Moon Shot Research Articles

Mutational Characteristics and Clinical Outcomes for Lung Adenocarcinoma With EGFR Germline Mutations

IntroductionGermline mutations driving lung cancer have been infrequently reported in the literature, with EGFR T790M being a known germline mutation identified in 1% of NSCLCs. Typically, a somatic EGFR mutation is acquired to develop lung adenocarcinoma. Osimertinib has become a standard-of-care treatment for EGFR T790M-positive lung cancer. MethodsWe perform a retrospective analysis through the Lung Cancer Moon Shot GEMINI database at the University of Texas MD Anderson Cancer Center. Of the patients that underwent cell-free DNA analysis, germline mutations were identified by those with high variant allelic fraction approximating 50%, followed by further confirmation on genetic testing. ResultsWe identified 22 patients with germline EGFR mutations, with the majority harboring an EGFR T790M mutation (95.5%) and an EGFR L858R somatic mutation (50%). Notably, most patients were female (86.4%), non-smokers (81.8%), white (86.4%), had a family history of lung cancer (59.1%), and stage IV at diagnosis (72.7%). A distinct radiographic pattern of small multifocal ground-glass pulmonary nodules was observed in the majority of our cohort (72.7%).Among the 18 with advanced-stage NSCLC, 12 patients (66.7%) were treated with first-line osimertinib, demonstrating a median progression-free survival (PFS) of 16.9 months (95% confidence interval [CI]: 6.3–not reached [NR]). Others were treated with first-line afatinib (11.1%) or chemotherapy (22.2%). Among the 17 patients treated with osimertinib (in first or second-line), median PFS was 20.4 months (95% CI: 6.3–NR) and median overall survival was 82.0 months (95% CI: 28.4–NR). ConclusionsBased on our institutional cohort, NSCLC driven by EGFR germline mutations occurs more frequently in non-smoking, white females with multi-focal pulmonary nodules radiographically. Osimertinib for advanced germline EGFR-mutated NSCLC renders similar PFS compared to somatic T790M EGFR-mutated NSCLC.

Oncogenic GNAS drives a pyloric-type transcriptomic program in pancreatic intraepithelial papillary mucinous neoplasms

BACKGROUND & AIMS: Intraductal Papillary Mucinous Neoplasms (IPMNs) are cystic lesions of the pancreas which can serve as precursors for pancreatic ductal adenocarcinoma (PDAC). Recently, we showed that acinar to ductal metaplasia (ADM), an injury repair program associated with pancreatic tumorigenesis, is characterized by a pyloric-type transcriptomic program similar to gastric spasmolytic polypeptide expressing metaplasia (SPEM), suggesting common mechanisms of reprogramming between the stomach and pancreas. The aims of this study were to assay IPMN for SPEM markers and to identify molecular drivers of this program. METHODS: Published RNA-seq studies of IPMN were assessed for SPEM markers, which were validated by immunostaining in patient samples. Murine cell lines expressing KrasG12D +/- GNASR201C were manipulated to identify distinct and overlapping transcriptomic programs driven by each oncogene. A PyScenic-based regulon analysis was performed to identify drivers of SPEM in the pancreas. Expression of candidate drivers was evaluated in patient samples by RNA-seq and immunostaining and a role for SPDEF was investigated. RESULTS: SPEM markers were identified in human IPMN. GNASR201C drove expression of these markers in murine cell lines and siRNA targeting of GNASR201C or KrasG12D demonstrates that GNASR201C amplifies a mucinous phenotype. Regulon analysis identified a role for transcription factors SPDEF, CREB3L1, and CREB3L4, which are expressed in patient samples. CONCLUSIONS: De novo expression of a pyloric-type/SPEM phenotype has been identified in pancreatitis, oncogenic KrasG12D-driven pancreatic neoplasia, and in KrasG12D;GNASR201C-driven IPMN, suggesting common mechanisms of reprogramming between these lesions and the stomach. IPMN-specific GNASR201C drives a SPEM phenotype characterized by the formation of mucus producing cells at the expense of other lineages. AMR was supported by NIH T32GM139400. AM is supported by the MD Anderson Pancreatic Cancer Moon Shot Program, the Sheikh Khalifa Bin Zayed Al-Nahyan Foundation and NIH (U01CA200468, U54CA274371, U24CA274274, R01CA220236). M.C.B.T is supported by a Vanderbilt Digestive Disease Research Center Pilot and Feasibility Grant (P30 DK058404) and a Nikki Mitchell Foundation Pancreas Club Seed Grant. M.C.B.T and N.J. are supported by The Department of Defense (DOD W81XWH2211121-1). The DelGiorno laboratory is supported by the Vanderbilt Ingram Cancer Center Support Grant (NIH/NCI P30 CA068485), the Vanderbilt-Ingram Cancer Center SPORE in Gastrointestinal Cancer (NIH/NCI 5P50 CA236733), the Vanderbilt Digestive Disease Research Center (NIH/NIDDK P30 DK058404), an American Gastroenterological Association Research Scholar Award (AGA2021-13-02), NIH/NIGMS R35 GM142709, The Department of Defense (DOD W81XWH2211121), The Sky Foundation, Inc (AWD00000079), and Linda’s Hope (Nashville, TN). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Reduced dose azacitidine plus venetoclax as maintenance therapy in acute myeloid leukaemia following intensive or low-intensity induction: a single-centre, single-arm, phase 2 trial

Reduced dose azacitidine plus venetoclax as maintenance therapy in acute myeloid leukaemia following intensive or low-intensity induction: a single-centre, single-arm, phase 2 trial

Abstract 2418: Copy number variation status of DNA in extracellular vesicles as novel biomarkers of high-grade serous ovarian carcinoma

Abstract Objective: Ovarian cancer is a gynecologic malignancy with a dismal prognosis due to the lack of accurate methods for early diagnosis methods and effective therapies. High-grade serous ovarian carcinoma (HGSOC) is the most common subtype and copy number variations (CNVs) are the dominant genomic events in HGSOC. Extracellular vesicles (EVs) circulate in body fluids and carry pathological genomic information positively. In this study, we evaluated the significance of EV-DNA as novel biomarkers for HGSOC patients. Methods: A total of 124 samples from HGSOC patients and cell lines were analyzed. EVs were isolated using the ultracentrifuge method. Comprehensive CNV statuses were analyzed by whole genome sequencing (WGS) and SNP array. In reference to the Ovarian Cancer Moon Shot database, 30 dominant CNVs in HGSOC were selected as dominant targets for analysis by droplet digital PCR (ddPCR). For predicting the response to PARP inhibitors, HGSOC patients who were treated with olaparib were collected, and DNA was extracted from FFPE tissue at the time of surgery. Results: NTA assays and cryo-electron microscopic analyses showed that the EVs were successfully isolated from all samples. Both WGS and SNP arrays detected correlating CNVs in cell-DNA and EV-DNA for cell lines, and in tissue-DNA and EV-DNA in ascites for patients. The CNV status was also accurately measured by ddPCR. Copy numbers of RAD51, BRCA1, AKT2, CCNE1, and MSH6 were significantly higher in malignant tissue than in benign tissue (p<0.0001, p<0.0001, p=0.0012, p=0.002. p=0.0328, respectively), and were detectable in EV-DNA from ascites. Additionally, the amount of DNA in malignant ascites was significantly higher than in benign ascites (p=0.016), and increased DNA in ascites itself suggested the presence of malignancy. Furthermore, EV-DNA more accurately reflected the CNV status of tumor DNA than cell-free DNA in ascites. Regarding the prediction of PARP inhibitor response, the CNV status in EV-DNA from patients who were treated with olaparib, a PARP inhibitor, demonstrated a marked difference between responders and non-responders. The equation calculated based on the combination of six genes (RB1, GABRA6, CTNNB1, MYC, RAD51, BARD1) could predict the response to olaparib (AUC: 1.0). The selected genes were validated in vitro using EV-DNA, and responders could be identified using the prediction equation calculated from CNV status of the selected genes in EV-DNA from ascites. Conclusion: CNV status of EV-DNA was correctly evaluated and can serve as novel diagnostic and prognostic biomarkers for HGSOC. Citation Format: Ryosuke Uekusa, Akira Yokoi, Kosuke Yoshida, Juntaro Matsuazki, Yusuke Yamamoto, Hiroaki Kajiyama. Copy number variation status of DNA in extracellular vesicles as novel biomarkers of high-grade serous ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2418.

Oral decitabine and cedazuridine plus venetoclax for older or unfit patients with acute myeloid leukaemia: a phase 2 study

Hypomethylating agents combined with venetoclax are effective regimens in patients with acute myeloid leukaemia who are ineligible for intensive chemotherapy. Decitabine and cedazuridine (ASTX727) is an oral formulation of decitabine that achieves equivalent area-under-curve exposure to intravenous decitabine. We performed a single centre phase 2 study to evaluate the efficacy and safety of ASTX727 plus venetoclax. This study enrolled patients with newly diagnosed (frontline treatment group) acute myeloid leukaemia who were ineligible for intensive chemotherapy (aged ≥75 years, an Eastern Cooperative Oncology Group [ECOG] performance status of 2-3, or major comorbidities) or relapsed or refractory acute myeloid leukaemia. Being aged 18 years or older and having an ECOG performance status of 2 or less were requirements for the relapsed or refractory disease treatment cohort, without any limits in the number of previous lines of therapy. Treatment consisted of ASTX727 (cedazuridine 100 mg and decitabine 35 mg) orally for 5 days and venetoclax 400 mg orally for 21-28 days in 28-day cycles. The primary outcome was overall response rate of ASTX727 plus venetoclax. Living patients who have not completed cycle one were not evaluable for response. Safety was analysed in all patients who started treatment. This study was registered on ClinicalTrials.gov (NCT04746235) and is ongoing. The data cutoff date for this analysis was Sept 22, 2023. Between March 16, 2021, and Sept 18, 2023, 62 patients were enrolled (49 frontline and 13 relapsed or refractory) with a median age of 78 years (IQR 73-82). 36 (58%) were male; 53 (85%) were White, 4 (6%) Black, 2 (3%) Asian and 3 (5%) other or did not answer. 48 (77%) of 62 patients were European LeukemiaNet 2022 adverse risk, 24 (39%) had antecedent myelodysplastic syndromes, 12 (19%) had previously failed a hypomethylating agent, ten (16%) had therapy-related acute myeloid leukaemia, and 11 (18%) had TP53 mutations. The median follow-up time was 18·3 months (IQR 8·8-23·3). The overall response rate was 30 (64%) of 47 patients (95% CI 49-77) in frontline cohort and six (46%) of 13 patients (19-75) in relapsed or refractory cohort. The most common grade 3 or worse treatment-emergent adverse events were febrile neutropenia in 11 (18%) of 62 patients, pneumonia in eight (13%), respiratory failure in five (8%), bacteraemia in four (6%), and sepsis in four (6%). Three deaths occurred in patients in remission (one sepsis, one gastrointestinal haemorrhage, and one respiratory failure) and were potentially treatment related. ASTX727 plus venetoclax is an active fully oral regimen and safe in most older or unfit patients with acute myeloid leukaemia. Our findings should be confirmed in larger multicentric studies. MD Anderson Cancer Center Support Grant, Myelodysplastic Syndrome/Acute Myeloid Leukaemia Moon Shot, Leukemia SPORE, Taiho Oncology, and Astex Pharmaceuticals.

Oral decitabine plus cedazuridine and venetoclax in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: a single-centre, phase 1/2 study

Hypomethylating agents are approved in higher-riskmyelodysplastic syndromes. The combination of a hypomethylating agent with venetoclax is standard of care in acute myeloid leukaemia. We investigated the safety and activity of the first totally oral combination of decitabine plus cedazuridine and venetoclax in patients with higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia. We did a single-centre, dose-escalation and dose-expansion, phase 1/2, clinical trial. Patients with treatment-naive higher-risk-myelodysplastic syndromes or chronic myelomonocytic leukaemia (risk level categorised as intermediate-2 or higher by the International Prognostic Scoring System) with excess blasts (>5%). Treatment consisted of oral decitabine 35 mg plus cedazuridine 100 mg on days 1-5 and venetoclax (variable doses of 100-400 mg, day 1 to 14, 28-day cycle). The primary outcomes were safety for the phase 1 part and the overall response for the phase 2 part of the study. The trial is ongoing and this analysis was not prespecified. This study is registered with ClinicalTrials.gov, NCT04655755, and is currently enrolling participants. Between Jan 21, 2021, and Jan 20, 2023, we enrolled 39 patients (nine in phase 1 and 30 in phase 2). The median age was 71 years (range 27-94), 28 (72%) patients were male, and 11 (28%) were female. The maximum tolerated dose was not reached, and the recommended phase 2 dose was established as oral decitabine 35 mg plus cedazuridine 100 mg for 5 days and venetoclax (400 mg) for 14 days. The most common grade 3-4 adverse events were thrombocytopenia (33 [85%] of 39), neutropenia (29 [74%]), and febrile neutropenia (eight [21%]). Four non-treatment-related deaths occurred on the study drugs due to sepsis (n=2), lung infection (n=1), and undetermined cause (n=1). The median follow-up time was 10·8 months (IQR 5·6-16·4). The overall response rate was 95% (95% CI 83-99; 37/39). 19 (49%) patients proceeded to hematopoietic stem-cell transplantation. This early analysis suggests that the combination of oral decitabine plus cedazuridine with venetoclax for higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia is safe in most patients, with encouraging activity. Longer follow-up will be needed to confirm these data. MD Anderson Cancer Center, MDS/AML Moon Shot, Genentech/AbbVie, and Astex Pharmaceuticals.

Inner ear therapeutics and the war on hearing loss: systemic barriers to success.

Despite over 20 years of effort in academic research centers, start-up companies, and established pharmaceutical companies, there are no FDA-approved inner ear therapeutics for treatment of sensorineural hearing loss. There are a number of systemic barriers to creation of this new field of inner ear therapeutics. These include insufficient understanding of the particularity of different causes of hearing loss at the cellular and molecular level, lack of diagnostics of adequate sensitivity and specificity to discern these differences in vivo, a tendency for start-up biotech/pharma companies to prioritize competition over collaboration, and a drug development ecosystem that is really in the "pre-competitive" phase and a lack of infrastructure to develop, validate, gain regulatory approval, and successfully market an inner ear therapeutic. These issues will be discussed in this perspective article and a proposed remedy in the form of an inner ear therapeutics "moon shot" will be offered.

Advanced Non-compressible Torso Hemorrhage Management is Combat Casualty Care's Moon Shot.

Non-compressible torso hemorrhage continues to cause considerable preventable mortality on the battlefield. In this editorial, we highlight the burden of deaths, the most at-risk torso structures, current interventions, and their limitations and recommendations for future research and device development.

Predicting benefit from immune checkpoint inhibitors in patients with non-small-cell lung cancer by CT-based ensemble deep learning: a retrospective study

Only around 20-30% of patients with non-small-cell lung cancer (NCSLC) have durable benefit from immune-checkpoint inhibitors. Although tissue-based biomarkers (eg, PD-L1) are limited by suboptimal performance, tissue availability, and tumour heterogeneity, radiographic images might holistically capture the underlying cancer biology. We aimed to investigate the application of deep learning on chest CT scans to derive an imaging signature of response to immune checkpoint inhibitors and evaluate its added value in the clinical context. In this retrospective modelling study, 976 patients with metastatic, EGFR/ALK negative NSCLC treated with immune checkpoint inhibitors at MD Anderson and Stanford were enrolled from Jan 1, 2014, to Feb 29, 2020. We built and tested an ensemble deep learning model on pretreatment CTs (Deep-CT) to predict overall survival and progression-free survival after treatment with immune checkpoint inhibitors. We also evaluated the added predictive value of the Deep-CT model in the context of existing clinicopathological and radiological metrics. Our Deep-CT model demonstrated robust stratification of patient survival of the MD Anderson testing set, which was validated in the external Stanford set. The performance of the Deep-CT model remained significant on subgroup analyses stratified by PD-L1, histology, age, sex, and race. In univariate analysis, Deep-CT outperformed the conventional risk factors, including histology, smoking status, and PD-L1 expression, and remained an independent predictor after multivariate adjustment. Integrating the Deep-CT model with conventional risk factors demonstrated significantly improved prediction performance, with overall survival C-index increases from 0·70 (clinical model) to 0·75 (composite model) during testing. On the other hand, the deep learning risk scores correlated with some radiomics features, but radiomics alone could not reach the performance level of deep learning, indicating that the deep learning model effectively captured additional imaging patterns beyond known radiomics features. This proof-of-concept study shows that automated profiling of radiographic scans through deep learning can provide orthogonal information independent of existing clinicopathological biomarkers, bringing the goal of precision immunotherapy for patients with NSCLC closer. National Institutes of Health, Mark Foundation Damon Runyon Foundation Physician Scientist Award, MD Anderson Strategic Initiative Development Program, MD Anderson Lung Moon Shot Program, Andrea Mugnaini, and Edward L C Smith.

Development of COVID-19 Vaccines—An Unanticipated Moon Shot Achieved at Warp Speed

Alfredo J. Mena Lora, MD; Jessica E. Long, PhD, MPH; Yunda Huang, PhD; Lindsey R. Baden, MD; Hana M. El Sahly, MD; Dean Follmann, PhD; Paul Goepfert, MD; Glenda Gray, MBBCh; Beatriz Grinsztejn, MD; Karen Kotloff, MD; Nadine Rouphael, MD; Magdelena Sobieszczyk, MD, MPH; Stephen R. Walsh, MD; Jessica Andriesen, PhD; Karan A. Shah, MSc; Yuanyuan Zhang, PhD; Peter Gilbert, PhD; Holly Janes, PhD; Cynthia L. Gay, MD, MPH; Ann R. Falsey, MD; Rebecca L. Tripp, MPH; Richard L. Gorman, MD; Tina Tong, DrPH(c), MS; Mary Marovich, MD, DTMH; Kathleen Neuzil, MD, MPH; Lawrence Corey, MD; James G. Kublin, MD, MPH; COVID-19 Prevention Network; Daniel Reirden; Lilly Immergluck; Colleen Kelley; Anna Durbin; Milagritos Tapia; Megan Deming; Karen Kotloff; Jorge Pinto; Paul Goepfert; Zaheer Hoosain; Johan Lombaard; Kathryn Stephenson; Lindsey Baden; Stephen Walsh; Ken Mayer; Pedro Cahn; Marcelo Losso; Isabel Cassetti; Steven Innes; Linda-Gail Bekker; Sheetal Kassim; Catherine Orrel; Graeme Meintjes; Amy Ward; Andreas Diacon; David Wohl; Cindy Gray; Chrinstine Turley; Temitope Oyedele; Babafemi O. Taiwo; Karen Krueger; Rick Novak; Beverly E. Sha; Laura Hammit; Carl Fichtenbaum; David Bernstein; Jeffrey Jacobson; Dima Dandachi; Hasan Naqvi; Susan Koletar; Nadine Rouphael; Sri Edupuganti; Thomas Campbell; Elizabeth Secord; Samantha Siva; Nitesha Jeenarain; Logashvari Naidoo; Nigel Garrett; Nivashnee Naicker; Vimla Naicker; Jayganthie Naidoo; Anamikah Premrajh; Emmanuel Walter; Jeff Henderson; Hugo Tempelman; Abraham Siika; Evan Anderson; Brenda Okech; Richard Rupp; Hana El Sahly; Catherine M. Healy; Robert Arduino; Patricia Winokur; Martin Casapia; Gailen Marshall; Bhagyashri D. Navalkele; Sharla Badel-Faeson; Ian Sanne; Lee Fairlie; Adeodata Kekitiinwa; Patricia Ntege; Peter J. Elyanu; Cissy K. Mutuluuza; Sandra Rwambuya; Philippa Musoke; Deo Wabwire; Barbara Pahud; Mario Castro; Fredrick Sawe; Samuel G. Ouma; Taraz Samandari; Grace Mboya; Craig Innes; Philip Kotze; Javier Lama; Jorge Sanchez; Jorge Gallardo; Pedro Gonzales; Robinson Cabello; Raphael Landovitz; Michael P. Dube; Tamela Gould-Porter; Steve Shoptaw; Jesse Clark; Sheena Kotze; Olivia Kasselman; Katherine Gill; Maphoshane Nchabeleng; Aditya Gaur; Carlos Cabrera; Susanne Doblecki-Lewis; Susan Kline; Scott McClelland; Mandaliya Kishorchandra; Pamela Mda; Thozama Dubula; Walter Jaoko; Spyros Kalams; David Haas; Vladimir Berthaud; Clarence Creech; Sue Ellen Abdalian; Jessica Justman; Delafontaine; Kristen Marks; Sharon Mannheimer; Hong Van Tieu; Magda Sobieszczyk; Mark Mulligan; Vanessa Raabe; Mary Olson; Juanita Erb; Shobha Swaminathan; Jose Pilotto; Christopher Hall; Diana Florescu; Edwin de Jesus; Ian Frank; Katie Barr; Deborah McMahon; Sharon Riddler; Judith M. Martin; Elizabeth Barranco; Breno Santos; Karen Tashima; Beatriz Grinsztejn; Esau J. Filho; Mike Keefer; Ann Falsey; William Brumskine; Stuart Cohen; Jason Okulicz; Barbara Taylor; Thomas Patterson; Ryan Maves; Susan Little; Susan Buchbinder; Annie Luetkemeyer; Carmen Zorrilla; Esper Kallas; Vivian A. Silva; Tamara Newman; Jose Valdez Madruga; Julie McElrath; Lisa Jackson; Anna Wald; Mookho Malahleha; Fatima Laher; Erica Lazarus; Anusha Nana; Daniel Hoft; Sharon Frey; Rachel Presti; Sharon Nachman; Benjamin Luft; Carina Rodriguez; Kathy Mngadi; Eric Daar; Shaun Barnabas; Mark Cotton; Stephen Spector; Karen Servilla; Kathleen A. Linder; Abeer Moana; Carol Kauffman; Mary Bessesen; Rohit Talwani; Louis Dell'Italia; Augusto Alonto; Daniel Liebman; Roger Bedimo; Christopher Woods; Peruvemba Sriram; Kalpana Padala; Gregory Holt; Edwin Swialto; Melanie Jay; Sabrina Felson; Nora Henderson; Sheldon Brown; Saumuel Aguayo; Mark Riddle ; Phyllis Tien; John Toney; Halima Dawood; Disebo Makhaza; Hugh Mighty; Siham Mahgoub; Wes Campbell; David Diemert; Tiffany Schwasinger-Schmidt; Caryn G. Morse; John W. Sanders; John Williamson; Angelique Luabeya; Elizabeth Bukusi; Nelly Mugo; Hannah Kibuuka; Betty Mwesigwe; Andrew Kambugu; Apolo P. Balyegisawa; Kathleen Mullane; Ben Andagalu; Lucas Tina; Nathaniel Copeland; Jack Hutter; Claudio L. de las Casas; Guillermo Ruiz-Palacios; Joseph J. Eron; Judith S. Currier; Myron S. Cohen; Kami Kim; Richard N. Greenberg; Margaret Kasaro; Sinead Delaney-Moretlwe; Rodney Dawson; Carmen Paez; Nicole Grunenberg; William O. Hahn; Huub C. Gelderbloom; Michele P. Andrasik; Stephaun E. Wallace

Climate Change and COP26: 21st Century Moon Shot will Come Down to Science

Climate Change and COP26: 21^st Century Moon Shot will Come Down to Science

Emerging infections and the integrative environment-health sciences: the road ahead.

The integrative environment-health sciences including One Health, Conservation Medicine, EcoHealth and Planetary Health embody the transdisciplinary synthesis needed to understand the multitude of factors that underpin emerging infections and their management. Future successes in confronting and resolving the complex causal basis of disease emergence to generate robust, systems-oriented risk reduction strategies that preserve both human health as well as promoting sustainable futures represent the ‘Moon Shot’ for the integrative environment-health sciences.

Cancer Immunotherapy Pilot Program- extended to June 30, 2022 – Launch your patent application under the Cancer Moon Shot Program before it is too late!

Patent protection for cancer treatments is critical to safeguard the considerable time, effort and expenses involved in such endeavors. The United States Patent Office has a special program that enables cancer researchers to obtain patent protection for their inventions with unprecedented speed (less than one year!) and without any additional fees required. The Cancer Immunotherapy Pilot Program has been extended to June 30, 2022. This program has proven to be exceptionally useful in advancing the protection and commercialization of cancer treatments and should be employed by everyone in the cancer research field. Andre Gide once said, “One doesn't discover new lands without consenting to lose sight of the shore for a very long time.” The journey every single inventor makes through the patenting process is admittedly uncertain, with no assurances that it will result in an issued patent. But a terrific program implemented by the United States Patent and Trademark Office (USPTO) makes such a journey far shorter than it would otherwise be. The “Patents 4 Patients” program, also known as the “Cancer Moon Shot” program, was introduced in 2016 and has now been extended until June 30, 2022, now entitled “Cancer Immunotherapy Pilot Program.” This program permits patent applications pertaining to cancer immunotherapy to be advanced out of turn for examination and reviewed earlier (accorded special status). It provides for the extremely prompt examination of qualifying patent applications – without any additional fees – and has resulted in the issuance of over 400 patents in the last few years – which otherwise would not have issued for years to come.

The TVs of Tomorrow: How RCA's Flat-screen Dreams Led to the First LCDs by Benjamin Gross

Reviewed by: The TVs of Tomorrow: How RCA's Flat-screen Dreams Led to the First LCDs by Benjamin Gross Michael Aaron Dennis (bio) The TVs of Tomorrow: How RCA's Flat-screen Dreams Led to the First LCDs By Benjamin Gross. Chicago: University of Chicago Press, 2019. Pp. 288. We live surrounded by LCD (liquid crystal display) screens; Ben Gross's volume explains the origins of this technology at RCA and how the iconic American firm failed to deliver it to the world. This fascinating story of industrial research, corporate politics, and technological change blends science, technology, and business histories. Gross locates the emergence, efflorescence, and decline of LCD screens at the intersection of three distinct axes—the material logic of LCDs, that is their physical chemistry and often recalcitrant behavior plus the infrastructure for their creation and use; RCA's strategic goals as well as the Sarnoff Laboratory's role in fulfilling them; and the interactions among researchers, their managers, and other RCA divisions. One of the many interesting things readers learn is that the technology dominating our lives received so little support from RCA management. Indeed, they ultimately seemed to value LCD patents more than developing televisions based on this novel display technology. Noteworthy are Gross's discussions about the problem of finding the sources needed to write the history of late twentieth-century corporate R&D. RCA's quest for a follow-up to its color television came in 1951, with legendary founder David Sarnoff's challenge to develop a light amplifier. Efforts ensued to find alternatives to the standard display technology, the CRT (cathode ray tube). RCA pioneered the mass production of these glass bubbles, and it proved hard to break from this anchoring technology. Only after it became clear that CRTs could not be flattened in order to hang from walls and display a quality picture did researchers and management explore and develop alternatives. By 1964, the company's research included liquid crystals and their chemistry; however, as Gross points out, it was never really a large research group. Compared to the well-studied RCA video disc, called a "Manhattan Project," RCA's work on LCDs was a modest effort. Although [End Page 1240] public relations people hyped the research and its potential, this was never a corporate moon shot. Gross rightly highlights the problems in manufacturing the new technology once researchers overcame problems at the bench. Using laboratory notebooks, he delineates how researchers solved the issue of LCDs working at room temperature. Building bridges with RCA's manufacturing divisions became as vital as laboratory research to keep LCD work alive, while management paid more attention to a struggling computer effort and the firm's traditional color television business. Even once the multiple manufacturing problems were solved, the LCDs produced by RCA were for watch displays, not the wall-hanging televisions of the future. The initial secrecy surrounding LCD research demonstrated how highly it was valued, yet RCA soon viewed patents as the real source of value compared to physical products, given the costs and difficulties of profitably manufacturing LCDs in America. Gross's interviews and archival work display the full range of skills required to move lab products to the factory, including individuals with the requisite social skills to borrow resources from other groups. This social aspect of intra-laboratory relations is especially well portrayed. Gross plays with Clayton Christensen's ideas of disruptive innovation in explaining why RCA failed to capitalize on its role as a pioneer in LCD research. He follows LCD researchers at RCA to a new start-up, Optel that fails to take advantage of new LCD chemistry, instead sticking to RCA-based technologies. Small size did not prevent an aversion to change. In his final eloquent chapter, Gross explains that it was only once LCD technology had left RCA that it really grew and developed—as multiple firms, first on the West Coast and then in Japan, invested in significant R&D with specific products in mind. Seiko developed a watch-sized LCD television more advanced than Dick Tracy's, while Sharp demonstrated a fourteen-inch color display in 1988. Ironically, Sharp had approached RCA in 1970 about...

1678PD - Immune classification of soft tissue sarcoma predicts clinical outcome

BackgroundSoft tissue sarcomas (STS) form a group of rare cancers which accounts for around 1% of tumours. Although up to 15% of patients respond in immunotherapy trials, there are no biomarkers predicting response of STS to checkpoint blockade therapies yet. MethodsWe analysed transcriptomic data of 4 publicly available cohorts, accounting for more than 600 STS. We used MCP-counter, a deconvolution method to estimate the tumour microenvironment (TME) composition Based on MCP-counter estimates, we established a robust immune classificationof STS tumors into 5 Sarcoma Immune Classes, labelled A, B, C, D and E. These classes exhibited different type and extents of TME. We validated the profiles of these 5 groups on a 72-patients cohort using immunohistochemichal (IHC) stainings for CD3, CD8, CD20 and CD34. ResultsOne group (A: 23.3% of tumours) exhibits a very low to low immune infiltrate for all TME cell types. Another class (C: 14.5% of all tumours) displays moderate immune infiltrate and a strong presence of endothelial cells. Finally, another group (E: 15.6%) is highly infiltrated by all immune cell types. The two remaining groups (B: 27.4% and D: 19.4%) are heterogeneous, respectively rather highly and lowly infiltrated. The immune high group E is associated with an overexpression of several immune checkpoint genes: PDCD1 (PD-1), CD274 (PD-L1), PDCD1LG2 (PD-L2), LAG3, HAVCR2 (TIM-3), CTLA4. On 72 patients, we showed that the immune-high group could be identified by the IHC-visible presence of tertiary lymphoid structures (TLS), defined as T cell aggregates juxtaposing B cell aggregates. The immune-high group also exhibited prolonged overall survival as compared with other groups. Using data from a phase II clinical trial with pembrolizumab, we show that responders can be identified as class E tumours, therefore allowing patient selection. ConclusionsWe have defined a novel immune-based classification of STS into 5 classes, among which an immune-high group characterized by a strong infiltration by all immune cell and expression of immune checkpoints, presence of TLS and longer overall survival. This class groups responders to PD-1 blockade in a phase II clinical trial. Legal entity responsible for the studyINSERM. FundingInstitut National de la Santé et de la Recherche Médicale, the University of Paris, Sorbonne University, the Programme Cartes d’Identité des Tumeurs (CIT) from the Ligue Nationale Contre le Cancer, Institut National du Cancer (HTE-INSERM plan cancer, C16082DS), Association pour la Recherche sur le Cancer (ARC), Cancer Research for Personalized Medecine programme, “FONCER contre le cancer” programme, Labex Immuno-Oncology, the National Institute of Health, Moon Shot program at MD Anderson Cancer Center, Ministry of Education and Ministry of Science and Technology of Taiwan, National Taiwan University, Merck, Inc, SARC, Sarcoma Foundation of America, and the QuadW Foundation. DisclosureT.W. Chen: Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy: Lilly. M.A. Burgess: Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Immune Design; Advisory / Consultancy: Eisai. J. Wargo: Advisory / Consultancy: Merck; Advisory / Consultancy: BMS; Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Genentech; Advisory / Consultancy: Illumina. H.A. Tawbi: Advisory / Consultancy, Research grant / Funding (self): BMS; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy, Research grant / Funding (self): Genentech; Research grant / Funding (self): Celgene; Research grant / Funding (self): GSK. W.H. Fridman: Advisory / Consultancy: MedImmune; Advisory / Consultancy: Novartis; Advisory / Consultancy: Servier; Advisory / Consultancy: Pierre Fabre. All other authors have declared no conflicts of interest.

Health Care Costs of Anal Cancer in a Commercially Insured Population in the United States.

The incidence and death rate of anal cancer in the United States has been increasing on average 2%-3% per year over the past 10 years. Human papillomavirus (HPV) vaccination is a potentially viable prevention strategy, since about 80% of anal cancers are attributable to HPV. To understand the effect of HPV vaccination, it is important to estimate the treatment costs for the HPV-related disease. To estimate the 2-year per patient mean direct health care costs associated with anal cancer in a commercially insured population in the United States. All newly diagnosed anal cancer patients were identified from a 2011-2014 Truven MarketScan database. Matched population controls were selected from the database with a 2-step matching method using demographic, comorbidity, and health care cost variables. Costs for the first 2 years were measured for cancer patients and controls. The difference in costs between the groups was calculated to estimate the costs associated with anal cancer treatment. A generalized linear model with gamma distribution and log link function was applied to estimate the costs for censored months for the patients who did not have at least 2 years of follow-up. 1,976 patients with anal cancer and 1,976 controls were included in the study. The first 2-year per patient adjusted mean cost associated with anal cancer treatment was $127,531 (SD = $189,064). Male sex, cancer diagnosis, higher Charlson Comorbidity Index score, and higher prediagnosis costs were significantly associated with higher monthly costs. Higher psychiatric diagnostic group scores were associated with lower monthly costs. Anal cancer treatment costs were highest in the first 6 months after diagnosis (per patient per month [PPPM] mean = $12,846), leveling off at a much lower monthly cost during the subsequent 18 months of the 2-year period (PPPM mean = $3,717). The first 2-year costs associated with anal cancer treatment were substantial. Given that approximately 80% of anal cancers are attributable to HPV infection, this study provides important parameters for estimating the potential economic benefit of HPV vaccination. This research was accomplished within the Oropharynx Program at The University of Texas MD Anderson Cancer Center and was funded in part through the Stiefel Oropharyngeal Research Fund. The authors report funding contributions from the Christopher and Susan Damico Chair in Viral Associated Malignancies (The University of Texas MD Anderson). This work was supported by generous philanthropic contributions, including a contribution from the Lyda Hill Foundation, to The University of Texas MD Anderson HPV-Related Cancers Moon Shot Program. The authors have nothing to disclose.

1928P - Pathologic assessment following neoadjuvant immunotherapy or chemotherapy demonstrates similar patterns in non-small cell lung cancer (NSCLC)

Background: Neoadjuvant chemotherapy (CT) and immunotherapy (IT) are associated with features of pathologic treatment response (PTR) in NSCLC. Comparison of such features in NSCLC following neoadjuvant CT, IT or upfront surgical resection is lacking. Nivolumab (N) and/or N plus ipilumumab (NI) are being investigated in resectable NSCLC (NCT03158129). We analyzed the histopathologic patterns of CT- and IT-treated NSCLC vs untreated surgically resected tumors. Methods: Histopathologic assessment of untreated, CT- and IT-treated NSCLC was performed (n = 30, 10/group). Hematoxylin and eosin-stained tumor sections were scored for parameters of PTR: percentage of viable tumor, fibrosis, and necrosis; inflammation, tertiary lymphoid structures (TLS), macrophages, lymphovascular invasion (LVI), cholesterol clefts (CC), giant cells (GC) and neovascularization (NV) were reported as a score (0-3). Values for each variable were expressed as a mean (± SD). Statistical comparison between two groups was calculated with unpaired two-sided t-test. Significance was defined as p-value <0.05. Results: CT and IT were associated with significantly less viable tumor cells (p = 0.04 and p = 0.02, respectively), IT with more fibrosis (p = 0.04) and CT with more CC (p = 0.03) than untreated tumors. Trends towards higher amounts of inflammation, macrophages and CC were seen in IT-treated compared to untreated tumors. CT had a trend towards more fibrosis and GC compared with untreated NSCLC (Table).Table: 1928PSummary of PTR parametersUntreatedCT-treatedIT-treatedViable tumor67.7%42.4%*p-value <0.0537.5%*p-value <0.05Fibrosis26.6%46.6%52.3%*p-value <0.05Necrosis5.6%11.0%10.1%Inflammation1.461.541.87TLS0.801.001.00LVI0.230.160.33Macrophages0.120.941.17CC0.130.92*p-value <0.051.04GC0.400.800.70NV000* p-value <0.05 Open table in a new tab Conclusions: Neoadjuvant CT and IT are associated with similar histopathological changes compared to untreated tumors but with lower proportions of viable tumor and higher degrees of fibrosis. Neoadjuvant treatment is also associated with a trend towards higher amounts of inflammation, macrophages, CC and GC. Analysis of a larger cohort, including comparison of N- vs NI-treated tumors (estimated n = 80) is ongoing and will be presented in due course. Clinical trial identification: NCT03158129. Legal entity responsible for the study: University of Texas MD Anderson Cancer Center. Funding: The University of Texas MD Anderson Lung Cancer Moon Shot Program, Bristol-Myers Squibb. Disclosure: B. Glisson: Research funding to institution: Medimmune, Pfizer, ISA Pharmaceuticals, Abbvie. G. Blumenschein: Consulting/advisory role: Bristol-Myers Squibb, Bayer, Clovis, Merck, Celgene, AbbVie, ARIAD; Research funding: Bristol-Myers Squibb, Novartis, Xcovery, AstraZeneca, Adaptimmune, Immatics, Macrogenetics, Bayer, Merck, Celegene, Genentech, GlaxoSmithKline, Kite Pharma; Travel, accomodations, expenses: BMS, AbbVie, Merck. J.V. Heymach: Advisory board: Bristol-Myers Squibb; Research/Grant: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

P3.03-28 LKB1 Mutation Status is Associated with Poor Radiation Outcome in Patients with Non-Small Cell Lung Cancer

Previously, we reported that the upregulation of the NRF2/KEAP1 pathway in non-small cell lung cancers (NSCLC) bearing co-mutations in KRAS and LKB1 is critical to maintain redox homeostasis which contribute to radiation resistance in these tumors. Here, we explore the role of the LKB1 mutation as a potential predictor radiation outcome in NSCLC. We retrospectively analyzed the patients undergoing definitive treatment for newly diagnosed NSCLC who were enrolled in the prospectively collected MD Anderson Lung Cancer Moon Shot GEMINI database according to LKB1 mutation status. Cox regression analysis and log-rank tests were used to correlate with radiation outcomes according to LKB1 mutation status and/or KRAS mutation subgroup. We then investigated the mechanisms of radiation resistance in these tumors in preclinical models. Of the 173 patients with stage III NSCLC treated with definitive radiotherapy, with or without chemotherapy were analyzed according to LKB1 mutation status demonstrated that LKB1 mutation had statistically significantly higher rate of loco-regional recurrence, and shorter disease-free survival than in patients with wild type LKB1 (P = 0.013 and P = 0.037, respectively). Moreover, additional loss of either LKB1 or TP53 in KRAS-mutant tumors renders these tumors higher loco-regional recurrence after radiation (P interaction = 0.045). We identified that LKB1 loss is associated with radio-resistance in part by KEAP1/NRF2 pathway activation. Re-expression of LKB1 or NRF2 pathway suppression (via KEAP1 expression) enhanced radiotherapy sensitivity in vivo. Our results suggest that LKB1 mutation is a potential predictive impact on radiation outcome of patients with NSCLC. The upregulation of the KEAP1/NRF2 pathway in NSCLC bearing co-mutations in KRAS and LKB1 is critical to maintain redox homeostasis and determine the sensitivity for radiation.

Window-of-Opportunity Clinical Trial of Pembrolizumab in Recurrent Glioblastoma (GBM) Patients

Background: We sought to ascertain the immune effector function of pembrolizumab within the glioblastoma (GBM) microenvironment during the therapeutic window. Methods: In an open-label, single-center, single-arm phase 2 window-of-opportunity trial, 15 patients with recurrent GBM, who were eligible for operation, were enrolled. Patients were treated with up to two doses of pembrolizumab (21 days and 1 day) before surgery and afterwards (every three weeks) until disease progression occurred or unacceptable toxicities developed. Findings: The most common adverse event was grade 1 or 2 fatigue in 40% of patients, and there was one case of cerebral edema requiring early reoperation. No treatment-related deaths occurred; 5 of 15 patients (33%) died from disease progression. The median follow-up time for all patients was 15 months (95% CI: 3-37). Of the 14 patients with radiographic follow up, 10 patients had progressive disease, 3 had a partial response, and 1 had stable disease. The longest response duration exceeded 37 months in two patients (one IDH1 mutant, one wild-type). The median progression-free survival (PFS) time was 5 months (95% CI: 3 months-8 months) and 6-month PFS (PFS6) rate was 40% (95% CI: 22%-74%). The median overall survival (OS) rate was 21 months (95% CI: 9 months to not reached), with an estimated 1-year OS rate of 65% (95% CI: 44%-95%). Immune monitoring on surgical specimens from GBM patients revealed a paucity of T cells but an enrichment of CD68 macrophages in the tumor microenvironment ofrecurrent GBM patients. The T cells in the GBM microenvironment were severly deficient in markers of immune activity. Interpretation: Although pembrolizumab was well tolerated, the immune analysis indicated that anti-PD-1 monotherapy is insufficient to induce effector immunologic response in most GBM patients, probably owing to a marked scarcity of T cells within the tumor microenvironment and a preponderance of CD68 macrophages. Clinical Trial Number: NCT02337686 Funding Statement: Merck Pharmaceuticals and The University of Texas MD Anderson Moon Shot Program Declaration of Interests: JdG and ABH have received clinical trial research support from Merck. JA owns stock in and has acted as a consultant or on advisory boards for Jounce, Kite Pharma, Evelo, Constellation, BristolMyers Squibb, GlaxoSmithKline, AstraZeneca, Amgen, and Neon. PSh owns stock in and has acted as a consultant for Jounce, Kite Pharma, Neon, Bristol-Myers Squibb, GlaskoSmithKline, AstraZeneca, Amgen, Constellation, and Evelo. ABH owns stock in Celldex Therapeutics and Caris Life Sciences, serves on the advisory board of Caris, and has acted as a consultant for BristolMyers Squibb, Celegene, Curtana Therapeutics, and Carthera Therapeutics. The remaining authors declare no competing interests. Ethics Approval Statement: Approval for the study was granted through the institutional review board at MD Anderson and all patients were provided written informed consent before study entry. This trial was performed according to the Declaration of Helsinki’s principles.

Abstract 2956: Mechanisms of resistance for osimertinib for patients with EGFR-mutant lung cancer: MD Anderson Cancer Center single institution experience with osimertinib resistance

Abstract PURPOSE: Osimertinib was initially approved for treating epidermal growth factor receptor (EGFR) T790M positive non-small cell lung cancer (NSCLC), and recently is moving forward as the first-line treatment for EGFR sensitizing mutation positive NSCLC. However, the types and frequencies of resistance mechanisms to osimertinib have been incompletely described, and currently there are no guidelines for managing these patients. We evaluated clinical and genetic characteristics of patients who received osimertinib for EGFR-mutant NSCLC. We also provide treatment experience after progression on osimertinib. PATIENTS AND METHODS: Using the MD Anderson Lung Cancer Moon Shot GEMINI database, we identified patients treated with osimertinib and performed clinical outcome analysis. Molecular profiling analysis was performed at the time of progression when available. RESULTS: Eighty two patients were identified. Median PFS on osimertinib was 8.8 months (95% CI, 6.7 to 10.9). Fifty three of the 82 patients had disease progression on osimertinib. Among them, 30 had molecular profiling upon progression. Other than two cases with germline T790M, 11 cases preserved and 17 cases lost T790M mutation. In T790M preserved cases, tertiary mutations of C797S (5 cases) and L792H (2 cases) in EGFR gene, as well as MET amplification (4 cases), were the most common mechanisms of resistance. In T790M lost cases, 12 cases were without known resistance mechanisms. Upon progression, osimertinib was continued in 34 of 51 patients and 17 (50%) of them received local consolidation radiation. The osimertinib continued patients had longer PFS2 compared to the patients who discontinued on osimertinib upon first progression. CONCLUSION: T790M loss is common (61%) in osimertinib resistance cases. In T790M-preserved cases, tertiary mutation within EGFR was the most common mechanism of resistance. MET amplification was observed in both T790M preserved and loss cases. In T790M loss cases, the mechanisms of resistance were mostly EGFR independent, highlighting the importance of understanding T790M-negative resistance mechanisms in the osimertinib era. Citation Format: Xiuning Le, Marcelo Vailati Negrao, Monique Nilsson, Jacqulyne Robichaux, Emily Roarty, Waree Rinsurongkawong, Bonnie Glisson, Jianjun Zhang, John V. Heymach. Mechanisms of resistance for osimertinib for patients with EGFR-mutant lung cancer: MD Anderson Cancer Center single institution experience with osimertinib resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2956.