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4. Author Correction: Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results

Author

Glitza Oliva, Isabella C., Ferguson, Sherise D., Bassett, Jr, Roland, Foster, Alexandra P., John, Ida, Hennegan, Tarin D., Rohlfs, Michelle, Richard, Jessie, Iqbal, Masood, Dett, Tina, Lacey, Carol, Jackson, Natalie, Rodgers, Theresa, Phillips, Suzanne, Duncan, Sheila, Haydu, Lauren, Lin, Ruitao, Amaria, Rodabe N., Wong, Michael K., Diab, Adi, Yee, Cassian, Patel, Sapna P., McQuade, Jennifer L., Fischer, Grant M., McCutcheon, Ian E., O’Brien, Barbara J., Tummala, Sudhakar, Debnam, Matthew, Guha-Thakurta, Nandita, Wargo, Jennifer A., Carapeto, Fernando C. L., Hudgens, Courtney W., Huse, Jason T., Tetzlaff, Michael T., Burton, Elizabeth M., Tawbi, Hussein A., and Davies, Michael A.

Published
2024
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5. Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results

Author

Glitza Oliva, Isabella C., Ferguson, Sherise D., Bassett, Jr, Roland, Foster, Alexandra P., John, Ida, Hennegan, Tarin D., Rohlfs, Michelle, Richard, Jessie, Iqbal, Masood, Dett, Tina, Lacey, Carol, Jackson, Natalie, Rodgers, Theresa, Phillips, Suzanne, Duncan, Sheila, Haydu, Lauren, Lin, Ruitao, Amaria, Rodabe N., Wong, Michael K., Diab, Adi, Yee, Cassian, Patel, Sapna P., McQuade, Jennifer L., Fischer, Grant M., McCutcheon, Ian E., O’Brien, Barbara J., Tummala, Sudhakar, Debnam, Matthew, Guha-Thakurta, Nandita, Wargo, Jennifer A., Carapeto, Fernando C. L., Hudgens, Courtney W., Huse, Jason T., Tetzlaff, Michael T., Burton, Elizabeth M., Tawbi, Hussein A., and Davies, Michael A.

Published
2023
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6. Multiplex Tissue Imaging Harmonization: A Multicenter Experience from CIMAC-CIDC Immuno-Oncology Biomarkers Network

Author

Akturk, Guray, Parra, Edwin R, Gjini, Evisa, Lako, Ana, Lee, J Jack, Neuberg, Donna, Zhang, Jiexin, Yao, Shen, Laface, Ilaria, Rogic, Anita, Chen, Pei-Hsuan, Sanchez-Espiridion, Beatriz, Del Valle, Diane M, Moravec, Radim, Kinders, Robert, Hudgens, Courtney, Wu, Catherine, Wistuba, Ignacio I, Thurin, Magdalena, Hewitt, Stephen M, Rodig, Scott, Gnjatic, Sacha, and Tetzlaff, Michael T

Subjects
Biotechnology, Clinical Research, Vaccine Related, Clinical Trials and Supportive Activities, Cancer, Biomarkers, Tumor, Fluorescent Antibody Technique, Humans, Image Processing, Computer-Assisted, Monitoring, Immunologic, Neoplasms, Staining and Labeling, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeThe Cancer Immune Monitoring and Analysis Centers - Cancer Immunologic Data Commons (CIMAC-CIDC) network supported by the NCI Cancer Moonshot initiative was established to provide correlative analyses for clinical trials in cancer immunotherapy, using state-of-the-art technology. Fundamental to this initiative is implementation of multiplex IHC assays to define the composition and distribution of immune infiltrates within tumors in the context of their potential role as biomarkers. A critical unanswered question involves the relative fidelity of such assays to reliably quantify tumor-associated immune cells across different platforms.Experimental designThree CIMAC sites compared across their laboratories: (i) image analysis algorithms, (ii) image acquisition platforms, (iii) multiplex staining protocols. Two distinct high-dimensional approaches were employed: multiplexed IHC consecutive staining on single slide (MICSSS) and multiplexed immunofluorescence (mIF). To eliminate variables potentially impacting assay performance, we completed a multistep harmonization process, first comparing assay performance using independent protocols followed by the integration of laboratory-specific protocols and finally, validating this harmonized approach in an independent set of tissues.ResultsData generated at the final validation step showed an intersite Spearman correlation coefficient (r) of ≥0.85 for each marker within and across tissue types, with an overall low average coefficient of variation ≤0.1.ConclusionsOur results support interchangeability of protocols and platforms to deliver robust, and comparable data using similar tissue specimens and confirm that CIMAC-CIDC analyses may therefore be used with confidence for statistical associations with clinical outcomes largely independent of site, antibody selection, protocol, and platform across different sites.

Published
2021

7. Resolution of tissue signatures of therapy response in patients with recurrent GBM treated with neoadjuvant anti-PD1.

Author

Lu, Yue, Ng, Alphonsus HC, Chow, Frances E, Everson, Richard G, Helmink, Beth A, Tetzlaff, Michael T, Thakur, Rohit, Wargo, Jennifer A, Cloughesy, Timothy F, Prins, Robert M, and Heath, James R

Subjects
CD8-Positive T-Lymphocytes, Humans, Glioblastoma, Melanoma, Brain Neoplasms, Neoplasm Recurrence, Local, Treatment Outcome, Neoadjuvant Therapy, Adult, Aged, Middle Aged, Female, Male, Tumor Microenvironment, CTLA-4 Antigen, Programmed Cell Death 1 Receptor, Biomarkers, Tumor, Antineoplastic Agents, Immunological, Ipilimumab, Nivolumab, Immune Checkpoint Inhibitors, Rare Diseases, Brain Disorders, Brain Cancer, Cancer, Neurosciences
Abstract

The response of patients with recurrent glioblastoma multiforme to neoadjuvant immune checkpoint blockade has been challenging to interpret due to the inter-patient and intra-tumor heterogeneity. We report on a comparative analysis of tumor tissues collected from patients with recurrent glioblastoma and high-risk melanoma, both treated with neoadjuvant checkpoint blockade. We develop a framework that uses multiplex spatial protein profiling, machine learning-based image analysis, and data-driven computational models to investigate the pathophysiological and molecular factors within the tumor microenvironment that influence treatment response. Using melanoma to guide the interpretation of glioblastoma analyses, we interrogate the protein expression in microscopic compartments of tumors, and determine the correlates of cytotoxic CD8+ T cells, tumor growth, treatment response, and immune cell-cell interaction. This work reveals similarities shared between glioblastoma and melanoma, immunosuppressive factors that are unique to the glioblastoma microenvironment, and potential co-targets for enhancing the efficacy of neoadjuvant immune checkpoint blockade.

Published
2021

9. Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy.

Author

Somasundaram, Rajasekharan, Connelly, Thomas, Choi, Robin, Choi, Hyeree, Samarkina, Anastasia, Li, Ling, Gregorio, Elizabeth, Chen, Yeqing, Thakur, Rohit, Abdel-Mohsen, Mohamed, Beqiri, Marilda, Kiernan, Meaghan, Perego, Michela, Wang, Fang, Xiao, Min, Brafford, Patricia, Yang, Xue, Xu, Xiaowei, Secreto, Anthony, Danet-Desnoyers, Gwenn, Traum, Daniel, Kaestner, Klaus H, Huang, Alexander C, Hristova, Denitsa, Wang, Joshua, Fukunaga-Kalabis, Mizuho, Krepler, Clemens, Ping-Chen, Fang, Zhou, Xiangyang, Gutierrez, Alexis, Rebecca, Vito W, Vonteddu, Prashanthi, Dotiwala, Farokh, Bala, Shashi, Majumdar, Sonali, Dweep, Harsh, Wickramasinghe, Jayamanna, Kossenkov, Andrew V, Reyes-Arbujas, Jorge, Santiago, Kenisha, Nguyen, Tran, Griss, Johannes, Keeney, Frederick, Hayden, James, Gavin, Brian J, Weiner, David, Montaner, Luis J, Liu, Qin, Peiffer, Lukas, Becker, Jürgen, Burton, Elizabeth M, Davies, Michael A, Tetzlaff, Michael T, Muthumani, Kar, Wargo, Jennifer A, Gabrilovich, Dmitry, and Herlyn, Meenhard

Subjects
B-Lymphocytes, T-Lymphocytes, Lymphocytes, Tumor-Infiltrating, Mast Cells, Animals, Mice, Transgenic, Humans, Melanoma, Drug Resistance, Neoplasm, Programmed Cell Death 1 Receptor, Sunitinib, Immune Checkpoint Inhibitors
Abstract

Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34+ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγnull (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3+ Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8+/Granz B+ T cells homeostasis are observed in tumor regions where FOXP3+ Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.

Published
2021

10. Multiplatform Analysis of Intratumoral PTEN Heterogeneity in Melanoma

Author

Chagani, Sharmeen, De Macedo, Mariana P., Carapeto, Fernando, Wang, Feng, Marzese, Diego M., Wani, Khalida, Haydu, Lauren E., Peng, Weiyi, Ong, Giang T., Warren, Sarah E., Beechem, Joseph M., Hoon, Dave S.B., Mills, Gordon B., Tetzlaff, Michael T., Lazar, Alexander J., Kwong, Lawrence N., and Davies, Michael A.

Published
2023
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11. B cells and tertiary lymphoid structures promote immunotherapy response

Author

Helmink, Beth A, Reddy, Sangeetha M, Gao, Jianjun, Zhang, Shaojun, Basar, Rafet, Thakur, Rohit, Yizhak, Keren, Sade-Feldman, Moshe, Blando, Jorge, Han, Guangchun, Gopalakrishnan, Vancheswaran, Xi, Yuanxin, Zhao, Hao, Amaria, Rodabe N, Tawbi, Hussein A, Cogdill, Alex P, Liu, Wenbin, LeBleu, Valerie S, Kugeratski, Fernanda G, Patel, Sapna, Davies, Michael A, Hwu, Patrick, Lee, Jeffrey E, Gershenwald, Jeffrey E, Lucci, Anthony, Arora, Reetakshi, Woodman, Scott, Keung, Emily Z, Gaudreau, Pierre-Olivier, Reuben, Alexandre, Spencer, Christine N, Burton, Elizabeth M, Haydu, Lauren E, Lazar, Alexander J, Zapassodi, Roberta, Hudgens, Courtney W, Ledesma, Deborah A, Ong, SuFey, Bailey, Michael, Warren, Sarah, Rao, Disha, Krijgsman, Oscar, Rozeman, Elisa A, Peeper, Daniel, Blank, Christian U, Schumacher, Ton N, Butterfield, Lisa H, Zelazowska, Monika A, McBride, Kevin M, Kalluri, Raghu, Allison, James, Petitprez, Florent, Fridman, Wolf Herman, Sautès-Fridman, Catherine, Hacohen, Nir, Rezvani, Katayoun, Sharma, Padmanee, Tetzlaff, Michael T, Wang, Linghua, and Wargo, Jennifer A

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Immunization, Cancer, Vaccine Related, Genetics, B-Lymphocytes, Biomarkers, Tumor, Carcinoma, Renal Cell, Cell Cycle Checkpoints, Clone Cells, Dendritic Cells, Follicular, Gene Expression Regulation, Neoplastic, Humans, Immunologic Memory, Immunotherapy, Mass Spectrometry, Melanoma, Neoplasm Metastasis, Phenotype, Prognosis, RNA-Seq, Receptors, Immunologic, Single-Cell Analysis, T-Lymphocytes, Tertiary Lymphoid Structures, Transcriptome, General Science & Technology
Abstract

Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1-10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11-15, although these have been less well-studied in ICB treatment16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter18) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.

Published
2020

12. Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy

Author

Vellano, Christopher P., White, Michael G., Andrews, Miles C., Chelvanambi, Manoj, Witt, Russell G., Daniele, Joseph R., Titus, Mark, McQuade, Jennifer L., Conforti, Fabio, Burton, Elizabeth M., Lastrapes, Matthew J., Ologun, Gabriel, Cogdill, Alexandria P., Morad, Golnaz, Prieto, Peter, Lazar, Alexander J., Chu, Yanshuo, Han, Guangchun, Khan, M. A. Wadud, Helmink, Beth, Davies, Michael A., Amaria, Rodabe N., Kovacs, Jeffrey J., Woodman, Scott E., Patel, Sapna, Hwu, Patrick, Peoples, Michael, Lee, Jeffrey E., Cooper, Zachary A., Zhu, Haifeng, Gao, Guang, Banerjee, Hiya, Lau, Mike, Gershenwald, Jeffrey E., Lucci, Anthony, Keung, Emily Z., Ross, Merrick I., Pala, Laura, Pagan, Eleonora, Segura, Rossana Lazcano, Liu, Qian, Borthwick, Mikayla S., Lau, Eric, Yates, Melinda S., Westin, Shannon N., Wani, Khalida, Tetzlaff, Michael T., Haydu, Lauren E., Mahendra, Mikhila, Ma, XiaoYan, Logothetis, Christopher, Kulstad, Zachary, Johnson, Sarah, Hudgens, Courtney W., Feng, Ningping, Federico, Lorenzo, Long, Georgina V., Futreal, P. Andrew, Arur, Swathi, Tawbi, Hussein A., Moran, Amy E., Wang, Linghua, Heffernan, Timothy P., Marszalek, Joseph R., and Wargo, Jennifer A.

Published
2022
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13. Histologic and Genomic Analysis of Conjunctival SCC in African and American Cohorts Reveal UV Light and HPV Signatures and High Tumor Mutation Burden

Author

Gleber-Netto, Frederico O., primary, Nagarajan, Priyadharsini, additional, Sagiv, Oded, additional, Pickering, Curtis R., additional, Gross, Neil, additional, Ning, Jing, additional, Yeshi, Melisachew M., additional, Mitku, Yonas, additional, Tetzlaff, Michael T., additional, and Esmaeli, Bita, additional

Published
2024
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14. Discordance in Diagnosis of Melanocytic Lesions and Its Impact on Clinical Management: A Melanoma Referral Center Experience With 1521 Cases

Author

Ronen, Shira, Rohil, Rami N. Al-, Keiser, Elizabeth, Jour, George, Nagarajan, Priyadharsini, Tetzlaff, Michael T., Curry, Jonathan L., Ivan, Doina, Middleton, Lavinia P., Torres-Cabala, Carlos A., Gershenwald, Jeffrey E., Aung, Phyu P., and Prieto, Victor G.

Subjects
Medical research, Medicine, Experimental, Medical referral -- Research, Diagnostic errors -- Research, Histology, Pathological -- Research, Melanoma -- Diagnosis -- Care and treatment -- Statistics, Health
Abstract

* Context.--Accurate diagnosis of melanocytic lesions is fundamental for appropriate clinical management. Objective.--To evaluate the degree of discordance, if any, between histopathologic diagnoses of melanocytic lesions at referring institutions and at a tertiary referral cancer center and the potential impact of such discordance on clinical management. Design.--We retrospectively identified all patients referred to our comprehensive cancer center for evaluation of a melanocytic lesion from January 2010 to January 2011. For each patient, the histopathologic diagnosis from the referring institution was compared with the histopathologic diagnosis from a dermatopathologist at our center. Discordances were classified as major if they resulted in a change in clinical management and minor if they did not. Results.--A total of 1521 cases were included. The concordance rates were 72.2% (52 of 72) for dysplastic nevus, 75.0% (15 of 20) for all other types of nevi, 91.1% (143 of 157) for melanoma in situ, 96.1% (758 of 789) for invasive melanoma, and 99.6% (478 of 480) for metastatic melanoma. Major discordances were found in 20.2% of cases (307 of 1521), and minor discordances were found in 48.8% of cases (742 of 1521). Compared with the guideline-based treatment recommendation based on the referring-institution diagnosis, the guideline-based treatment recommendation based on the cancer center diagnosis was more extensive in 5.9% (89 of 1521) of patients and less extensive in 5.0% (76 of 1521) of patients. Conclusions.--Our findings underscore the importance of secondary histopathologic review of melanocytic lesions by expert dermatopathologists because significant changes in the diagnosis, tumor classification, and/or staging may be identified, thus, resulting in critical changes in recommendations for clinical management., The diagnosis of pigmented lesions has historically been based on a systematic appraisal of the light microscopic features of the lesion. However, particularly in the case of borderline lesions, interobserver [...]

Published
2021
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15. Skin

Author

Torres-Cabala, Carlos A., Tetzlaff, Michael T., Nagarajan, Priyadharsini, Ivan, Doina, Curry, Jonathan L., Aung, Phyu P., Prieto, Victor G., Moran, Cesar A., editor, Kalhor, Neda, editor, and Weissferdt, Annikka, editor

Published
2020
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17. Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphomas: reappraisal of a provisional entity in the 2016 WHO classification of cutaneous lymphomas

Author

Guitart, Joan, Martinez-Escala, M Estela, Subtil, Antonio, Duvic, Madeleine, Pulitzer, Melissa P, Olsen, Elise A, Kim, Ellen, Rook, Alain H, Samimi, Sara S, Wood, Gary S, Girardi, Michael, Junkins-Hopkins, Jacqueline, Ivan, Doina S, Selim, M Angelica, Sable, Kimberly A, Virmani, Pooja, Pincus, Laura B, Tetzlaff, Michael T, Kim, Jinah, and Kim, Youn H

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Oncology and Carcinogenesis, Rare Diseases, Clinical Research, Clinical Trials and Supportive Activities, Hematology, Lymphoma, Cancer, Adult, Aged, Aged, 80 and over, Female, Humans, Lymphoma, T-Cell, Cutaneous, Male, Middle Aged, Skin Neoplasms, T-Lymphocytes, Cytotoxic, World Health Organization, Young Adult, Medical and Health Sciences, Pathology, Clinical sciences
Abstract

Primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma is a rare and poorly characterized variant of cutaneous lymphoma still considered a provisional entity in the latest 2016 World Health Organization Classification of Cutaneous lymphomas. We sought to better characterize and provide diagnostic and therapeutic guidance of this rare cutaneous lymphoma. Thirty-four patients with a median age of 77 years (range 19-89 years) presented primarily with extensive annular necrotic plaques or tumor lesions with frequent mucous membrane involvement. The 5-year survival was 32% with a median survival of 12 months. A subset of 17 patients had a prodrome of chronic patches prior to the development of aggressive ulcerative lesions. We identified cases with lack of CD8 or αβ T-cell receptor expression yet with similar clinical and pathological presentation. Allogeneic stem cell transplantation provided partial or complete remissions in 5/6 patients. We recommend the term primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma as this more broad designation better describes this clinical-pathologic presentation, which allows the inclusion of cases with CD8 negative and/or αβ/γδ T-cell receptor chain double-positive or double-negative expression. We have identified early skin signs of chronic patch/plaque lesions that are often misdiagnosed as eczema, psoriasis, or mycosis fungoides. Our experience confirms the poor prognosis of this entity and highlights the inefficacy of our standard therapies with the exception of allogeneic stem cell transplantation in selected cases.

Published
2017

18. Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade

Author

Andrews, Miles C., Duong, Connie P. M., Gopalakrishnan, Vancheswaran, Iebba, Valerio, Chen, Wei-Shen, Derosa, Lisa, Khan, Md Abdul Wadud, Cogdill, Alexandria P., White, Michael G., Wong, Matthew C., Ferrere, Gladys, Fluckiger, Aurélie, Roberti, Maria P., Opolon, Paule, Alou, Maryam Tidjani, Yonekura, Satoru, Roh, Whijae, Spencer, Christine N., Curbelo, Irina Fernandez, Vence, Luis, Reuben, Alexandre, Johnson, Sarah, Arora, Reetakshi, Morad, Golnaz, Lastrapes, Matthew, Baruch, Erez N., Little, Latasha, Gumbs, Curtis, Cooper, Zachary A., Prieto, Peter A., Wani, Khalida, Lazar, Alexander J., Tetzlaff, Michael T., Hudgens, Courtney W., Callahan, Margaret K., Adamow, Matthew, Postow, Michael A., Ariyan, Charlotte E., Gaudreau, Pierre-Olivier, Nezi, Luigi, Raoult, Didier, Mihalcioiu, Catalin, Elkrief, Arielle, Pezo, Rossanna C., Haydu, Lauren E., Simon, Julie M., Tawbi, Hussein A., McQuade, Jennifer, Hwu, Patrick, Hwu, Wen-Jen, Amaria, Rodabe N., Burton, Elizabeth M., Woodman, Scott E., Watowich, Stephanie, Diab, Adi, Patel, Sapna P., Glitza, Isabella C., Wong, Michael K., Zhao, Li, Zhang, Jianhua, Ajami, Nadim J., Petrosino, Joseph, Jenq, Robert R., Davies, Michael A., Gershenwald, Jeffrey E., Futreal, P. Andrew, Sharma, Padmanee, Allison, James P., Routy, Bertrand, Zitvogel, Laurence, and Wargo, Jennifer A.

Published
2021
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21. Author Correction: Neoadjuvant relatlimab and nivolumab in resectable melanoma

Author

Amaria, Rodabe N., Postow, Michael, Burton, Elizabeth M., Tetzlaff, Michael T., Ross, Merrick I., Torres-Cabala, Carlos, Glitza, Isabella C., Duan, Fei, Milton, Denái R., Busam, Klaus, Simpson, Lauren, McQuade, Jennifer L., Wong, Michael K., Gershenwald, Jeffrey E., Lee, Jeffrey E., Goepfert, Ryan P., Keung, Emily Z., Fisher, Sarah B., Betof-Warner, Allison, Shoushtari, Alexander N., Callahan, Margaret, Coit, Daniel, Bartlett, Edmund K., Bello, Danielle, Momtaz, Parisa, Nicholas, Courtney, Gu, Aidi, Zhang, Xuejun, Korivi, Brinda Rao, Patnana, Madhavi, Patel, Sapna P., Diab, Adi, Lucci, Anthony, Prieto, Victor G., Davies, Michael A., Allison, James P., Sharma, Padmanee, Wargo, Jennifer A., Ariyan, Charlotte, and Tawbi, Hussein A.

Published
2023
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22. Author Correction: Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy

Author

Vellano, Christopher P., White, Michael G., Andrews, Miles C., Chelvanambi, Manoj, Witt, Russell G., Daniele, Joseph R., Titus, Mark, McQuade, Jennifer L., Conforti, Fabio, Burton, Elizabeth M., Lastrapes, Matthew J., Ologun, Gabriel, Cogdill, Alexandria P., Morad, Golnaz, Prieto, Peter, Lazar, Alexander J., Chu, Yanshuo, Han, Guangchun, Khan, M. A. Wadud, Helmink, Beth, Davies, Michael A., Amaria, Rodabe N., Kovacs, Jeffrey J., Woodman, Scott E., Patel, Sapna, Hwu, Patrick, Peoples, Michael, Lee, Jeffrey E., Cooper, Zachary A., Zhu, Haifeng, Gao, Guang, Banerjee, Hiya, Lau, Mike, Gershenwald, Jeffrey E., Lucci, Anthony, Keung, Emily Z., Ross, Merrick I., Pala, Laura, Pagan, Eleonora, Segura, Rossana Lazcano, Liu, Qian, Borthwick, Mikayla S., Lau, Eric, Yates, Melinda S., Westin, Shannon N., Wani, Khalida, Tetzlaff, Michael T., Haydu, Lauren E., Mahendra, Mikhila, Ma, XiaoYan, Logothetis, Christopher, Kulstad, Zachary, Johnson, Sarah, Hudgens, Courtney W., Feng, Ningping, Federico, Lorenzo, Long, Georgina V., Futreal, P. Andrew, Arur, Swathi, Tawbi, Hussein A., Moran, Amy E., Wang, Linghua, Heffernan, Timothy P., Marszalek, Joseph R., and Wargo, Jennifer A.

Published
2023
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23. T-Cell Repertoire in Combination with T-Cell Density Predicts Clinical Outcomes in Patients with Merkel Cell Carcinoma

Author

Farah, Maya, Reuben, Alexandre, Spassova, Ivelina, Yang, Richard K., Kubat, Linda, Nagarajan, Priyadharsini, Ning, Jing, Li, Wen, Aung, Phyu P., Curry, Jonathan L., Torres-Cabala, Carlos A., Hudgens, Courtney W., Ugurel, Selma, Schadendorf, Dirk, Gumbs, Curtis, Little, Latasha D., Futreal, Andrew, Wistuba, Ignacio I., Prieto, Victor G., Wang, Linghua, Wong, Michael K., Wargo, Jennifer A., Becker, Jürgen C., and Tetzlaff, Michael T.

Published
2020
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25. Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC)

Author

Menzies, Alexander M., Amaria, Rodabe N., Rozeman, Elisa A., Huang, Alexander C., Tetzlaff, Michael T., van de Wiel, Bart A., Lo, Serigne, Tarhini, Ahmad A., Burton, Elizabeth M., Pennington, Thomas E., Saw, Robyn P. M., Xu Xiaowei, Karakousis, Giorgos C., Ascierto, Paolo A., Spillane, Andrew J., Van Akkooi, Alexander C. J., and Davies, Michael A.

Subjects
Neoadjuvant therapy -- Usage -- Patient outcomes, Immunotherapy -- Usage -- Patient outcomes, Melanoma -- Drug therapy -- Patient outcomes, Molecular targeted therapy -- Usage -- Patient outcomes, Biological sciences, Health
Abstract

The association among pathological response, recurrence-free survival (RFS) and overall survival (OS) with neoadjuvant therapy in melanoma remains unclear. In this study, we pooled data from six clinical trials of anti-PD-1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192 patients were included; 141 received immunotherapy (104, combination of ipilimumab and nivolumab; 37, anti-PD-1 monotherapy), and 51 received targeted therapy. A pathological complete response (pCR) occurred in 40% of patients: 47% with targeted therapy and 33% with immunotherapy (43% combination and 20% monotherapy). pCR correlated with improved RFS (pCR 2-year 89% versus no pCR 50%, P < 0.001) and OS (pCR 2-year OS 95% versus no pCR 83%, P = 0.027). In patients with pCR, near pCR or partial pathological response with immunotherapy, very few relapses were seen (2-year RFS 96%), and, at this writing, no patient has died from melanoma, whereas, even with pCR from targeted therapy, the 2-year RFS was only 79%, and OS was only 91%. Pathological response should be an early surrogate endpoint for clinical trials and a new benchmark for development and approval in melanoma. A pooled analysis of neoadjuvant immunotherapy trials in melanoma shows that the degree of pathological response associates with patient survival and might represent a surrogate marker for long-term outcomes., Author(s): Alexander M. Menzies [sup.1] [sup.2] [sup.3] , Rodabe N. Amaria [sup.4] , Elisa A. Rozeman [sup.5] , Alexander C. Huang [sup.6] [sup.7] , Michael T. Tetzlaff [sup.4] , Bart [...]

Published
2021
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27. Prognostic model for patient survival in primary anorectal mucosal melanoma: stage at presentation determines relevance of histopathologic features

Author

Nagarajan, Priyadharsini, Piao, Jin, Ning, Jing, Noordenbos, Laura E., Curry, Jonathan L., Torres-Cabala, Carlos A., Diwan, A.Hafeez, Ivan, Doina, Aung, Phyu P., Ross, Merrick I., Royal, Richard E., Wargo, Jennifer A., Wang, Wei-Lien, Samdani, Rashmi, Lazar, Alexander J., Rashid, Asif, Davies, Michael A., Prieto, Victor G., Gershenwald, Jeffrey E., and Tetzlaff, Michael T.

Published
2020
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29. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance

Author

Kaur, Amanpreet, Webster, Marie R, Marchbank, Katie, Behera, Reeti, Ndoye, Abibatou, Kugel, Curtis H, Dang, Vanessa M, Appleton, Jessica, O’Connell, Michael P, Cheng, Phil, Valiga, Alexander A, Morissette, Rachel, McDonnell, Nazli B, Ferrucci, Luigi, Kossenkov, Andrew V, Meeth, Katrina, Tang, Hsin-Yao, Yin, Xiangfan, Wood, William H, Lehrmann, Elin, Becker, Kevin G, Flaherty, Keith T, Frederick, Dennie T, Wargo, Jennifer A, Cooper, Zachary A, Tetzlaff, Michael T, Hudgens, Courtney, Aird, Katherine M, Zhang, Rugang, Xu, Xiaowei, Liu, Qin, Bartlett, Edmund, Karakousis, Giorgos, Eroglu, Zeynep, Lo, Roger S, Chan, Matthew, Menzies, Alexander M, Long, Georgina V, Johnson, Douglas B, Sosman, Jeffrey, Schilling, Bastian, Schadendorf, Dirk, Speicher, David W, Bosenberg, Marcus, Ribas, Antoni, and Weeraratna, Ashani T

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Adult, Aging, Animals, Cell Line, Tumor, Culture Media, Conditioned, DNA Damage, DNA-(Apurinic or Apyrimidinic Site) Lyase, Disease Progression, Drug Resistance, Neoplasm, Fibroblasts, Humans, Indoles, Male, Melanoma, Membrane Proteins, Mice, Microphthalmia-Associated Transcription Factor, Middle Aged, Molecular Targeted Therapy, Neoplasm Metastasis, Neovascularization, Pathologic, Oxidative Stress, Phenotype, Reactive Oxygen Species, Sulfonamides, Tumor Microenvironment, Vemurafenib, Wnt Signaling Pathway, Wnt1 Protein, beta Catenin, General Science & Technology
Abstract

Cancer is a disease of ageing. Clinically, aged cancer patients tend to have a poorer prognosis than young. This may be due to accumulated cellular damage, decreases in adaptive immunity, and chronic inflammation. However, the effects of the aged microenvironment on tumour progression have been largely unexplored. Since dermal fibroblasts can have profound impacts on melanoma progression, we examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy. Here we find that aged fibroblasts secrete a Wnt antagonist, sFRP2, which activates a multi-step signalling cascade in melanoma cells that results in a decrease in β-catenin and microphthalmia-associated transcription factor (MITF), and ultimately the loss of a key redox effector, APE1. Loss of APE1 attenuates the response of melanoma cells to DNA damage induced by reactive oxygen species, rendering the cells more resistant to targeted therapy (vemurafenib). Age-related increases in sFRP2 also augment both angiogenesis and metastasis of melanoma cells. These data provide an integrated view of how fibroblasts in the aged microenvironment contribute to tumour progression, offering new possibilities for the design of therapy for the elderly.

Published
2016

32. Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium

Author

Andrews, Miles C, Berry, Donald A, Block, Matthew S, Boland, Genevieve M, Bollin, Kathryn B, Carlino, Matteo S, Carvajal, Richard D, Cohen, Jonathan, Davar, Diwakar, Delman, Keith A, Dummer, Reinhard, Farwell, Michael D, Fisher, David E, Fusi, Alberto, Glitza, Isabella C, de Gruijl, Tanja D, Gyorki, David E, Hauschild, Axel, Hieken, Tina J, Larkin, James, Lawson, David H, Lebbe, Celeste, Lee, Jeffrey E, Lowe, Michael C, Luke, Jason J, McArthur, Grant A, McDermott, David F, McQuade, Jennifer L, Mitchell, Tara C, Petrella, Teresa M, Prieto, Peter A, Puzanov, Igor, Robert, Caroline, Salama, April K, Sandhu, Shaneen, Schadendorf, Dirk, Shoushtari, Alexander N, Sosman, Jeffrey A, Swetter, Susan M, Tanabe, Ken K, Turajlic, Samra, Tyler, Douglas S, Woodman, Scott E, Wright, Frances C, Zager, Jonathan S, Amaria, Rodabe N, Menzies, Alexander M, Burton, Elizabeth M, Scolyer, Richard A, Tetzlaff, Michael T, Antdbacka, Robert, Ariyan, Charlotte, Bassett, Roland, Carter, Brett, Daud, Adil, Faries, Mark, Fecher, Leslie A, Flaherty, Keith T, Gershenwald, Jeffrey E, Hamid, Omid, Hong, Angela, Kirkwood, John M, Lo, Serigne, Margolin, Kim, Messina, Jane, Postow, Michael A, Rizos, Helen, Ross, Merrick I, Rozeman, Elisa A, Saw, Robyn P M, Sondak, Vernon, Sullivan, Ryan J, Taube, Janis M, Thompson, John F, van de Wiel, Bart A, Eggermont, Alexander M, Davies, Michael A, Ascierto, Paolo A, Spillane, Andrew J, van Akkooi, Alexander C J, Wargo, Jennifer A, Blank, Christian U, Tawbi, Hussein A, and Long, Georgina V

Published
2019
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42. Spatially resolved analyses link genomic and immune diversity and reveal unfavorable neutrophil activation in melanoma

Author

Mitra, Akash, Andrews, Miles C., Roh, Whijae, De Macedo, Marianna Petaccia, Hudgens, Courtney W., Carapeto, Fernando, Singh, Shailbala, Reuben, Alexandre, Wang, Feng, Mao, Xizeng, Song, Xingzhi, Wani, Khalida, Tippen, Samantha, Ng, Kwok-Shing, Schalck, Aislyn, Sakellariou-Thompson, Donald A., Chen, Eveline, Reddy, Sangeetha M., Spencer, Christine N., Wiesnoski, Diana, Little, Latasha D., Gumbs, Curtis, Cooper, Zachary A., Burton, Elizabeth M., Hwu, Patrick, Davies, Michael A., Zhang, Jianhua, Bernatchez, Chantale, Navin, Nicholas, Sharma, Padmanee, Allison, James P., Wargo, Jennifer A., Yee, Cassian, Tetzlaff, Michael T., Hwu, Wen-Jen, Lazar, Alexander J., and Futreal, P. Andrew

Published
2020
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