and persistence of TC-210 T cells.

Summary of trial conduct, baseline characteristics and TC-210 dose:

Screening: Forty-eight percent of patients met the mesothelin expression cut-off as defined per protocol.

Manufacturing: TC-210 T cell products meeting protocol defined specifications have been manufactured successfully for each patient enrolled in the clinical trial.

Patient Characteristics: TC-210 treated patients included four with mesothelioma and one with ovarian cancer with a median age of 61 years (range, 36-74 years). The median number of prior therapies was five (range, 3-9), including immune checkpoint inhibitor therapy (n=3) and the anti-mesothelin ADC anetumab ravtansine (n=1).

TC-210 Dose: All patients received the same TC-210 dose either with or without lymphodepletion. One patient with mesothelioma was enrolled to dose level (DL) 0 (5×107 TC-210 T cells/m2 without lymphodepletion) whereas four patients (three with mesothelioma and one with ovarian cancer) were enrolled to DL1 (5×107 TC-210 T cells/m2 following lymphodepletion with fludarabine 30 mg/m2/day x4 and cyclophosphamide 600 mg/m2/day x3).

Key clinical findings from the first five patients treated with TRuC-T cells include:

Safety: TC-210 was generally well tolerated, with no patients experiencing neurotoxicity or on-target, off-tumor toxicities. Three (60%) patients experienced Cytokine Release Syndrome (CRS), which was Grade 1 in two patients and Grade 3 in one patient. The patient experiencing Grade 3 CRS also developed Grade 3 pneumonitis during the first week post infusion that responded to tocilizumab and steroid therapy. This patient died 34 days post treatment due to fungal sepsis, which was deemed unrelated to TC-210. Because of the earlier pneumonitis event, however, the Safety Review Team recommended the expansion of the cohort from three to six patients. None of the subsequent three patients treated at DL1 developed pneumonitis or CRS above Grade 1.

Clinical Activity: All five patients treated with TC-210 T cells have had at least one disease response assessment. The DCR was 100%, with all patients experiencing tumor regression. The median change in the sum of diameters of target lesions was -42% (range, -17% to -67%). The ORR was 40% (2 unconfirmed PRs) according to RECIST v1.1. TC-210 therapy induced a significant reduction in FDG uptake by PET imaging in two evaluable patients, including one patient who achieved a complete metabolic response (PR by RECIST v1.1).

Translational Data: Peak TC-210 expansion (Cmax) occurred between days 7 and 22. The median peak TC-210 expansion was 821 copies/µg of genomic DNA (range, 520 to 5,901 copies/µg). Cmax increased when TC-210 was administered following lymphodepletion. Cytokine induction post-TC-210 infusion was observed in all evaluable patients suggesting target engagement.

About the Phase 1/2 Clinical Trial in Advanced Mesothelin-Expressing Solid Tumors

The Phase 1/2 clinical trial (NCT03907852) is evaluating the safety and efficacy of TC-210, TCR2’s T-cell receptor fusion construct directed against mesothelin. The trial is enrolling patients with mesothelin expressing NSCLC, ovarian cancer, cholangiocarcinoma, and malignant pleural/peritoneal mesothelioma. The Phase 1 dose escalation portion of the clinical trial utilizes a modified 3+3 design with four increasing TC-210 T cell doses. At each dose, TC-210 will be tested in two separate dose levels: first without lymphodepletion and then following lymphodepleting chemotherapy. The Phase 1 portion of the clinical trial is ongoing.

In the Phase 2 portion of the clinical trial, approximately 50 patients are planned to receive TC-210 at the RP2D in four distinct cohorts according to their cancer diagnosis: NSCLC, ovarian cancer, malignant pleural/peritoneal mesothelioma and cholangiocarcinoma. Each cohort will include ten patients, except the NSCLC cohort which will include 20 patients with eight patients to receive TC-210 as single agent and 12 patients to receive TC-210 in combination with a programmed cell death 1 (PD-1) blocking antibody.

About Mesothelin-Expressing Solid Tumors

Mesothelin is a cell-surface glycoprotein highly expressed in a wide range of solid tumors, including malignant pleural/peritoneal mesothelioma, ovarian cancer, cholangiocarcinoma, breast cancer, pancreatic cancer and others. Overexpression of mesothelin is associated with poorer prognosis in some cancers due to its active role in both malignant transformation and tumor aggressiveness by promoting cancer cell proliferation, invasion, and metastasis. Of the wide range of solid tumors expressing mesothelin, non-small cell lung cancer, ovarian cancer, mesothelioma and cholangiocarcinoma represent a significant patient population up to 80,000 in the United States alone.

TCR2 Therapeutics Conference Call and Webcast

TCR2 Therapeutics will host a conference call and webcast on Monday, July 27th at 8:00am E.T. The webcast and presentation will be made available on the TCR2 Therapeutics website in the Investors section under Eventsat View Source Following the live audio webcast, a replay will be available on the Company’s website for approximately 30 days.

On July 24, 2020 Researchers at Children’s Hospital of Philadelphia (CHOP) reported that have developed a new computational algorithm that has, for the first time, identified a spectrum of mutations in the noncoding portion of the human genome across five major pediatric cancers (Press release, Children’s Hospital of Philadelphia, JUL 24, 2020, View Source [SID1234562375]). The study, which was published today in Science Advances, used the algorithm to analyze more than 500 pediatric cancer patients’ mutations and gene expression profiles to develop a comprehensive list of potentially cancer-causing mutations.

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"Noncoding mutations are very important because the noncoding portion of the genome typically regulates how genes are turned on and off, much like a control switch, which has implications for the uncontrolled growth that occurs in cancer," said Kai Tan, PhD, Professor of Pediatrics at CHOP and senior author of the study. "However, these regions are also challenging to study, and our knowledge about them not as developed as that of coding regions. Our computational model has identified a set of targets in pediatric cancers that we hope to study further and eventually move to clinical practice."

The researchers developed a computation tool called PANGEA (predictive analysis of noncoding genomic enhancer/promoter alterations) to analyze noncoding mutations and their impact on gene expression in more than 500 pediatric cancer patients who had five major types of pediatric cancer: B cell acute lymphoblastic leukemia (B-ALL), acute myeloid leukemia (AML), neuroblastoma, Wilms tumor, and osteosarcoma. PANGEA identified all types of mutations that are associated with gene expression changes, including single nucleotide variants, small indels, copy number variations, and structural variants.

Previous studies on noncoding mutations have focused on single nucleotide variants and small indels, which are insertions or deletions of bases in the genome that are relatively short in length. However, structural variants are regions of DNA much larger in size – 1 kilobase or larger – a quality that makes them more difficult to identify but also more likely to contribute to changes in gene regulation that lead to cancer.

Using PANGEA, the researchers found that structural variants are indeed the most frequent cause of potentially cancer-causing mutations and identified 1,137 structural variants that affect the expression of more than 2,000 genes across the five pediatric cancer types.

In analyzing the data, the researchers found that coding and noncoding mutations affect distinct sets of genes and pathways, which is likely due to the different genomic locations of these two types of genes. The researchers found that genes involved in metabolism – the rewiring of which is a hallmark of cancer – are more frequently affected by noncoding mutations. However, it is unclear to what degree noncoding mutations facilitate metabolism rewiring in the five cancer types the researchers studied.

"Our results highlight the need for comparative analysis of both coding and noncoding mutations, which might reveal novel cancer-related genes and pathways," said Tan. "Identifying putative mutations is a starting point that will facilitate experimental work to validates these predictions."

This work was supported by grants from the National Institutes of Health, including the National Cancer Institute and the National Institute of General Medical Sciences.

B. He et al. "Diverse noncoding mutations contribute to deregulation of cis-regulatory landscape in pediatric cancers," Science Advances, July 24, 2020. DOI: 10.1126/sciadv.aba3064