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2. Humoral Immune Response against Nontargeted Tumor Antigens after Treatment with Sipuleucel-T and Its Association with Improved Clinical Outcome

Author

GuhaThakurta, Debraj, Sheikh, Nadeem A, Fan, Li-Qun, Kandadi, Harini, Meagher, T Craig, Hall, Simon J, Kantoff, Philip W, Higano, Celestia S, Small, Eric J, Gardner, Thomas A, Bailey, Kate, Vu, Tuyen, DeVries, Todd, Whitmore, James B, Frohlich, Mark W, Trager, James B, and Drake, Charles G

Subjects
Urologic Diseases, Clinical Research, Cancer, Immunization, Prostate Cancer, Aged, Antigens, Neoplasm, Cancer Vaccines, Humans, Immunity, Humoral, Immunoglobulin G, Immunotherapy, Kaplan-Meier Estimate, Male, Middle Aged, Prostate-Specific Antigen, Prostatic Neoplasms, Castration-Resistant, Tissue Extracts, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeAntitumor activity of cancer immunotherapies may elicit immune responses to nontargeted (secondary) tumor antigens, or antigen spread. We evaluated humoral antigen spread after treatment with sipuleucel-T, an immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC), designed to target prostatic acid phosphatase (PAP; primary antigen).Experimental designSerum samples from patients with mCRPC enrolled in the placebo-controlled phase III IMPACT study (evaluable n = 142) were used to assess humoral antigen spread after treatment with sipuleucel-T. Immunoglobulin G (IgG) responses to self-antigens (including tumor antigens) were surveyed using protein microarrays and confirmed using Luminex xMAP. IgG responses were subsequently validated in ProACT (n = 33), an independent phase II study of sipuleucel-T. Association of IgG responses with overall survival (OS) was assessed using multivariate Cox models adjusted for baseline prostate-specific antigen (PSA) and lactate dehydrogenase levels.ResultsIn patients from IMPACT and ProACT, levels of IgG against multiple secondary antigens, including PSA, KLK2/hK2, K-Ras, E-Ras, LGALS8/PCTA-1/galectin-8, and LGALS3/galectin-3, were elevated after treatment with sipuleucel-T (P < 0.01), but not control. IgG responses (≥ 2-fold elevation posttreatment) occurred in ≥ 25% of patients, appeared by 2 weeks after sipuleucel-T treatment, and persisted for up to 6 months. IgG responses to PSA and LGALS3 were associated with improved OS in sipuleucel-T-treated patients from IMPACT (P ≤ 0.05).ConclusionsSipuleucel-T induced humoral antigen spread in patients with mCRPC. IgG responses were associated with improved OS in IMPACT. The methods and results reported may identify pharmacodynamic biomarkers of clinical outcome after sipuleucel-T treatment, and help in clinical assessments of other cancer immunotherapies. See related commentary by Hellstrom and Hellstrom, p. 3581.

Published
2015

4. Supplementary Figure SF2 from Humoral Immune Response against Nontargeted Tumor Antigens after Treatment with Sipuleucel-T and Its Association with Improved Clinical Outcome

Author

GuhaThakurta, Debraj, primary, Sheikh, Nadeem A., primary, Fan, Li-Qun, primary, Kandadi, Harini, primary, Meagher, T. Craig, primary, Hall, Simon J., primary, Kantoff, Philip W., primary, Higano, Celestia S., primary, Small, Eric J., primary, Gardner, Thomas A., primary, Bailey, Kate, primary, Vu, Tuyen, primary, DeVries, Todd, primary, Whitmore, James B., primary, Frohlich, Mark W., primary, Trager, James B., primary, and Drake, Charles G., primary

Published
2023
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5. Supplementary Materials and Methods, Tables ST1-13 from Humoral Immune Response against Nontargeted Tumor Antigens after Treatment with Sipuleucel-T and Its Association with Improved Clinical Outcome

Author

GuhaThakurta, Debraj, primary, Sheikh, Nadeem A., primary, Fan, Li-Qun, primary, Kandadi, Harini, primary, Meagher, T. Craig, primary, Hall, Simon J., primary, Kantoff, Philip W., primary, Higano, Celestia S., primary, Small, Eric J., primary, Gardner, Thomas A., primary, Bailey, Kate, primary, Vu, Tuyen, primary, DeVries, Todd, primary, Whitmore, James B., primary, Frohlich, Mark W., primary, Trager, James B., primary, and Drake, Charles G., primary

Published
2023
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8. Humanization of T cell–mediated immunity in mice

Author

Moore, Michael J., primary, Zhong, Maggie, additional, Hansen, Johanna, additional, Gartner, Hans, additional, Grant, Craig, additional, Huang, Mei, additional, Harris, Faith M., additional, Tu, Naxin, additional, Bowerman, Natalie A., additional, Edelmann, Kurt H., additional, Barry, Thomas, additional, Herbin, Olivier, additional, Tay, Chin-Siean, additional, DiLillo, David J., additional, Decker, Corinne E., additional, Levenkova, Natasha, additional, Shevchuk, James, additional, Dhanik, Ankur, additional, Meagher, Karoline A., additional, Karr, Amanda, additional, Roos, Jan, additional, Lee, Wen-yi, additional, Suh, David, additional, Eckersdorff, Mark, additional, Meagher, T. Craig, additional, Koss, Matthew, additional, Esau, Lakeisha, additional, Sleeman, Matthew A., additional, Babb, Robert, additional, Chen, Gang, additional, Kyratsous, Christos A., additional, Poueymirou, William T., additional, McWhirter, John R., additional, Voronina, Vera A., additional, Guo, Chunguang, additional, Gurer, Cagan, additional, Yancopoulos, George D., additional, Murphy, Andrew J., additional, and Macdonald, Lynn E., additional

Published
2021
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12. Abnormalities on diffusion weighted magnetic resonance imaging performed several weeks after a minor stroke or transient ischaemic attack. (Paper)

Author

Schulz, U.G.R., Briley, D., Meagher, T., Molyneux, A., and Rothwell, P.M.

Subjects
Stroke (Disease) -- Prognosis, Cerebral ischemia -- Prognosis, Cerebral circulation -- Abnormalities -- Medical examination -- Methods, Diagnostic imaging -- Methods -- Evaluation, Health, Psychology and mental health, Evaluation, Medical examination, Prognosis, Abnormalities, Methods
Abstract

Objectives: Diffusion weighted brain imaging (DWI) is used in acute stroke, and also shows an acute ischaemic lesion in most transient ischamic attack (TIA) patients scanned acutely. However, it may [...]

Published
2003

23. REGN5458, a Bispecific BCMAxCD3 T Cell Engaging Antibody, Demonstrates Robust In Vitro and In Vivo Anti-Tumor Efficacy in Multiple Myeloma Models, Comparable to That of BCMA CAR T Cells

Author

Dilillo, David J, primary, Olson, Kara, additional, Mohrs, Katja, additional, Meagher, T. Craig, additional, Bray, Kevin, additional, Sineshchekova, Olga, additional, Startz, Thomas, additional, Retter, Marc, additional, Godin, Stephen, additional, Delfino, Frank, additional, Lin, John, additional, Smith, Eric, additional, Thurston, Olin Gavin, additional, and Kirshner, Jessica R., additional

Published
2018
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26. Green plants in the red: A baseline global assessment for the IUCN Sampled Red List Index for Plants

Author

Brummitt, N, Bachman, S, Griffiths-lee, J, Lutz, M, Moat, J, Farjon, A, Donaldson, J, Hilton-taylor, C, Meagher, T, Albuquerque, S, Aletrari, E, Andrews, A, Atchison, G, Baloch, E, Barlozzini, B, Brunazzi, A, Carretero, J, Celesti, M, Chadburn, H, Cianfoni, E, Cockel, C, Coldwell, V, Concetti, B, Contu, S, Crook, V, Dyson, P, Gardiner, L, Ghanim, N, Greene, H, Groom, A, Harker, R, Hopkins, D, Khela, S, Lakeman-fraser, P, Lindon, H, Lockwood, H, Loftus, C, Lombrici, D, Lopez-poveda, L, Lyon, J, Malcolm-tompkins, P, Mcgregor, K, Moreno, L, Murray, L, Nazar, K, Power, E, Quiton Tuijtelaars, M, Salter, R, Segrott, R, Thacker, H, Thomas, L, Tingvoll, S, Watkinson, G, Wojtaszekova, K, Nic Lughadha, E, Brummitt, Neil A, Bachman, Steven P, Griffiths-lee, Janine, Lutz, Maiko, Moat, Justin F, Farjon, Aljos, Donaldson, John S, Hilton-taylor, Craig, Meagher, Thomas R, Albuquerque, Sara, Aletrari, Elina, Andrews, A. Kei, Atchison, Guy, Baloch, Elisabeth, Barlozzini, Barbara, Brunazzi, Alice, Carretero, Julia, Celesti, Marco, Chadburn, Helen, Cianfoni, Eduardo, Cockel, Chris, Coldwell, Vanessa, Concetti, Benedetta, Contu, Sara, Crook, Vicki, Dyson, Philippa, Gardiner, Lauren, Ghanim, Nadia, Greene, Hannah, Groom, Alice, Harker, Ruth, Hopkins, Della, Khela, Sonia, Lakeman-fraser, Poppy, Lindon, Heather, Lockwood, Helen, Loftus, Christine, Lombrici, Debora, Lopez-poveda, Lucia, Lyon, James, Malcolm-tompkins, Patricia, Mcgregor, Kirsty, Moreno, Laura, Murray, Linda, Nazar, Keara, Power, Emily, Quiton Tuijtelaars, Mireya, Salter, Ruth, Segrott, Robert, Thacker, Hannah, Thomas, Leighton J, Tingvoll, Sarah, Watkinson, Gemma, Wojtaszekova, Katerina, Nic Lughadha, Eimear M., Brummitt, N, Bachman, S, Griffiths-lee, J, Lutz, M, Moat, J, Farjon, A, Donaldson, J, Hilton-taylor, C, Meagher, T, Albuquerque, S, Aletrari, E, Andrews, A, Atchison, G, Baloch, E, Barlozzini, B, Brunazzi, A, Carretero, J, Celesti, M, Chadburn, H, Cianfoni, E, Cockel, C, Coldwell, V, Concetti, B, Contu, S, Crook, V, Dyson, P, Gardiner, L, Ghanim, N, Greene, H, Groom, A, Harker, R, Hopkins, D, Khela, S, Lakeman-fraser, P, Lindon, H, Lockwood, H, Loftus, C, Lombrici, D, Lopez-poveda, L, Lyon, J, Malcolm-tompkins, P, Mcgregor, K, Moreno, L, Murray, L, Nazar, K, Power, E, Quiton Tuijtelaars, M, Salter, R, Segrott, R, Thacker, H, Thomas, L, Tingvoll, S, Watkinson, G, Wojtaszekova, K, Nic Lughadha, E, Brummitt, Neil A, Bachman, Steven P, Griffiths-lee, Janine, Lutz, Maiko, Moat, Justin F, Farjon, Aljos, Donaldson, John S, Hilton-taylor, Craig, Meagher, Thomas R, Albuquerque, Sara, Aletrari, Elina, Andrews, A. Kei, Atchison, Guy, Baloch, Elisabeth, Barlozzini, Barbara, Brunazzi, Alice, Carretero, Julia, Celesti, Marco, Chadburn, Helen, Cianfoni, Eduardo, Cockel, Chris, Coldwell, Vanessa, Concetti, Benedetta, Contu, Sara, Crook, Vicki, Dyson, Philippa, Gardiner, Lauren, Ghanim, Nadia, Greene, Hannah, Groom, Alice, Harker, Ruth, Hopkins, Della, Khela, Sonia, Lakeman-fraser, Poppy, Lindon, Heather, Lockwood, Helen, Loftus, Christine, Lombrici, Debora, Lopez-poveda, Lucia, Lyon, James, Malcolm-tompkins, Patricia, Mcgregor, Kirsty, Moreno, Laura, Murray, Linda, Nazar, Keara, Power, Emily, Quiton Tuijtelaars, Mireya, Salter, Ruth, Segrott, Robert, Thacker, Hannah, Thomas, Leighton J, Tingvoll, Sarah, Watkinson, Gemma, Wojtaszekova, Katerina, and Nic Lughadha, Eimear M.

Abstract

Plants provide fundamental support systems for life on Earth and are the basis for all terrestrial ecosystems; a decline in plant diversity will be detrimental to all other groups of organisms including humans. Decline in plant diversity has been hard to quantify, due to the huge numbers of known and yet to be discovered species and the lack of an adequate baseline assessment of extinction risk against which to track changes. The biodiversity of many remote parts of the world remains poorly known, and the rate of new assessments of extinction risk for individual plant species approximates the rate at which new plant species are described. Thus the question 'How threatened are plants?' is still very difficult to answer accurately. While completing assessments for each species of plant remains a distant prospect, by assessing a randomly selected sample of species the Sampled Red List Index for Plants gives, for the first time, an accurate view of how threatened plants are across the world. It represents the first key phase of ongoing efforts to monitor the status of the world's plants. More than 20% of plant species assessed are threatened with extinction, and the habitat with the most threatened species is overwhelmingly tropical rain forest, where the greatest threat to plants is anthropogenic habitat conversion, for arable and livestock agriculture, and harvesting of natural resources. Gymnosperms (e.g. conifers and cycads) are the most threatened group, while a third of plant species included in this study have yet to receive an assessment or are so poorly known that we cannot yet ascertain whether they are threatened or not. This study provides a baseline assessment from which trends in the status of plant biodiversity can be measured and periodically reassessed.

Published
2015

44. Ambulatory care training during core internal medicine residency training: the Canadian experience

Author

McLeod, P J and Meagher, T W

Subjects
education, health care economics and organizations, Research Article
Abstract

OBJECTIVE: To determine the status of ambulatory care training of core internal medicine residents in Canada. DESIGN: Mail survey. PARTICIPANTS: All 16 program directors of internal medicine residency training programs in Canada. OUTCOME MEASURES: The nature and amount of ambulatory care training experienced by residents, information about the faculty tutors, and the sources and types of patients seen by the residents. As well, the program directors were asked for their opinions on the ideal ambulatory care program and the kinds of teaching skills required of tutors. RESULTS: All of the directors responded. Fifteen stated that the ambulatory care program is mandatory, and the other stated that it is an elective. Block rotations are more common than continuity-of-care assignments. In 12 of the programs 10% or less of the overall training time is spent in ambulatory care. In 11 the faculty tutors comprise a mixture of generalists and subspecialists. The tutors simultaneously care for patients and teach residents in the ambulatory care setting in 14 of the schools. Most are paid through fee-for-service billing. The respondents felt that the ideal program should contain a mix of general and subspecialty ambulatory care training. There was no consensus on whether it should be a block or continuity-of-care experience, but the directors felt that consultation and communication skills should be emphasized regardless of which type of experience prevails. CONCLUSIONS: Although there is a widespread commitment to provide core internal medicine residents with experience in ambulatory care, there is little uniformity in how this is achieved in Canadian training programs.

Published
1993

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