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US Fed News Service, Including US State News, 2021

INTERNATIONAL PATENT: BOSTONGENE CORPORATION , ZAITSEV, ALEXANDER , CHELUSHKIN, MAKSIM , NUZHDINA, EKATERINA , ZYRIN, VLADIMIR , DYIKANOV, DANIIAR , BAGAEV, ALEXANDER , ATAULLAKHANOV, RAVSHAN , CHEREMUSHKIN, ILYA , SHPAK, BORIS , OOO BOSTONDZHIN FILES APPLICATION FOR "SYSTEMS AND METHODS FOR DECONVOLUTION OF EXPRESSION DATA"

BackgroundWhile PD-1 inhibitors are promising therapies for HNSCC, better methods are needed to predict response. We used integrated immunoprofiling of peripheral blood mononuclear cells (PBMCs) and RNA-seq of tumor tissue to identify novel predictors of anti-PD-1 response in HNSCC.MethodsImmunoprofiling using multiparameter flow cytometry was applied to PBMCs collected from a large internal cohort of cancer patients and healthy donors (n=850). Unsupervised clustering of normalized cell population frequencies from batched flow cytometry data utilizing a common backbone and variable functional staining panels was used to classify patients into five different immunotypes. We then analytically validated populations by cellular deconvolution of matched RNA-seq data with KassandraTM from the same specimens.2 PBMCs from previously untreated stage II-IV HNSCC patients (n=36) were analyzed at baseline and on-treatment with the anti-PD-1 inhibitor nivolumab ± an IDO inhibitor as a validation cohort. RNA-seq was retrospectively performed on tumors at baseline and on-treatment, along with transcriptome-based tumor microenvironment (TME) subtyping1 and cellular deconvolution with KassandraTM.2 All disease sites were assigned a pathologic Treatment Response (pTR)3 and analysis was completed based on primary site response alone and overall response (OR) based on all disease sites.ResultsBlood immunoprofiling of the internal cohort revealed five conserved immunotypes enriched in certain cell types (G1-naive T and B cells; G2-central memory CD4+ T cells; G3-transitional memory CD8+ T cells; G4-effector memory CD8+ T cells; G5-monocytes/granulocytes; figure 1), with immunotypes clustering to different disease states in these patients. We then stratified the 36 HNSCC patients treated with nivolumab into the same G1-G5 immunotypes as a validation cohort. At baseline, the G2 group had higher OR rates than other groups (p=0.02; figure 2). Baseline primary tumors showed OR correlated with PD-L1 and PD-L2 expression, interferon responsive genes, T-cell trafficking, and MHC class I pathway (higher values in Responders versus Non-responders, p<0.05; figure 3). Cell deconvolution showed greater CD8+ T cells in the TME correlated with primary site response (p<0.01). All 12 patients with immune-desert TMEs showed no primary site response (p=0.003); 4/5 patients with an immune-enriched TME showed a primary site response (p=0.002; figure 4). Primary tumors with fibrotic TMEs showed no response. However, in patients with a fibrotic TME and a positive OR, indicated by a significant pTR, the G2 immunotype was identified (figure 5).ConclusionsOur results suggest that this integrated approach shows potential for the development of more accurate prediction of response to ICI therapies for HNSCC.ReferencesBagaev A, Kotlov N, Nomie K, et al. Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. Cancer Cell. 2021;39(6):845–865.e7. doi:10.1016/j.ccell.2021.04.014Zaitsev A, Chelushkin M, Dyikanov D, et al. Precise reconstruction of the TME using bulk RNA-seq and a machine learning algorithm trained on artificial transcriptomes. Cancer Cell. 2022;40(8):879–894.e16. doi:10.1016/j.ccell.2022.07.006Luginbuhl AJ, Johnson JM, Harshyne LA, et al. Tadalafil enhances immune signatures in response to neoadjuvant nivolumab in resectable head and neck squamous cell carcinoma. Clin Cancer Res. 2022;28(5):915–927. doi:10.1158/1078-0432.CCR-21-1816Ethics ApprovalThe cohort from Thomas Jefferson University was collected under ClinicalTrials.gov identifier NCT03854032.Abstract 222-K Figure 1Classification of immune cells of the blood into five immunotypesAbstract 222-K Figure 2Immunotype analysis of the HNSCC cohort (n = 36) and treatment response (R) and non-response (NR) to nivolumab; Fisher’s exact test was used for statistical comparisonAbstract 222-K Figure 3Tumor expression-based biomarkers of response (R) and non-response (NR) to nivolumab. *p < 0.05; **p < 0.01; ***p < 0.001Abstract 222-K Figure 4Transcriptome-based classification of primary tumor samples of responders (R) and non-responders (NR) from the HNSCC cohort (n = 36) into four TME subtypes (Fibrotic; Immune Desert; Immune-Enriched, Fibrotic; Immune-Enriched, Non-fibrotic)Abstract 222-K Figure 5Association of TME subtypes (Fibrotic; Immune Desert; Immune-Enriched, Fibrotic; Immune-Enriched, Non-fibrotic) at baseline with primary and overall response to nivolumab. R - Response; NR - Non-response

Journal for immunotherapy of cancer, 2023-11, Vol.11 (Suppl 2), p.A1779-A1781

222-K Integrated immunoprofiling and RNA sequencing (RNA-seq) for anti-PD-1 response prediction in head and neck squamous cell carcinomas (HNSCC)

Aanur Praveen, 1530 Abassi Yama, 442-G Abbadessa Giovanni, 782-I Abelin Jennifer, 1040-B Abera Abenezer, 442-N Abrouk Nacer, 1523 Achar Sooraj, 1317-A Ackerman Shelley, 1147-D Adenis Antoine, 1519, 1521 Aftabizadeh Maryam, 1525 Aguado Jacqueline, 1403-A Aguilar Brenda, 1520, 1525 Aguirre Fernando, 222-G Ahn Kyung Jin, 222-J Aizawa Yasunori, 1228-A Al Hallak Mohammed, 782-E Alanio Cecile, 579-C Alanko Tuomo, 1518 Alekseeva Evgeniia, 222-K Alistar Angela, 782-E Alizadeh Darya, 1520 Alli Shanta, 1516 Allu Bhargavi, 1147-B Alnemri Angela, 629-B Alonso Michael, 1147-D Altan-Bonnet Grégoire, 1317-A Alvarado Dulce, 1535 Alvarsson Alexandra, 1509-H Alves Costa Silva Carolina, 1510 Alves Quixabeira Dafne, 1518 Alwosaibai Kholoud, 1509-D Amaravadi Ravi, 579-C Amoozgar Zohreh, 897-F An Daniel, 579-D An Wenfeng, 1509-C Anderson Warren, 442-C, 442-D Andersson Anne-Marie, 1147-F Andersson Patrik, 897-F Antonia Scott, 629-D Antonucci Laura, 1526 Argiris Athanassios, 629-B Argulian Anna, 1537 Ariss Majd, 1513 Arrowood Christy, 629-D Asare Ebenezer, 629-E Ascierto Paolo, 782-H, 1541 Audigier-valette Clarisse, 782-C Avila Omar, 1403-A Baakili Adyb, 782-I Babu Vasandan Anoop, 1516 Backus Carey, 1403-A Badie Behnam, 1520, 1525 Bagaev Alexander, 222-K Bagashev Asen, 1514 Bagger Frederik, 1147-F Bahleda Rastilav, 1519 Bai Shoumei, 1536 Bak Rasmus, 442-E Bak Yeeun, 442-L Baker Alexander, 897-C Ball Michael, 1514 Balon Tyler, 1403-A Bandyopadhyay Som, 222-H Banerjee Monali, 782-D Banovich Nicholas, 1520 Banta Karl, 579-B Bao Li, 1528 Bar-Ad Voichita, 629-B Baras Alexander, 1511 Barberis Massimo, 1541 Baretti Marina, 897-B Barish Michael, 1520, 1525 Barlesi Fabrice, 782-C Barlow Clare, 1533 Barré Patricia, 782-C Barry Walter, 442-N Bartkowski Wojciech, 1535 Basu Sourav, 782-D Bauman Julie, 1530 Baumert Thomas, 897-H Baumgartner Christina, 1403-A Baxter Amy, 222-J Baylin Stephen, 1516 Beasley Georgia, 629-D Beasley Mary, 1524 Beauregard Clay, 1403-A Beg Amer, 629-D Behren Andreas, 442-P Bellera Carine, 1519 Ben-Ahmed Tarek, 1510 BenDavid Ethan, 442-I Benovich Nicholas, 1525 Benzekry Sebastien, 782-C Berglund Anders, 1509-B Bermejo Amaia, 1147-F Bernard Quentin, 1515 Bernard Vincent, 629-A Bernstein Bradley, 1040-D Berrios Nolasco David, 1040-B Berzofsky Jay, 1147-I Bessede Alban, 782-G, 1519, 1521 Beyaz Semir, 1428-A Bhagat Milan, 222-E Bhatia Sanil, 1403-C Bhatia Shailender, 1534 Bhutkar Arjun, 1517 Birebent Roxanne, 1510 Birger Anastasya, 442-C Bjerg Tobias, 442-E Blampey Quentin, 1510 Blanchard Marie, 1520, 1525 Blum Sperisen Stephanie, 1147-C Bodner William, 1522 Boghossian Andrew, 1403-A Boissel Laurent, 442-Q Bona Amanda, 1514 Borger Darrell, 222-H Borkhardt Arndt, 1403-C Bory Pierre, 782-C Boulate David, 1510 Bowler Jeffrey, 1040-G Boyer Arnaud, 782-C Brahmer Julie, 629-C Braun Monika, 1515 Breckheimer Beatrice, 442-C Brinkman Adam, 1040-A Briscadieu Martin, 1515 Brocks David, 579-C Brockstedt Dirk, 629-C Brown Christine, 1520, 1525 Brown Michelle, 1530 Brown Powel H., 1526 Buckanovich Ronald, 1536 Buetz Christen, 1147-A Buggert Marcus, 579-C Bulic Marinka, 1403-A Buonaguro Luigi, 1541 Burbano Erica, 1523 Burcham Austin, 1147-B Burris III Howard, 1530 Byrne-Steele Miranda, 1040-H Cai Zhen, 1528 Call Justin, 1532 Calleja Veronique, 222-G Campbell Ryan, 442-N Cantarel Coralie, 1519 Cantwell Mark, 629-D Capitini Christian, 1040-F Capodagli Glenn, 1147-A Capone Mariaelena, 1541 Carbajal Kevin, 442-D, 442-C Carnevale Christina, 1147-A Caron Olivier, 1510 Carr Steven, 1040-B Carrasco Hope Helen, 1147-C, 1540 Carrera Diane, 1147-D Carson Shala, 1516 Carvajal Richard, 1534 Cascio Sandra, 1536 Cassier Philippe, 1519, 1521 Castro Sarah, 1517 Catozzi Carlotta, 1541 Cervera-Carrascon Victor, 1518 Chaddha Udit, 1524 Chakraborty Debjani, 782-D Chan Kok Fei, 442-P Chan Vivien, 442-F Chang Wen-Chung, 442-F Chapin Steven, 1147-D Chappaz Stephane, 1538 Chaudagar Kiranj, 1537 Chaudhry Ammar, 1520 Chauhan Vikash, 1517 Chavis Yhana, 629-E Chean Borom, 1040-G Chen Angeline, 1403-A Chen Chia-hui, 222-J Chen Hui, 1510 Chen Ivy, 1517 Chen Joe, 629-E Chen John W., 1040-E Chen Krista, 1511 Chen Mike, 1520 Chen Ximin, 442-I Chen Zeyu, 1040-D Chen Zirong, 1147-B Cheng Haiying, 1522 Chiang Eugene, 579-B Chiang Yi-Hsuan, 1147-C, 1540 Chin Theodore, 1524 Chisamore Michael, 629-C, 782-H Chmielowski Bartosz, 1534 Cho Duck, 897-D Choi Yeon Sook, 1403-B Chong Li Yen, 222-D, 1512 Chu Timothy, 1428-A Chuang Charlie, 1428-A Chun Stefan, 1147-D Chung Grace, 1524 Chuong Cun, 1403-A Cimino-Mathews Ashley, 1511 Clarke Jeffrey, 1530 Clauser Karl, 1040-B Clifton Guy Travis, 1509-H Cloarec Nicolas, 782-C Clubb James, 1518 Cocorocchio Emilia, 1541 Coder Brandon, 1530 Cognetti David, 629-B Coindre Jean-Michel, 782-G Cole David, 897-C Cole Kristina, 222-J Colombo Mario Paolo, 1509-E Colvin Kayla, 1403-A Conaway Mark, 629-E Condamine Thomas, 1514 Conine Mason, 442-M Conley Anthony, 1523 Coronnello Claudia, 1536 Correa Natasha, 1524 Corria Osorio Jesús, 1540 Cottrell Tricia, 1511 Cotugno Gabriella, 1526 Coukos George, 1147-C, 1540 Courter Daniel, 442-M Cousin Sophie, 1519, 1521 Cousins David, 629-E Coutifaris Paulina, 579-C Couturier Charles, 1040-D Cox Bryan, 1534 Crawford Jeremy, 897-B Cruz-Correa Marcia, 1526 Ctortecka Claudia, 1040-B Cui Jiajia, 442-I Cui Ziyou, 442-F Cumberbatch Marie, 222-E Curry Joseph, 629-B Cursons Joe, 1538 D'Alise Morena, 1526 D'Antonio Joshua, 1040-D D'Apuzzo Massimo, 1520, 1525 Dada Hannah, 1317-A Daghestani Hikmat, 1530 Dangl Markus, 1515 Danson Sarah, 1533 Dao Hung, 1147-D Daradoumis Joana, 1147-F Datta Meenal, 897-F Davar Diwakar, 1534 Davies James, 897-C Davis Thomas, 1403-A Davitt Christopher, 222-K Dawson Travis, 1524 de Andrea Carlos, 1511 De Jesus Aribet, 222-A de Sostoa Jana, 1540 Decker Joshua, 1403-A Del Cid Natasha, 1147-A Del Valle Diane, 1524 Delaloge Suzette, 1510 Delcommenne Marc, 1040-H Demarest Stephen, 1147-A Deng Qiumei, 1528 Derosa Lisa, 1510 Desai Kunal, 1537 Desai Pratibha, 629-C Deutsch Julie, 222-N, 1511 DeWitt Anna, 1509-H Dhakal Sabin, 1403-B Diaconu Iulia, 442-E Dillon Laura, 1509-H Dong Bowen, 1040-A Dong Jianying, 1147-A Doroshow Deborah, 1524 Drubay Damien, 1510 DSouza Sabina, 1537 Dudley Andrew, 1509-A Duggan Ryan, 1403-A Duong Ellen, 579-B Duquette Mark, 897-F Durand Sylvere, 1510 Durbin Brian, 897-G Durgin Joseph, 442-B Durrant Lindy, 1533 Dutertre Charles-Antoine, 1510 Dutta Sunil, 629-E Duvnjak Lara, 1147-F Dyikanov Daniiar, 222-K Ebrahimi-Nik Hakimeh, 1403-A Eitler Jiri, 442-Q Ekambaram Prasanna, 442-D El-Bardeesy Nabeel, 1403-A El-Haddad Ghassan, 629-D Engelhard Victor, 1509-A Entrance Ground, 442-N Epstein Michael, 1515 Esquerré Michael, 1515 Esquivel Matthew, 442-C, 442-D Falahat Rana, 1509-B Falchero Lionel, 782-C Farney Elliot, 1403-A Farran Chadi, 1040-D Fay Brittany, 442-K Fazilov Gabriela, 1524 Feldman Igor, 1530 Feng Yin-Hsun, 629-C Ferrucci Pier, 1541 Fidelle Marine, 1510 Fiel Maria, 1524 Fieschi Jacques, 782-C Filippov Aleksandr, 1520 Fiset Pierre-Olivier, 1511 Fitzgerald Lisa, 1524 Flowers Ahron, 579-C Foord Orit, 442-I Foresman Dana, 629-D Forman Stephen, 1520, 1525 Forsberg Matthew, 1040-F Fossey Stacey, 1403-A Fountzilas Christos, 782-I Fraietta Joseph, 442-B Frederick Joshua, 1530 Frikha Ahmed, 782-C Frost Jennifer, 1403-A Fu Chi-Ling, 1147-D Fukumura Dai, 897-F Fukunaga Tetsu, 1040-C Fukuoka Shota, 1521 Fung Jeremy, 1403-B Gabbasov Rashid, 1514 Gagnon Etienne, 442-A Gainor Justin, 1530 Gao Changshou, 1147-D Gao Hanlin (Harry), 222-B Gao John, 222-B Gao Xing, 1040-E Garcia-Gonzalez Araceli, 1526 Garcia-Reyes Kirema, 1524 Garg Madhur, 1522 Garipcan Aybuke, 1428-A Garzia Irene, 1526 Gautam Anuj, 782-D Geda Prasanthi, 1403-A Geiger Jessica, 1530 Geller David, 1534 George Sangeeth, 579-C Georges Joseph, 1520 Gerbereux Lauren, 1530 Germain Ronald, 579-D German Mirok, 1040-G Gerry Andrew, 897-C Ghassemi Saba, 442-B Ghinnagow Rheem, 579-C Ghosh Chandra, 1534 Ghosh Rajib, 782-D Ghosh-Halder Tithi, 897-G Giles Josephine, 579-C, 1522 Gill Stefanie, 897-H Gille Jasmin, 1147-F Gillig Marc, 1040-G, 1040-F Ginefra Pierpaolo, 1147-C, 1540 Giudice Elena, 579-D Gnjatic Sacha, 1524 Gogov Sven, 1526 Goh Denise, 1512 Goldberg Michael, 222-K Gomez-Roca Carlos, 1521 Gonzalez-Kozlova Edgar, 1524 Gordon Gary, 782-E Gouxette Lucie, 1515 Goyal Rakesh, 629-C Grant Nathan, 1509-H Gray Jhanelle, 629-D Greillier Laurent, 782-C Grgich Rachel, 1147-D Griffin Gabriel, 1403-A Grimaldo Sammy, 1537 Groenbæk Kristen, 1516 Grunddal Kaare, 1147-F Gu Lin, 629-D Gucalp Rasim, 1522 Gudipati Venugopal, 442-Q Guégan Jean-Philippe, 782-G, 1519, 1521 Guerra Coelho Nuno Miranda, 897-H Guerra-Guevara Luiziane, 629-D Guey Lin, 1514 Guha Chandan, 1522 Guha Prajna, 1534 Guillemin-Paveau Helene, 782-I Gumuzio Juan, 222-G Gunasekaran Ganesh, 1524 Gupta Nitasha, 579-D Gutierrez Martin, 1530 Gutierrez-Chavez Claudia, 1522 Gutowski Stephen, 1147-B Gutowsky Katelyn, 897-G Haahr Nicolai, 442-E Haake Kathrin, 1515 Hall Michael J., 1526 Halliwill Kyle, 1403-A Halmos Balazs, 1522 Halvorsen Geoff, 1403-A Hamdad Chafik, 782-C Hamel Keith, 1403-A Hamel Steve, 222-E Hammet Andrew, 442-P Hamon Pauline, 1524 Han Nicholas, 579-C Han Ruolan, 1147-B Hanna Diana, 782-E Hannah Jayd, 1147-A Hansen Aida, 442-E Hapanowicz Olivia, 1524 Harada Naozumi, 1147-E Harada Yui, 782-F Harkin Timothy, 1524 Haseda Yasunari, 1147-E Häussinger Dieter, 1403-C Havunen Riikka, 1518 Haybout Lyna, 1518 Haymaker Cara, 1534 He Yu, 1201-A Heath James, 1539 Hemminki Akseli, 1518 Hennequin Clotilde, 1524 Henning Karla, 1147-D Herati Ramin, 579-C Hernandez Gabrielle, 1040-B Herrmann Volker, 1403-B Hett Erik, 1403-B Hibbard Jonathan, 1520 Highley Martin, 1533 Hinkelmann Alica, 1515 Hirz Taghreed, 1537 Ho William, 1517 Ho William, 629-C Hollebecque Antoine, 1521 Holly Ryan, 222-F Holst Peter, 1147-F Holtzinger Audrey, 1515 Homey Bernhard, 1403-C Hominal Stéphane, 782-C Hou Peijie, 1530 Hou Xiaohong, 1040-H Hrusch Cara, 1403-A Hsu Kevin, 1147-I Hu Changyun, 1201-B Hu Ya-Mei, 1537 Huang Alexander,

Journal for immunotherapy of cancer, 2023-11, Vol.11 (Suppl 2), p.A1861-A1866

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INTERNATIONAL PATENT: BOSTONGENE CORPORATION , ZAITSEV, ALEXANDER , CHELUSHKIN, MAKSIM , NUZHDINA, EKATERINA , ZYRIN, VLADIMIR , DYIKANOV, DANIIAR , BAGAEV, ALEXANDER , ATAULLAKHANOV, RAVSHAN , CHEREM...

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222-K Integrated immunoprofiling and RNA sequencing (RNA-seq) for anti-PD-1 response prediction in head and neck squamous cell carcinomas (HNSCC)

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