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Image-based multiplex immune profiling of cancer tissues: translational implications. A report of the International Immuno-oncology Biomarker Working Group on Breast Cancer

Jahangir, Chowdhury Arif; Page, David B; Broeckx, Glenn; Gonzalez, Claudia A; Burke, Caoimbhe; Murphy, Clodagh; Reis-Filho, Jorge S; Ly, Amy; Harms, Paul W; Gupta, Rajarsi R; Vieth, Michael; Hida, Akira I; Kahila, Mohamed; Kos, Zuzana; van Diest, Paul J; Verbandt, Sara; Thagaard, Jeppe; Khiroya, Reena; Abduljabbar, Khalid; Acosta Haab, Gabriela; Acs, Balazs; Adams, Sylvia; Almeida, Jonas S; Alvarado-Cabrero, Isabel; Azmoudeh-Ardalan, Farid; Badve, Sunil; Baharun, Nurkhairul Bariyah; Bellolio, Enrique R; Bheemaraju, Vydehi; Blenman, Kim Rm; Botinelly Mendonça Fujimoto, Luciana; Burgues, Octavio; Chardas, Alexandros; Cheang, Maggie Chon U; Ciompi, Francesco; Cooper, Lee Ad; Coosemans, An; Corredor, Germán; Dantas Portela, Flavio Luis; Deman, Frederik; Demaria, Sandra; Dudgeon, Sarah N; Elghazawy, Mahmoud; Fernandez-Martín, Claudio; Fineberg, Susan; Fox, Stephen B; Giltnane, Jennifer M; Gnjatic, Sacha; Gonzalez-Ericsson, Paula I; Grigoriadis, Anita; Halama, Niels; Hanna, Matthew G; Harbhajanka, Aparna; Hart, Steven N; Hartman, Johan; Hewitt, Stephen; Horlings, Hugo M; Husain, Zaheed; Irshad, Sheeba; Janssen, Emiel Am; Kataoka, Tatsuki R; Kawaguchi, Kosuke; Khramtsov, Andrey I; Kiraz, Umay; Kirtani, Pawan; Kodach, Liudmila L; Korski, Konstanty; Akturk, Guray; Scott, Ely; Kovács, Anikó; Laenkholm, Anne-Vibeke; Lang-Schwarz, Corinna; Larsimont, Denis; Lennerz, Jochen K; Lerousseau, Marvin; Li, Xiaoxian; Madabhushi, Anant; Maley, Sai K; Manur Narasimhamurthy, Vidya; Marks, Douglas K; McDonald, Elizabeth S; Mehrotra, Ravi; Michiels, Stefan; Kharidehal, Durga; Minhas, Fayyaz Ul Amir Afsar; Mittal, Shachi; Moore, David A; Mushtaq, Shamim; Nighat, Hussain; Papathomas, Thomas; Penault-Llorca, Frederique; Perera, Rashindrie D; Pinard, Christopher J; Pinto-Cardenas, Juan Carlos; Pruneri, Giancarlo; Pusztai, Lajos; Rajpoot, Nasir Mahmood; Rapoport, Bernardo Leon; Rau, Tilman T; Ribeiro, Joana M; Rimm, David; Vincent-Salomon, Anne; Saltz, Joel; Sayed, Shahin; Hytopoulos, Evangelos; Mahon, Sarah; Siziopikou, Kalliopi P; Sotiriou, Christos; Stenzinger, Albrecht; Sughayer, Maher A; Sur, Daniel; Symmans, Fraser; Tanaka, Sunao; Taxter, Timothy; Tejpar, Sabine; Teuwen, Jonas; Thompson, E Aubrey; Tramm, Trine; Tran, William T; van der Laak, Jeroen; Verghese, Gregory E; Viale, Giuseppe; Wahab, Noorul; Walter, Thomas; Waumans, Yannick; Wen, Hannah Y; Yang, Wentao; Yuan, Yinyin; Bartlett, John; Loibl, Sibylle; Denkert, Carsten; Savas, Peter; Loi, Sherene; Specht Stovgaard, Elisabeth; Salgado, Roberto; Gallagher, William M; Rahman, Arman
Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi-marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
PMID: 38230434
ISSN: 1096-9896
CID: 5633182

Image-based multiplex immune profiling of cancer tissues: translational implications. A report of the International Immuno-oncology Biomarker Working Group on Breast Cancer

Jahangir, Chowdhury Arif; Page, David B.; Broeckx, Glenn; Gonzalez, Claudia A.; Burke, Caoimbhe; Murphy, Clodagh; Reis-Filho, Jorge S.; Ly, Amy; Harms, Paul W.; Gupta, Rajarsi R.; Vieth, Michael; Hida, Akira I.; Kahila, Mohamed; Kos, Zuzana; van Diest, Paul J.; Verbandt, Sara; Thagaard, Jeppe; Khiroya, Reena; Abduljabbar, Khalid; Acosta Haab, Gabriela; Acs, Balazs; Adams, Sylvia; Almeida, Jonas S.; Alvarado-Cabrero, Isabel; Azmoudeh-Ardalan, Farid; Badve, Sunil; Baharun, Nurkhairul Bariyah; Bellolio, Enrique R.; Bheemaraju, Vydehi; Blenman, Kim R.M.; Botinelly Mendonça Fujimoto, Luciana; Burgues, Octavio; Chardas, Alexandros; Cheang, Maggie Chon U.; Ciompi, Francesco; Cooper, Lee A.D.; Coosemans, An; Corredor, Germán; Dantas Portela, Flavio Luis; Deman, Frederik; Demaria, Sandra; Dudgeon, Sarah N.; Elghazawy, Mahmoud; Fernandez-Martin, Claudio; Fineberg, Susan; Fox, Stephen B.; Giltnane, Jennifer M.; Gnjatic, Sacha; Gonzalez-Ericsson, Paula I.; Grigoriadis, Anita; Halama, Niels; Hanna, Matthew G.; Harbhajanka, Aparna; Hart, Steven N.; Hartman, Johan; Hewitt, Stephen; Horlings, Hugo M.; Husain, Zaheed; Irshad, Sheeba; Janssen, Emiel A.M.; Kataoka, Tatsuki R.; Kawaguchi, Kosuke; Khramtsov, Andrey I.; Kiraz, Umay; Kirtani, Pawan; Kodach, Liudmila L.; Korski, Konstanty; Akturk, Guray; Scott, Ely; Kovács, Anikó; Lænkholm, Anne Vibeke; Lang-Schwarz, Corinna; Larsimont, Denis; Lennerz, Jochen K.; Lerousseau, Marvin; Li, Xiaoxian; Madabhushi, Anant; Maley, Sai K.; Manur Narasimhamurthy, Vidya; Marks, Douglas K.; McDonald, Elizabeth S.; Mehrotra, Ravi; Michiels, Stefan; Kharidehal, Durga; Minhas, Fayyaz ul Amir Afsar; Mittal, Shachi; Moore, David A.; Mushtaq, Shamim; Nighat, Hussain; Papathomas, Thomas; Penault-Llorca, Frederique; Perera, Rashindrie D.; Pinard, Christopher J.; Pinto-Cardenas, Juan Carlos; Pruneri, Giancarlo; Pusztai, Lajos; Rajpoot, Nasir Mahmood; Rapoport, Bernardo Leon; Rau, Tilman T.; Ribeiro, Joana M.; Rimm, David; Vincent-Salomon, Anne; Saltz, Joel; Sayed, Shahin; Hytopoulos, Evangelos; Mahon, Sarah; Siziopikou, Kalliopi P.; Sotiriou, Christos; Stenzinger, Albrecht; Sughayer, Maher A.; Sur, Daniel; Symmans, Fraser; Tanaka, Sunao; Taxter, Timothy; Tejpar, Sabine; Teuwen, Jonas; Thompson, E. Aubrey; Tramm, Trine; Tran, William T.; van der Laak, Jeroen; Verghese, Gregory E.; Viale, Giuseppe; Wahab, Noorul; Walter, Thomas; Waumans, Yannick; Wen, Hannah Y.; Yang, Wentao; Yuan, Yinyin; Bartlett, John; Loibl, Sibylle; Denkert, Carsten; Savas, Peter; Loi, Sherene; Specht Stovgaard, Elisabeth; Salgado, Roberto; Gallagher, William M.; Rahman, Arman
Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi-marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
SCOPUS:85182480446
ISSN: 0022-3417
CID: 5629662

Pitfalls in machine learning-based assessment of tumor-infiltrating lymphocytes in breast cancer: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer

Thagaard, Jeppe; Broeckx, Glenn; Page, David B; Jahangir, Chowdhury Arif; Verbandt, Sara; Kos, Zuzana; Gupta, Rajarsi; Khiroya, Reena; Abduljabbar, Khalid; Acosta Haab, Gabriela; Acs, Balazs; Akturk, Guray; Almeida, Jonas S; Alvarado-Cabrero, Isabel; Amgad, Mohamed; Azmoudeh-Ardalan, Farid; Badve, Sunil; Baharun, Nurkhairul Bariyah; Balslev, Eva; Bellolio, Enrique R; Bheemaraju, Vydehi; Blenman, Kim Rm; Botinelly Mendonça Fujimoto, Luciana; Bouchmaa, Najat; Burgues, Octavio; Chardas, Alexandros; Chon U Cheang, Maggie; Ciompi, Francesco; Cooper, Lee Ad; Coosemans, An; Corredor, Germán; Dahl, Anders B; Dantas Portela, Flavio Luis; Deman, Frederik; Demaria, Sandra; Doré Hansen, Johan; Dudgeon, Sarah N; Ebstrup, Thomas; Elghazawy, Mahmoud; Fernandez-Martín, Claudio; Fox, Stephen B; Gallagher, William M; Giltnane, Jennifer M; Gnjatic, Sacha; Gonzalez-Ericsson, Paula I; Grigoriadis, Anita; Halama, Niels; Hanna, Matthew G; Harbhajanka, Aparna; Hart, Steven N; Hartman, Johan; Hauberg, Søren; Hewitt, Stephen; Hida, Akira I; Horlings, Hugo M; Husain, Zaheed; Hytopoulos, Evangelos; Irshad, Sheeba; Janssen, Emiel Am; Kahila, Mohamed; Kataoka, Tatsuki R; Kawaguchi, Kosuke; Kharidehal, Durga; Khramtsov, Andrey I; Kiraz, Umay; Kirtani, Pawan; Kodach, Liudmila L; Korski, Konstanty; Kovács, Anikó; Laenkholm, Anne-Vibeke; Lang-Schwarz, Corinna; Larsimont, Denis; Lennerz, Jochen K; Lerousseau, Marvin; Li, Xiaoxian; Ly, Amy; Madabhushi, Anant; Maley, Sai K; Manur Narasimhamurthy, Vidya; Marks, Douglas K; McDonald, Elizabeth S; Mehrotra, Ravi; Michiels, Stefan; Minhas, Fayyaz Ul Amir Afsar; Mittal, Shachi; Moore, David A; Mushtaq, Shamim; Nighat, Hussain; Papathomas, Thomas; Penault-Llorca, Frederique; Perera, Rashindrie D; Pinard, Christopher J; Pinto-Cardenas, Juan Carlos; Pruneri, Giancarlo; Pusztai, Lajos; Rahman, Arman; Rajpoot, Nasir Mahmood; Rapoport, Bernardo Leon; Rau, Tilman T; Reis-Filho, Jorge S; Ribeiro, Joana M; Rimm, David; Roslind, Anne; Vincent-Salomon, Anne; Salto-Tellez, Manuel; Saltz, Joel; Sayed, Shahin; Scott, Ely; Siziopikou, Kalliopi P; Sotiriou, Christos; Stenzinger, Albrecht; Sughayer, Maher A; Sur, Daniel; Fineberg, Susan; Symmans, Fraser; Tanaka, Sunao; Taxter, Timothy; Tejpar, Sabine; Teuwen, Jonas; Thompson, E Aubrey; Tramm, Trine; Tran, William T; van der Laak, Jeroen; van Diest, Paul J; Verghese, Gregory E; Viale, Giuseppe; Vieth, Michael; Wahab, Noorul; Walter, Thomas; Waumans, Yannick; Wen, Hannah Y; Yang, Wentao; Yuan, Yinyin; Zin, Reena Md; Adams, Sylvia; Bartlett, John; Loibl, Sibylle; Denkert, Carsten; Savas, Peter; Loi, Sherene; Salgado, Roberto; Specht Stovgaard, Elisabeth
The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. We categorize our findings into four main topics: (1) technical slide issues, (2) ML and image analysis aspects, (3) data challenges, and (4) validation issues. The main reason for discordant assessments is the inclusion of false-positive areas or cells identified by performance on certain tissue patterns or design choices in the computational implementation. To aid the adoption of ML for TIL assessment, we provide an in-depth discussion of ML and image analysis, including validation issues that need to be considered before reliable computational reporting of TILs can be incorporated into the trial and routine clinical management of patients with triple-negative breast cancer. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
PMCID:10518802
PMID: 37608772
ISSN: 1096-9896
CID: 5598512

Spatial analyses of immune cell infiltration in cancer: current methods and future directions: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer

Page, David B; Broeckx, Glenn; Jahangir, Chowdhury Arif; Verbandt, Sara; Gupta, Rajarsi R; Thagaard, Jeppe; Khiroya, Reena; Kos, Zuzana; Abduljabbar, Khalid; Acosta Haab, Gabriela; Acs, Balazs; Akturk, Guray; Almeida, Jonas S; Alvarado-Cabrero, Isabel; Azmoudeh-Ardalan, Farid; Badve, Sunil; Baharun, Nurkhairul Bariyah; Bellolio, Enrique R; Bheemaraju, Vydehi; Blenman, Kim Rm; Botinelly Mendonça Fujimoto, Luciana; Bouchmaa, Najat; Burgues, Octavio; Cheang, Maggie Chon U; Ciompi, Francesco; Cooper, Lee Ad; Coosemans, An; Corredor, Germán; Dantas Portela, Flavio Luis; Deman, Frederik; Demaria, Sandra; Dudgeon, Sarah N; Elghazawy, Mahmoud; Ely, Scott; Fernandez-Martín, Claudio; Fineberg, Susan; Fox, Stephen B; Gallagher, William M; Giltnane, Jennifer M; Gnjatic, Sacha; Gonzalez-Ericsson, Paula I; Grigoriadis, Anita; Halama, Niels; Hanna, Matthew G; Harbhajanka, Aparna; Hardas, Alexandros; Hart, Steven N; Hartman, Johan; Hewitt, Stephen; Hida, Akira I; Horlings, Hugo M; Husain, Zaheed; Hytopoulos, Evangelos; Irshad, Sheeba; Janssen, Emiel Am; Kahila, Mohamed; Kataoka, Tatsuki R; Kawaguchi, Kosuke; Kharidehal, Durga; Khramtsov, Andrey I; Kiraz, Umay; Kirtani, Pawan; Kodach, Liudmila L; Korski, Konstanty; Kovács, Anikó; Laenkholm, Anne-Vibeke; Lang-Schwarz, Corinna; Larsimont, Denis; Lennerz, Jochen K; Lerousseau, Marvin; Li, Xiaoxian; Ly, Amy; Madabhushi, Anant; Maley, Sai K; Manur Narasimhamurthy, Vidya; Marks, Douglas K; McDonald, Elizabeth S; Mehrotra, Ravi; Michiels, Stefan; Minhas, Fayyaz Ul Amir Afsar; Mittal, Shachi; Moore, David A; Mushtaq, Shamim; Nighat, Hussain; Papathomas, Thomas; Penault-Llorca, Frederique; Perera, Rashindrie D; Pinard, Christopher J; Pinto-Cardenas, Juan Carlos; Pruneri, Giancarlo; Pusztai, Lajos; Rahman, Arman; Rajpoot, Nasir Mahmood; Rapoport, Bernardo Leon; Rau, Tilman T; Reis-Filho, Jorge S; Ribeiro, Joana M; Rimm, David; Vincent-Salomon, Anne; Salto-Tellez, Manuel; Saltz, Joel; Sayed, Shahin; Siziopikou, Kalliopi P; Sotiriou, Christos; Stenzinger, Albrecht; Sughayer, Maher A; Sur, Daniel; Symmans, Fraser; Tanaka, Sunao; Taxter, Timothy; Tejpar, Sabine; Teuwen, Jonas; Thompson, E Aubrey; Tramm, Trine; Tran, William T; van der Laak, Jeroen; van Diest, Paul J; Verghese, Gregory E; Viale, Giuseppe; Vieth, Michael; Wahab, Noorul; Walter, Thomas; Waumans, Yannick; Wen, Hannah Y; Yang, Wentao; Yuan, Yinyin; Adams, Sylvia; Bartlett, John Mark Seaverns; Loibl, Sibylle; Denkert, Carsten; Savas, Peter; Loi, Sherene; Salgado, Roberto; Specht Stovgaard, Elisabeth
Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector-based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers. We conclude by discussing two well-described clinical biomarkers, the breast cancer stromal tumor infiltrating lymphocytes score and the colon cancer Immunoscore, and describe investigative opportunities to improve clinical utility of these spatial biomarkers. © 2023 The Pathological Society of Great Britain and Ireland.
PMID: 37608771
ISSN: 1096-9896
CID: 5598482

The "Great Debate" at Melanoma Bridge 2021, December 2nd-4th, 2021

Ascierto, Paolo A; Warner, Allison Betof; Blank, Christian; Caracò, Corrado; Demaria, Sandra; Gershenwald, Jeffrey E; Khushalani, Nikhil I; Long, Georgina V; Luke, Jason J; Mehnert, Janice M; Robert, Caroline; Rutkowski, Piotr; Tawbi, Hussein A; Osman, Iman; Puzanov, Igor
The Great Debate session at the 2021 Melanoma Bridge virtual congress (December 2-4) featured counterpoint views from experts on seven important issues in melanoma. The debates considered the use of adoptive cell therapy versus use of bispecific antibodies, mitogen-activated protein kinase (MAPK) inhibitors versus immunotherapy in the adjuvant setting, whether the use of corticosteroids for the management of side effects have an impact on outcomes, the choice of programmed death (PD)-1 combination therapy with cytotoxic T-lymphocyte-associated antigen (CTLA)-4 or lymphocyte-activation gene (LAG)-3, whether radiation is needed for brain metastases, when lymphadenectomy should be integrated into the treatment plan and then the last debate, telemedicine versus face-to-face. As with previous Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their respective personal view. Audiences voted both before and after each debate.
PMCID:9087170
PMID: 35538491
ISSN: 1479-5876
CID: 5214372

Tumor infiltrating lymphocyte stratification of prognostic staging of early-stage triple negative breast cancer

Loi, Sherene; Salgado, Roberto; Adams, Sylvia; Pruneri, Giancarlo; Francis, Prudence A; Lacroix-Triki, Magali; Joensuu, Heikki; Dieci, Maria Vittoria; Badve, Sunil; Demaria, Sandra; Gray, Robert; Munzone, Elisabetta; Drubay, Damien; Lemonnier, Jerome; Sotiriou, Christos; Kellokumpu-Lehtinen, Pirkko Liisa; Vingiani, Andrea; Gray, Kathryn; André, Fabrice; Denkert, Carsten; Piccart, Martine; Roblin, Elvire; Michiels, Stefan
The importance of integrating biomarkers into the TNM staging has been emphasized in the 8th Edition of the American Joint Committee on Cancer (AJCC) Staging system. In a pooled analysis of 2148 TNBC-patients in the adjuvant setting, TILs are found to strongly up and downstage traditional pathological-staging in the Pathological and Clinical Prognostic Stage Groups from the AJJC 8th edition Cancer Staging System. This suggest that clinical and research studies on TNBC should take TILs into account in addition to stage, as for example patients with stage II TNBC and high TILs have a better outcome than patients with stage I and low TILs.
PMID: 35017545
ISSN: 2374-4677
CID: 5118652

The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group

El Bairi, Khalid; Haynes, Harry R; Blackley, Elizabeth; Fineberg, Susan; Shear, Jeffrey; Turner, Sophia; de Freitas, Juliana Ribeiro; Sur, Daniel; Amendola, Luis Claudio; Gharib, Masoumeh; Kallala, Amine; Arun, Indu; Azmoudeh-Ardalan, Farid; Fujimoto, Luciana; Sua, Luz F; Liu, Shi-Wei; Lien, Huang-Chun; Kirtani, Pawan; Balancin, Marcelo; El Attar, Hicham; Guleria, Prerna; Yang, Wenxian; Shash, Emad; Chen, I-Chun; Bautista, Veronica; Do Prado Moura, Jose Fernando; Rapoport, Bernardo L; Castaneda, Carlos; Spengler, Eunice; Acosta-Haab, Gabriela; Frahm, Isabel; Sanchez, Joselyn; Castillo, Miluska; Bouchmaa, Najat; Md Zin, Reena R; Shui, Ruohong; Onyuma, Timothy; Yang, Wentao; Husain, Zaheed; Willard-Gallo, Karen; Coosemans, An; Perez, Edith A; Provenzano, Elena; Ericsson, Paula Gonzalez; Richardet, Eduardo; Mehrotra, Ravi; Sarancone, Sandra; Ehinger, Anna; Rimm, David L; Bartlett, John M S; Viale, Giuseppe; Denkert, Carsten; Hida, Akira I; Sotiriou, Christos; Loibl, Sibylle; Hewitt, Stephen M; Badve, Sunil; Symmans, William Fraser; Kim, Rim S; Pruneri, Giancarlo; Goel, Shom; Francis, Prudence A; Inurrigarro, Gloria; Yamaguchi, Rin; Garcia-Rivello, Hernan; Horlings, Hugo; Afqir, Said; Salgado, Roberto; Adams, Sylvia; Kok, Marleen; Dieci, Maria Vittoria; Michiels, Stefan; Demaria, Sandra; Loi, Sherene
The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.
PMID: 34853355
ISSN: 2374-4677
CID: 5065742

3-hydroxy-L-kynurenamine is an immunomodulatory biogenic amine

Clement, Cristina C; D'Alessandro, Angelo; Thangaswamy, Sangeetha; Chalmers, Samantha; Furtado, Raquel; Spada, Sheila; Mondanelli, Giada; Ianni, Federica; Gehrke, Sarah; Gargaro, Marco; Manni, Giorgia; Cara, Luisa Carlota Lopez; Runge, Peter; Tsai, Wanxia Li; Karaman, Sinem; Arasa, Jorge; Fernandez-Rodriguez, Ruben; Beck, Amanda; Macchiarulo, Antonio; Gadina, Massimo; Halin, Cornelia; Fallarino, Francesca; Skobe, Mihaela; Veldhoen, Marc; Moretti, Simone; Formenti, Silvia; Demaria, Sandra; Soni, Rajesh K; Galarini, Roberta; Sardella, Roccaldo; Lauvau, Gregoire; Putterman, Chaim; Alitalo, Kari; Grohmann, Ursula; Santambrogio, Laura
Tryptophan catabolism is a major metabolic pathway utilized by several professional and non-professional antigen presenting cells to maintain immunological tolerance. Here we report that 3-hydroxy-L-kynurenamine (3-HKA) is a biogenic amine produced via an alternative pathway of tryptophan metabolism. In vitro, 3-HKA has an anti-inflammatory profile by inhibiting the IFN-γ mediated STAT1/NF-κΒ pathway in both mouse and human dendritic cells (DCs) with a consequent decrease in the release of pro-inflammatory chemokines and cytokines, most notably TNF, IL-6, and IL12p70. 3-HKA has protective effects in an experimental mouse model of psoriasis by decreasing skin thickness, erythema, scaling and fissuring, reducing TNF, IL-1β, IFN-γ, and IL-17 production, and inhibiting generation of effector CD8+ T cells. Similarly, in a mouse model of nephrotoxic nephritis, besides reducing inflammatory cytokines, 3-HKA improves proteinuria and serum urea nitrogen, overall ameliorating immune-mediated glomerulonephritis and renal dysfunction. Overall, we propose that this biogenic amine is a crucial component of tryptophan-mediated immune tolerance.
PMID: 34290243
ISSN: 2041-1723
CID: 4951192

Perspectives in immunotherapy: meeting report from the immunotherapy bridge (December 2nd-3rd, 2020, Italy)

Ascierto, Paolo A; Bifulco, Carlo; Ciardiello, Fortunato; Demaria, Sandra; Emens, Leisha A; Ferris, Robert; Formenti, Silvia C; Galon, Jerome; Khleif, Samir N; Kirchhoff, Tomas; McQuade, Jennifer; Odunsi, Kunle; Patnaik, Akash; Paulos, Chrystal M; Taube, Janis M; Timmerman, John; Fox, Bernard A; Hwu, Patrick; Puzanov, Igor
Improved understanding of tumor immunology has enabled the development of therapies that harness the immune system and prevent immune escape. Numerous clinical trials and real-world experience has provided evidence of the potential for long-term survival with immunotherapy in various types of malignancy. Recurring observations with immuno-oncology agents include their potential for clinical application across a broad patient population with different tumor types, conventional and unconventional response patterns, durable responses, and immune-related adverse events. Despite the substantial achievements to date, a significant proportion of patients still fail to benefit from current immunotherapy options, and ongoing research is focused on transforming non-responders to responders through the development of novel treatments, new strategies to combination therapy, adjuvant and neoadjuvant approaches, and the identification of biomarkers of response. These topics were the focus of the virtual Immunotherapy Bridge (December 2nd-3rd, 2020), organized by the Fondazione Melanoma Onlus, Naples, Italy, in collaboration with the Society for Immunotherapy of Cancer and are summarised in this report.
PMID: 34078406
ISSN: 1479-5876
CID: 4891672

Potentiating anti-tumor efficacy through radiation and sustained intratumoral delivery of anti-CD40 and anti-PDL1

Liu, Hsuan-Chen; Viswanath, Dixita I; Pesaresi, Federica; Xu, Yitian; Zhang, Licheng; Di Trani, Nicola; Paez-Mayorga, Jesus; Hernandez, Nathanael; Wang, Yu; Erm, Donald R; Ho, Jeremy; Susnjar, Antonia; Liu, Xuewu; Demaria, Sandra; Chen, Shu-Hsia; Teh, Bin S; Butler, Edward Brian; Xuan Chua, Corrine Ying; Grattoni, Alessandro
PURPOSE/OBJECTIVE:Mounting evidence demonstrates that combining radiotherapy (RT) with immunotherapy can reduce tumor burden in a subset of patients. However, conventional systemic delivery of immunotherapeutics is often associated with significant adverse effects, which force treatment cessation. The aim of this study is to investigate a minimally invasive therapeutics delivery approach to improve clinical response while attenuating toxicity. METHODS:We utilized a nanofluidic drug-eluting seed (NDES) for the sustained intratumoral delivery of combinational antibodies, CD40 and PDL1. To enhance immune and tumor response, we combined the NDES intratumoral platform with RT to treat the 4T1 murine model of advanced triple negative breast cancer (TNBC). We compared the efficacy of NDES against intraperitoneal (IP) administration, which mimics conventional systemic treatment. Tumor growth was recorded, and local and systemic immune responses were assessed via imaging mass cytometry and flow cytometry. Livers and lungs were histologically analyzed for evaluation of toxicity and metastasis, respectively. RESULTS:The combination of RT and sustained intratumoral immunotherapy delivery of CD40 and PDL1 via the NDES (NDES CD40/PDL1) showed an increase in both local and systemic immune response. In combination with RT, NDES CD40/PDL1 achieved significant tumor burden reduction and liver inflammation mitigation when compared to systemic treatment. Importantly, our treatment strategy boosted the abscopal effect towards attenuating lung metastatic burden. CONCLUSIONS:Overall, our study demonstrated superior efficacy of combination treatment with RT and sustained intratumoral immunotherapy via the NDES, offering promise for improving therapeutic index and clinical response.
PMID: 32768562
ISSN: 1879-355x
CID: 4555772