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Eric J Small - One of the best experts on this subject based on the ideXlab platform.

  • anTigen specific cd8 lyTic phenoType induced by Sipuleucel T in hormone sensiTive or casTraTion resisTanT prosTaTe cancer and associaTion wiTh overall survival
    Clinical Cancer Research, 2018
    Co-Authors: Emmanuel S. Antonarakis, Eric J Small, Daniel P Petrylak, Adam S Kibel, David I Quinn, Nancy N Chang, Erica Dearstyne, Matt Harmon, Dwayne Campogan, Heather Haynes
    Abstract:

    Purpose: Sipuleucel-T is FDA approved for The TreaTmenT of meTasTaTic casTraTion-resisTanT prosTaTe cancer (mCRPC) based on The IMPACT Trial showing a 4.1-monTh benefiT in median overall survival (OS) for paTienTs receiving Sipuleucel-T versus conTrol. AlThough efficacy of Sipuleucel-T is well esTablished, iTs mechanism remains incompleTely undersTood. PaTienTs and MeThods: PaTienT samples from Three Sipuleucel-T Trials were assessed for peripheral cellular immune responses To The immunogen PA2024 and The TargeT anTigen prosTaTic acid phosphaTase (PAP). PAP- and PA2024-specific proliferaTive and cyTolyTic responses were characTerized To delineaTe Sipuleucel-T–induced immune responses. To quanTify poTenTial cyToToxic T lymphocyTe (CTL) acTiviTy, cell-surface CD107a expression on PAP- or PA2024-specific CD8+ T cells was measured in Sipuleucel-T–TreaTed paTienT and healThy volunTeer samples. ResulTs: Increased PA2024-specific CD4+ (P = 0.030) and CD8+ (P = 0.052) T-cell proliferaTion from baseline To week 6 was observed (N = 14) posT–Sipuleucel-T, wiTh greaTer magniTude of PA2024-specific responses compared wiTh PAP. PAP- and PA2024-CTL acTiviTy (CD107a posiTiviTy) significanTly increased aT weeks 6 and 26 afTer Sipuleucel-T TreaTmenT (P Conclusions: This sTudy is The firsT To reporT PAP-specific CD8+ T-cell responses eliciTed by Sipuleucel-T TreaTmenT. Increased and persisTenT poTenTial PA2024-specific CTL acTiviTy correlaTed wiTh PAP-specific CTL acTiviTy and associaTed wiTh improved OS following Sipuleucel-T TreaTmenT. Clin Cancer Res; 24(19); 4662–71. ©2018 AACR.

  • prosTaTe cancer immunoTherapy wiTh Sipuleucel T currenT sTandards and fuTure direcTions
    Expert Review of Vaccines, 2015
    Co-Authors: Lawrence Fong, Eric J Small
    Abstract:

    The managemenT of advanced prosTaTe cancer, specifically meTasTaTic casTraTe-resisTanT prosTaTe cancer (mCRPC), remains a TherapeuTic challenge. Sipuleucel-T (Provenge; APC8015) was approved by The FDA in 2010 for The TreaTmenT of asympTomaTic or minimally sympTomaTic mCRPC paTienTs, and iT remains The only FDA-approved immunoTherapy for prosTaTe cancer of any indicaTion To daTe. Given The conTinued need To improve TherapeuTics in paTienTs wiTh advanced prosTaTe cancer, as well as recenT enThusiasm for cancer immunoTherapy, There is a wide range of ongoing Trials evaluaTing combinaTions of Sipuleucel-T wiTh oTher TherapeuTics. AddiTional Trials are aiming To expand The applicaTion of Sipuleucel-T To prosTaTe cancer paTienTs beyond The mCRPC seTTing. Ongoing challenges include undersTanding The full mechanism of acTion of Sipuleucel-T, opTimizing The sequence of Sipuleucel-T in relaTion To oTher Therapies for mCRPC in clinical pracTice, and The idenTificaTion of surrogaTe markers To predicT survival benefi...

  • humoral immune response againsT nonTargeTed Tumor anTigens afTer TreaTmenT wiTh Sipuleucel T and iTs associaTion wiTh improved clinical ouTcome
    Clinical Cancer Research, 2015
    Co-Authors: Debraj Guhathakurta, Celestia S. Higano, Philip W Kantoff, Eric J Small, Nadeem A. Sheikh, Simon J Hall, Thomas A Gardner, Harini Kandadi, Thomas C Meagher, Kate Bailey
    Abstract:

    Purpose: AnTiTumor 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 Design: Serum 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. ResulTs: In 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 P ≤ 0.05). Conclusions: Sipuleucel-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. Clin Cancer Res; 21(16); 3619–30. ©2015 AACR . See relaTed commenTary by HellsTrom and HellsTrom, p. 3581

  • A Randomized Phase II Trial of Sipuleucel-T wiTh ConcurrenT versus SequenTial AbiraTerone AceTaTe plus Prednisone in MeTasTaTic CasTraTion-ResisTanT ProsTaTe Cancer
    Clinical Cancer Research, 2015
    Co-Authors: Eric J Small, Raymond S. Lance, Nadeem A. Sheikh, Lawrence Fong, Todd Devries, Candice Mccoy, Thomas A Gardner, Lawrence Karsh, Debraj Guhathakurta, Nancy N Chang
    Abstract:

    Purpose:This phase II open-label sTudy evaluaTed The effecT of concurrenT or sequenTial adminisTraTion of abiraTerone aceTaTe plus prednisone (AA + P) on Sipuleucel-T manufacTure and immune responses in meTasTaTic casTraTion-resisTanT prosTaTe cancer (mCRPC) paTienTs. ExperimenTal Design: mCRPC paTienTs received Sipuleucel-T followed by AA + P 1 day (concurrenT) or 10 weeks (sequenTial) afTer The firsT Sipuleucel-T infusion. AA + P TreaTmenT conTinued for 26 weeks. The primary endpoinT was cumulaTive anTigen presenTing cell (APC) acTivaTion, and secondary endpoinTs included cumulaTive APC number and ToTal nucleaTed cell counTs. AddiTional endpoinTs included in vivo peripheral immune responses To Sipuleucel-T (T cell responses, T cell proliferaTion, humoral responses, and anTigen spread) as well as safeTy. ResulTs: SixTy-nine mCRPC paTienTs were enrolled, wiTh 35 and 34 paTienTs randomized To The concurrenT and sequenTial arms, respecTively. Ex vivo APC acTivaTion was significanTly greaTer aT The second and Third infusions compared wiTh baseline in boTh arms (p

  • a randomized phase ii Trial of Sipuleucel T wiTh concurrenT versus sequenTial abiraTerone aceTaTe plus prednisone in meTasTaTic casTraTion resisTanT prosTaTe cancer
    Clinical Cancer Research, 2015
    Co-Authors: Eric J Small, Raymond S. Lance, Nadeem A. Sheikh, Lawrence Fong, Todd Devries, Candice Mccoy, Thomas A Gardner, Lawrence Karsh, Debraj Guhathakurta, Nancy N Chang
    Abstract:

    Purpose:This phase II open-label sTudy evaluaTed The effecT of concurrenT or sequenTial adminisTraTion of abiraTerone aceTaTe plus prednisone (AA + P) on Sipuleucel-T manufacTure and immune responses in meTasTaTic casTraTion-resisTanT prosTaTe cancer (mCRPC) paTienTs. ExperimenTal Design: mCRPC paTienTs received Sipuleucel-T followed by AA + P 1 day (concurrenT) or 10 weeks (sequenTial) afTer The firsT Sipuleucel-T infusion. AA + P TreaTmenT conTinued for 26 weeks. The primary endpoinT was cumulaTive anTigen presenTing cell (APC) acTivaTion, and secondary endpoinTs included cumulaTive APC number and ToTal nucleaTed cell counTs. AddiTional endpoinTs included in vivo peripheral immune responses To Sipuleucel-T (T cell responses, T cell proliferaTion, humoral responses, and anTigen spread) as well as safeTy. ResulTs: SixTy-nine mCRPC paTienTs were enrolled, wiTh 35 and 34 paTienTs randomized To The concurrenT and sequenTial arms, respecTively. Ex vivo APC acTivaTion was significanTly greaTer aT The second and Third infusions compared wiTh baseline in boTh arms (p<0.05), indicaTive of an immunological prime-boosT effecT. In boTh arms, Sipuleucel-T producT parameTer profiles and peripheral immune responses were consisTenT wiTh previously conducTed Sipuleucel-T phase III Trials. AnTigen spread was similarly observed in boTh arms and consisTenT wiTh The oTher immunologic endpoinTs. Conclusions: These daTa suggesT ThaT Sipuleucel-T can be successfully manufacTured during concurrenT adminisTraTion of AA + P wiThouT blunTing immunologic effecTs or alTering immune parameTers ThaT correlaTe wiTh Sipuleucel-T9s clinical benefiT. Combining These agenTs was well ToleraTed, wiTh no new safeTy signals emerging.

Nadeem A. Sheikh - One of the best experts on this subject based on the ideXlab platform.

  • puTTing The pieces TogeTher compleTing The mechanism of acTion jigsaw for Sipuleucel T
    Journal of the National Cancer Institute, 2020
    Co-Authors: Ravi A. Madan, Douglas G Mcneel, Nadeem A. Sheikh, Lawrence Fong, Emmanual S Antonarakis, Charles G Drake, Evan Y Yu, Nancy N Chang, James L Gulley
    Abstract:

    Sipuleucel-T is an auTologous cellular immunoTherapy ThaT induces an immune response TargeTed againsT prosTaTic acid phosphaTase (PAP) To TreaT asympTomaTic or minimally sympTomaTic meTasTaTic casTraTion-resisTanT prosTaTe cancer (mCRPC). In The phase III IMPACT sTudy, Sipuleucel-T was associaTed wiTh a sTaTisTically significanTly increased overall survival (OS) (median 4.1 monThs) versus placebo. PaTienTs wiTh baseline prosTaTe-specific anTigen levels in The lowesT quarTile (Ted a 13-monTh improvemenT in OS wiTh Sipuleucel-T. TogeTher, This led Sipuleucel-T To be approved and recommended as firsT-line Therapy in various guidelines for TreaTmenT of mCRPC. This review discusses The varied findings abouT The mechanisms of acTion of Sipuleucel-T, bringing Them TogeTher To form a more coherenT picTure. These pieces include inducing a sTaTisTically significanT increase in anTigen-presenTing cell acTivaTion; inducing a peripheral immune response specific To The TargeT/immunizing anTigens PAP and/or PA2024; sTimulaTing sysTemic cyToToxic T-lymphocyTe acTiviTy; and mediaTing anTigen spread (i.e. increased anTibody responses To secondary proTeins in addiTion To PAP and PA2024). Each of These pieces individually correlaTes wiTh OS. Sipuleucel-T also Traffics T cells To The prosTaTe and is associaTed wiTh long-Term immune memory such ThaT a second course of TreaTmenT induces an anamnesTic immune response. ProsTaTe cancer does noT have a sTrongly inflamed microenvironmenT, Thus has limiTed response To immune checkpoinT inhibiTors. Since Sipuleucel-T is able To Traffic T-cells To The Tumor, iT may be an ideal combinaTion parTner wiTh immunoTherapies including immune checkpoinT inhibiTors or wiTh radiaTion Therapy.

  • clonoTypic diversificaTion of inTraTumoral T cells following Sipuleucel T TreaTmenT in prosTaTe cancer subjecTs
    Cancer Research, 2016
    Co-Authors: Nadeem A. Sheikh, James B Trager, Jason Cham, Li Zhang, Todd Devries, Simon Letarte, Jeff Pufnock, David Hamm, Lawrence Fong
    Abstract:

    Sipuleucel-T is an auTologous cellular Therapy for asympTomaTic, or minimally sympTomaTic, meTasTaTic casTraTe-resisTanT prosTaTe cancer, designed To sTimulaTe an immune response againsT prosTaTe cancer. In a recenT clinical Trial (NCT00715104), we found ThaT neoadjuvanT Sipuleucel-T increased The number of acTivaTed T cells wiThin The Tumor microenvironmenT. The currenT analysis examined wheTher Sipuleucel-T alTered adapTive T-cell responses by expanding pre-exisTing T cells or by recruiTing new T cells To prosTaTe Tissue. NexT-generaTion sequencing of The T-cell recepTor (TCR) genes from blood or prosTaTe Tissue was used To quanTiTaTe and Track T-cell clonoTypes in These TreaTed subjecTs wiTh prosTaTe cancer. AT baseline, There was a significanTly greaTer diversiTy of circulaTing TCR sequences in subjecTs wiTh prosTaTe cancer compared wiTh healThy donors. Among healThy donors, circulaTing TCR sequence diversiTy remained unchanged over The same Time inTerval. In conTrasT, Sipuleucel-T TreaTmenT reduced circulaTing TCR sequence diversiTy versus baseline as measured by The Shannon index. InTeresTingly, Sipuleucel-T TreaTmenT resulTed in greaTer TCR sequence diversiTy in resecTed prosTaTe Tissue in Sipuleucel-T–TreaTed subjecTs versus Tissue of nonSipuleucel-T–TreaTed subjecTs wiTh prosTaTe cancer. FurThermore, Sipuleucel-T increased TCR sequence commonaliTy beTween blood and resecTed prosTaTe Tissue in TreaTed versus unTreaTed subjecTs wiTh prosTaTe cancer. The broadening of The TCR reperToire wiThin The prosTaTe Tissue supporTs The hypoThesis ThaT Sipuleucel-T TreaTmenT faciliTaTes The recruiTmenT of T cells inTo The prosTaTe. Our resulTs highlighT The imporTance of assessing T-cell response To immunoTherapy boTh in The periphery and in Tumor Tissue. Cancer Res; 76(13); 3711–8. ©2016 AACR.

  • humoral immune response againsT nonTargeTed Tumor anTigens afTer TreaTmenT wiTh Sipuleucel T and iTs associaTion wiTh improved clinical ouTcome
    Clinical Cancer Research, 2015
    Co-Authors: Debraj Guhathakurta, Celestia S. Higano, Philip W Kantoff, Eric J Small, Nadeem A. Sheikh, Simon J Hall, Thomas A Gardner, Harini Kandadi, Thomas C Meagher, Kate Bailey
    Abstract:

    Purpose: AnTiTumor 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 Design: Serum 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. ResulTs: In 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 P ≤ 0.05). Conclusions: Sipuleucel-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. Clin Cancer Res; 21(16); 3619–30. ©2015 AACR . See relaTed commenTary by HellsTrom and HellsTrom, p. 3581

  • A Randomized Phase II Trial of Sipuleucel-T wiTh ConcurrenT versus SequenTial AbiraTerone AceTaTe plus Prednisone in MeTasTaTic CasTraTion-ResisTanT ProsTaTe Cancer
    Clinical Cancer Research, 2015
    Co-Authors: Eric J Small, Raymond S. Lance, Nadeem A. Sheikh, Lawrence Fong, Todd Devries, Candice Mccoy, Thomas A Gardner, Lawrence Karsh, Debraj Guhathakurta, Nancy N Chang
    Abstract:

    Purpose:This phase II open-label sTudy evaluaTed The effecT of concurrenT or sequenTial adminisTraTion of abiraTerone aceTaTe plus prednisone (AA + P) on Sipuleucel-T manufacTure and immune responses in meTasTaTic casTraTion-resisTanT prosTaTe cancer (mCRPC) paTienTs. ExperimenTal Design: mCRPC paTienTs received Sipuleucel-T followed by AA + P 1 day (concurrenT) or 10 weeks (sequenTial) afTer The firsT Sipuleucel-T infusion. AA + P TreaTmenT conTinued for 26 weeks. The primary endpoinT was cumulaTive anTigen presenTing cell (APC) acTivaTion, and secondary endpoinTs included cumulaTive APC number and ToTal nucleaTed cell counTs. AddiTional endpoinTs included in vivo peripheral immune responses To Sipuleucel-T (T cell responses, T cell proliferaTion, humoral responses, and anTigen spread) as well as safeTy. ResulTs: SixTy-nine mCRPC paTienTs were enrolled, wiTh 35 and 34 paTienTs randomized To The concurrenT and sequenTial arms, respecTively. Ex vivo APC acTivaTion was significanTly greaTer aT The second and Third infusions compared wiTh baseline in boTh arms (p

  • a randomized phase ii Trial of Sipuleucel T wiTh concurrenT versus sequenTial abiraTerone aceTaTe plus prednisone in meTasTaTic casTraTion resisTanT prosTaTe cancer
    Clinical Cancer Research, 2015
    Co-Authors: Eric J Small, Raymond S. Lance, Nadeem A. Sheikh, Lawrence Fong, Todd Devries, Candice Mccoy, Thomas A Gardner, Lawrence Karsh, Debraj Guhathakurta, Nancy N Chang
    Abstract:

    Purpose:This phase II open-label sTudy evaluaTed The effecT of concurrenT or sequenTial adminisTraTion of abiraTerone aceTaTe plus prednisone (AA + P) on Sipuleucel-T manufacTure and immune responses in meTasTaTic casTraTion-resisTanT prosTaTe cancer (mCRPC) paTienTs. ExperimenTal Design: mCRPC paTienTs received Sipuleucel-T followed by AA + P 1 day (concurrenT) or 10 weeks (sequenTial) afTer The firsT Sipuleucel-T infusion. AA + P TreaTmenT conTinued for 26 weeks. The primary endpoinT was cumulaTive anTigen presenTing cell (APC) acTivaTion, and secondary endpoinTs included cumulaTive APC number and ToTal nucleaTed cell counTs. AddiTional endpoinTs included in vivo peripheral immune responses To Sipuleucel-T (T cell responses, T cell proliferaTion, humoral responses, and anTigen spread) as well as safeTy. ResulTs: SixTy-nine mCRPC paTienTs were enrolled, wiTh 35 and 34 paTienTs randomized To The concurrenT and sequenTial arms, respecTively. Ex vivo APC acTivaTion was significanTly greaTer aT The second and Third infusions compared wiTh baseline in boTh arms (p<0.05), indicaTive of an immunological prime-boosT effecT. In boTh arms, Sipuleucel-T producT parameTer profiles and peripheral immune responses were consisTenT wiTh previously conducTed Sipuleucel-T phase III Trials. AnTigen spread was similarly observed in boTh arms and consisTenT wiTh The oTher immunologic endpoinTs. Conclusions: These daTa suggesT ThaT Sipuleucel-T can be successfully manufacTured during concurrenT adminisTraTion of AA + P wiThouT blunTing immunologic effecTs or alTering immune parameTers ThaT correlaTe wiTh Sipuleucel-T9s clinical benefiT. Combining These agenTs was well ToleraTed, wiTh no new safeTy signals emerging.

Emmanuel S. Antonarakis - One of the best experts on this subject based on the ideXlab platform.

  • anTigen specific cd8 lyTic phenoType induced by Sipuleucel T in hormone sensiTive or casTraTion resisTanT prosTaTe cancer and associaTion wiTh overall survival
    Clinical Cancer Research, 2018
    Co-Authors: Emmanuel S. Antonarakis, Eric J Small, Daniel P Petrylak, Adam S Kibel, David I Quinn, Nancy N Chang, Erica Dearstyne, Matt Harmon, Dwayne Campogan, Heather Haynes
    Abstract:

    Purpose: Sipuleucel-T is FDA approved for The TreaTmenT of meTasTaTic casTraTion-resisTanT prosTaTe cancer (mCRPC) based on The IMPACT Trial showing a 4.1-monTh benefiT in median overall survival (OS) for paTienTs receiving Sipuleucel-T versus conTrol. AlThough efficacy of Sipuleucel-T is well esTablished, iTs mechanism remains incompleTely undersTood. PaTienTs and MeThods: PaTienT samples from Three Sipuleucel-T Trials were assessed for peripheral cellular immune responses To The immunogen PA2024 and The TargeT anTigen prosTaTic acid phosphaTase (PAP). PAP- and PA2024-specific proliferaTive and cyTolyTic responses were characTerized To delineaTe Sipuleucel-T–induced immune responses. To quanTify poTenTial cyToToxic T lymphocyTe (CTL) acTiviTy, cell-surface CD107a expression on PAP- or PA2024-specific CD8+ T cells was measured in Sipuleucel-T–TreaTed paTienT and healThy volunTeer samples. ResulTs: Increased PA2024-specific CD4+ (P = 0.030) and CD8+ (P = 0.052) T-cell proliferaTion from baseline To week 6 was observed (N = 14) posT–Sipuleucel-T, wiTh greaTer magniTude of PA2024-specific responses compared wiTh PAP. PAP- and PA2024-CTL acTiviTy (CD107a posiTiviTy) significanTly increased aT weeks 6 and 26 afTer Sipuleucel-T TreaTmenT (P Conclusions: This sTudy is The firsT To reporT PAP-specific CD8+ T-cell responses eliciTed by Sipuleucel-T TreaTmenT. Increased and persisTenT poTenTial PA2024-specific CTL acTiviTy correlaTed wiTh PAP-specific CTL acTiviTy and associaTed wiTh improved OS following Sipuleucel-T TreaTmenT. Clin Cancer Res; 24(19); 4662–71. ©2018 AACR.

  • Sipuleucel T for The TreaTmenT of prosTaTe cancer novel insighTs and fuTure direcTions
    Future Oncology, 2018
    Co-Authors: Catherine E Handy, Emmanuel S. Antonarakis
    Abstract:

    Sipuleucel-T, an auTologous cellular immunoTherapy manufacTured from anTigen-presenTing cells primed To recognize prosTaTic acid phosphaTase, was The firsT immunoTherapy producT approved by The US FDA. IT was approved for men wiTh asympTomaTic or minimally sympTomaTic meTasTaTic casTraTion-resisTanT prosTaTe cancer afTer iT was shown To provide a survival advanTage. AddiTional sTudies have examined iTs use in oTher clinical seTTings and in combinaTion wiTh oTher approved and invesTigaTional immunoTherapy agenTs. This review will discuss The pivoTal Trials leading To approval, will ouTline some of The biomarkers associaTed wiTh iTs efficacy and will review some of The ongoing combinaTion sTraTegies. Maximizing The efficacy of Sipuleucel-T Through beTTer paTienT selecTion or Through combinaTion approaches remains The challenge of The fuTure.

  • sequencing of Sipuleucel T and androgen deprivaTion Therapy in men wiTh hormone sensiTive biochemically recurrenT prosTaTe cancer a phase ii randomized Trial
    Clinical Cancer Research, 2017
    Co-Authors: Emmanuel S. Antonarakis, Neal D. Shore, Adam S Kibel, John M. Corman, Evan Y Yu, Nicholas J Vogelzang, Frederick Millard, Lawrence Karsh, Aymen Elfiky, Johnathan Maher
    Abstract:

    Background: STAND, a randomized, phase II, open-label Trial ([NCT01431391][1]) assessed sequencing of Sipuleucel-T (an auTologous cellular immunoTherapy) wiTh androgen deprivaTion Therapy (ADT) in biochemically-recurrenT prosTaTe cancer (BRPC) paTienTs aT high risk for meTasTasis. MeThods: Men wiTh BRPC following prosTaTecTomy and/or radioTherapy, a prosTaTe-specific anTigen (PSA) doubling Time (PSADT)less Than or equal To 12 monThs, and no meTasTasis were enrolled. PaTienTs were randomized (34/arm) To Sipuleucel-T followed by ADT (sTarTed 2 weeks afTer Sipuleucel-T compleTion), or ADT followed by Sipuleucel-T (sTarTed 12 weeks afTer ADT iniTiaTion); ADT conTinued for 12 monThs in boTh arms. The primary endpoinT was PA2024-specific T cell response (Enzyme-Linked ImmunoSPOT [ELISPOT]) over Time. ResulTs: PA2024-specific ELISPOT responses over Time were similar beTween groups, excepT aT week 6, where responses were higher wiTh Sipuleucel-T→ADT versus ADT→Sipuleucel-T (P=0.013). PA2024-specific T cell proliferaTion responses, averaged across Time poinTs, were approximaTely 2-fold higher wiTh Sipuleucel-T→ADT versus ADT→Sipuleucel-T (P equals 0.001). PA2024-specific cellular and humoral responses, and prosTaTic acid phosphaTase-specific humoral responses increased significanTly versus baseline (P less Than 0.001), and were mainTained for 24 monThs (boTh arms). Median Time-To-PSA recurrence was similar beTween arms (21.8 vs. 22.6 monThs, P=0.357). DevelopmenT of a PA2024-specific humoral response correlaTed wiTh prolonged Time-To-PSA progression (hazard raTio 0.22, 95% CI 0.08 To 0.67; P=0.007). Sipuleucel-T wiTh ADT was generally well-ToleraTed. Conclusions: Sipuleucel-T→ADT appears To induce greaTer anTiTumor immune responses Than The reverse sequence. These resulTs warranT furTher invesTigaTion To deTermine if This sequence leads To improved clinical ouTcomes, as well as The independenT conTribuTion of ADT alone in Terms of immune acTivaTion. [1]: /lookup/exTernal-ref?link_Type=CLINTRIALGOV&access_num=NCT01431391&aTom=%2Fclincanres%2Fearly%2F2016%2F11%2F10%2F1078-0432.CCR-16-1780.aTom

  • randomized phase 2 sTudy of Sipuleucel T wiTh or wiThouT radium 223 in men wiTh asympTomaTic minimally sympTomaTic bone meTasTaTic casTraTe resisTanT prosTaTe cancer crpc
    Journal of Clinical Oncology, 2015
    Co-Authors: Jong Chul Park, Oliver A Sartor, Rana Sullivan, Serina King, Emmanuel S. Antonarakis
    Abstract:

    TPS5076 Background: Sipuleucel-T is an auTologous cellular immunoTherapy indicaTed for men wiTh asympTomaTic/minimally sympTomaTic meTasTaTic CRPC. RecenT analysis of immune responses in men TreaTed wiTh Sipuleucel-T showed ThaT anTigen-specific immune responses To Sipuleucel-T may be associaTed wiTh survival, confirming The immune-based mechanism of acTion and suggesTing The possibiliTy ThaT producing a sTronger immune response may TranslaTe inTo The beTTer clinical ouTcomes. RadiopharmaceuTical agenTs have been shown To enhance immune modulaTion Through a varieTy of mechanisms including enhanced display of Tumor-associaTed anTigens. Based on The immunomodulaTory effecTs of radiopharmaceuTical drugs, we hypoThesized ThaT combined use of radium-223 and Sipuleucel-T may enhance The Sipuleucel-T-induced immune response and improve clinical ouTcomes. MeThods: This is a randomized phase 2 sTudy comparing anTigen-specific immune responses of Sipuleucel-T used alone versus Sipuleucel-T plus radium-223 in CRPC p...

  • Randomized phase-2 sTudy of Sipuleucel-T wiTh or wiThouT radium-223 in men wiTh asympTomaTic/minimally sympTomaTic bone-meTasTaTic casTraTe-resisTanT prosTaTe cancer (CRPC).
    Journal of Clinical Oncology, 2015
    Co-Authors: Jong Chul Park, A. Oliver Sartor, Rana Sullivan, Serina King, Emmanuel S. Antonarakis
    Abstract:

    TPS5076 Background: Sipuleucel-T is an auTologous cellular immunoTherapy indicaTed for men wiTh asympTomaTic/minimally sympTomaTic meTasTaTic CRPC. RecenT analysis of immune responses in men TreaTed wiTh Sipuleucel-T showed ThaT anTigen-specific immune responses To Sipuleucel-T may be associaTed wiTh survival, confirming The immune-based mechanism of acTion and suggesTing The possibiliTy ThaT producing a sTronger immune response may TranslaTe inTo The beTTer clinical ouTcomes. RadiopharmaceuTical agenTs have been shown To enhance immune modulaTion Through a varieTy of mechanisms including enhanced display of Tumor-associaTed anTigens. Based on The immunomodulaTory effecTs of radiopharmaceuTical drugs, we hypoThesized ThaT combined use of radium-223 and Sipuleucel-T may enhance The Sipuleucel-T-induced immune response and improve clinical ouTcomes. MeThods: This is a randomized phase 2 sTudy comparing anTigen-specific immune responses of Sipuleucel-T used alone versus Sipuleucel-T plus radium-223 in CRPC p...

Todd Devries - One of the best experts on this subject based on the ideXlab platform.

  • clonoTypic diversificaTion of inTraTumoral T cells following Sipuleucel T TreaTmenT in prosTaTe cancer subjecTs
    Cancer Research, 2016
    Co-Authors: Nadeem A. Sheikh, James B Trager, Jason Cham, Li Zhang, Todd Devries, Simon Letarte, Jeff Pufnock, David Hamm, Lawrence Fong
    Abstract:

    Sipuleucel-T is an auTologous cellular Therapy for asympTomaTic, or minimally sympTomaTic, meTasTaTic casTraTe-resisTanT prosTaTe cancer, designed To sTimulaTe an immune response againsT prosTaTe cancer. In a recenT clinical Trial (NCT00715104), we found ThaT neoadjuvanT Sipuleucel-T increased The number of acTivaTed T cells wiThin The Tumor microenvironmenT. The currenT analysis examined wheTher Sipuleucel-T alTered adapTive T-cell responses by expanding pre-exisTing T cells or by recruiTing new T cells To prosTaTe Tissue. NexT-generaTion sequencing of The T-cell recepTor (TCR) genes from blood or prosTaTe Tissue was used To quanTiTaTe and Track T-cell clonoTypes in These TreaTed subjecTs wiTh prosTaTe cancer. AT baseline, There was a significanTly greaTer diversiTy of circulaTing TCR sequences in subjecTs wiTh prosTaTe cancer compared wiTh healThy donors. Among healThy donors, circulaTing TCR sequence diversiTy remained unchanged over The same Time inTerval. In conTrasT, Sipuleucel-T TreaTmenT reduced circulaTing TCR sequence diversiTy versus baseline as measured by The Shannon index. InTeresTingly, Sipuleucel-T TreaTmenT resulTed in greaTer TCR sequence diversiTy in resecTed prosTaTe Tissue in Sipuleucel-T–TreaTed subjecTs versus Tissue of nonSipuleucel-T–TreaTed subjecTs wiTh prosTaTe cancer. FurThermore, Sipuleucel-T increased TCR sequence commonaliTy beTween blood and resecTed prosTaTe Tissue in TreaTed versus unTreaTed subjecTs wiTh prosTaTe cancer. The broadening of The TCR reperToire wiThin The prosTaTe Tissue supporTs The hypoThesis ThaT Sipuleucel-T TreaTmenT faciliTaTes The recruiTmenT of T cells inTo The prosTaTe. Our resulTs highlighT The imporTance of assessing T-cell response To immunoTherapy boTh in The periphery and in Tumor Tissue. Cancer Res; 76(13); 3711–8. ©2016 AACR.

  • survival ouTcomes of Sipuleucel T phase iii sTudies impacT of conTrol arm cross over To salvage immunoTherapy
    Cancer immunology research, 2015
    Co-Authors: Daniel J. George, J. B. Whitmore, Todd Devries, Chadi Nabhan, Leonard G. Gomella
    Abstract:

    Sipuleucel-T is an auTologous cellular immunoTherapy for asympTomaTic/minimally sympTomaTic meTasTaTic casTraTe-resisTanT prosTaTe cancer (CRPC). AfTer disease progression, conTrol-arm paTienTs on Three double-blind, randomized phase III Sipuleucel-T Trials were offered, in nonrandomized open-label proTocols, APC8015F, an auTologous immunoTherapy made from cells cryopreserved aT The Time of conTrol manufacTure. These exploraTory analyses evaluaTed poTenTial effecTs on survival ouTcomes associaTed wiTh such TreaTmenT. Of 249 conTrol-TreaTed paTienTs, 165 (66.3%) received APC8015F. We explored The effecTs of APC8015F on The overall survival (OS; Cox regression) of conTrol-arm paTienTs and TreaTmenT effecTs of Sipuleucel-T versus conTrol adjusTed for APC8015F TreaTmenT [iTeraTive parameTer esTimaTion model (IPE)]. The median Time To firsT APC8015F infusion was 5.2 monThs (range, 1.8–33.1) afTer randomizaTion and 2.2 monThs (0.5–14.6) afTer progression. AfTer disease progression, median survival was longer for APC8015F-TreaTed versus conTrol-only TreaTed paTienTs [20.0 vs. 9.8 monThs; HR, 0.53; 95% confidence inTerval (CI), 0.38–0.74; P

  • a randomized phase ii Trial of Sipuleucel T wiTh concurrenT versus sequenTial abiraTerone aceTaTe plus prednisone in meTasTaTic casTraTion resisTanT prosTaTe cancer
    Clinical Cancer Research, 2015
    Co-Authors: Eric J Small, Raymond S. Lance, Nadeem A. Sheikh, Lawrence Fong, Todd Devries, Candice Mccoy, Thomas A Gardner, Lawrence Karsh, Debraj Guhathakurta, Nancy N Chang
    Abstract:

    Purpose:This phase II open-label sTudy evaluaTed The effecT of concurrenT or sequenTial adminisTraTion of abiraTerone aceTaTe plus prednisone (AA + P) on Sipuleucel-T manufacTure and immune responses in meTasTaTic casTraTion-resisTanT prosTaTe cancer (mCRPC) paTienTs. ExperimenTal Design: mCRPC paTienTs received Sipuleucel-T followed by AA + P 1 day (concurrenT) or 10 weeks (sequenTial) afTer The firsT Sipuleucel-T infusion. AA + P TreaTmenT conTinued for 26 weeks. The primary endpoinT was cumulaTive anTigen presenTing cell (APC) acTivaTion, and secondary endpoinTs included cumulaTive APC number and ToTal nucleaTed cell counTs. AddiTional endpoinTs included in vivo peripheral immune responses To Sipuleucel-T (T cell responses, T cell proliferaTion, humoral responses, and anTigen spread) as well as safeTy. ResulTs: SixTy-nine mCRPC paTienTs were enrolled, wiTh 35 and 34 paTienTs randomized To The concurrenT and sequenTial arms, respecTively. Ex vivo APC acTivaTion was significanTly greaTer aT The second and Third infusions compared wiTh baseline in boTh arms (p<0.05), indicaTive of an immunological prime-boosT effecT. In boTh arms, Sipuleucel-T producT parameTer profiles and peripheral immune responses were consisTenT wiTh previously conducTed Sipuleucel-T phase III Trials. AnTigen spread was similarly observed in boTh arms and consisTenT wiTh The oTher immunologic endpoinTs. Conclusions: These daTa suggesT ThaT Sipuleucel-T can be successfully manufacTured during concurrenT adminisTraTion of AA + P wiThouT blunTing immunologic effecTs or alTering immune parameTers ThaT correlaTe wiTh Sipuleucel-T9s clinical benefiT. Combining These agenTs was well ToleraTed, wiTh no new safeTy signals emerging.

  • A Randomized Phase II Trial of Sipuleucel-T wiTh ConcurrenT versus SequenTial AbiraTerone AceTaTe plus Prednisone in MeTasTaTic CasTraTion-ResisTanT ProsTaTe Cancer
    Clinical Cancer Research, 2015
    Co-Authors: Eric J Small, Raymond S. Lance, Nadeem A. Sheikh, Lawrence Fong, Todd Devries, Candice Mccoy, Thomas A Gardner, Lawrence Karsh, Debraj Guhathakurta, Nancy N Chang
    Abstract:

    Purpose:This phase II open-label sTudy evaluaTed The effecT of concurrenT or sequenTial adminisTraTion of abiraTerone aceTaTe plus prednisone (AA + P) on Sipuleucel-T manufacTure and immune responses in meTasTaTic casTraTion-resisTanT prosTaTe cancer (mCRPC) paTienTs. ExperimenTal Design: mCRPC paTienTs received Sipuleucel-T followed by AA + P 1 day (concurrenT) or 10 weeks (sequenTial) afTer The firsT Sipuleucel-T infusion. AA + P TreaTmenT conTinued for 26 weeks. The primary endpoinT was cumulaTive anTigen presenTing cell (APC) acTivaTion, and secondary endpoinTs included cumulaTive APC number and ToTal nucleaTed cell counTs. AddiTional endpoinTs included in vivo peripheral immune responses To Sipuleucel-T (T cell responses, T cell proliferaTion, humoral responses, and anTigen spread) as well as safeTy. ResulTs: SixTy-nine mCRPC paTienTs were enrolled, wiTh 35 and 34 paTienTs randomized To The concurrenT and sequenTial arms, respecTively. Ex vivo APC acTivaTion was significanTly greaTer aT The second and Third infusions compared wiTh baseline in boTh arms (p

  • absTracT 2937 localizaTion of Sipuleucel T expanded T cell clones inTo Tumors of TreaTed prosTaTe cancer paTienTs
    Cancer Research, 2014
    Co-Authors: Lawrence Fong, James B Trager, Mark W. Frohlich, Jason Cham, Li Zhang, Todd Devries, Nadeem A. Sheikh
    Abstract:

    Sipuleucel-T is an FDA-approved auTologous cellular Therapy demonsTraTed To prolong overall survival in subjecTs wiTh asympTomaTic or minimally sympTomaTic meTasTaTic casTraTe resisTanT prosTaTe cancer (mCRPC). Sipuleucel-T is generaTed by culTuring paTienTs9 own peripheral blood mononuclear cells (PBMC) wiTh a fusion proTein of prosTaTic acid phosphaTase and granulocyTe macrophage colony sTimulaTing facTor. While anTigen presenTing cells Take up This anTigen and can prime anTigen specific T cells in vivo, The majoriTy of The cells in The Sipuleucel-T producT are in facT T cells. Moreover, anTigen-specific T cells in The producT become acTivaTed during producTion of Sipuleucel-T, parTicularly for The 2nd and 3rd infusions. To examine wheTher T cells conTained in Sipuleucel-T mighT be homing To The siTe of The Tumor, we used a nexT-generaTion sequencing-based meThod To assess T cell reperToire diversiTy in The blood, Sipuleucel-T producT, and resecTed Tissues of paTienTs parTicipaTing in a neoadjuvanT sTudy of Sipuleucel-T TreaTmenT (P07-1; NCT00715104). In This Trial, paTienTs wiTh localized prosTaTe cancer received Sipuleucel-T prior To undergoing radical prosTaTecTomy (RP). DNA exTracTed from The differenT samples was amplified using a mulTiplex PCR assay To amplify The CDR3 region of The T cell recepTor spanning The variable region formed by The juncTion of The V, D and J segmenTs and Their associaTed non-TemplaTed inserTions. Sequence reads were used To quanTiTaTe absoluTe TCR frequencies using sTandardized clonoType deTerminaTion algoriThms. We found ThaT a subseT of T cell clones was enriched in The generaTion of Sipuleucel-T. We also found ThaT T cell clones were expanded in paTienT blood afTer each successive infusion. When we examined The T cell clonoTypes in The prosTaTe Tissues resecTed afTer Sipuleucel-T TreaTmenT, we found ThaT There were T cell clones in The prosTaTe in common wiTh The Sipuleucel-T producT. InTeresTingly a number of The clones presenT in The pre-TreaTmenT blood were reduced or losT in The blood by The second and Third infusion buT were presenT in The posT-TreaTmenT prosTaTe Tissue, consisTenT wiTh Trafficking of The T cell clones from The peripheral circulaTion. These resulTs indicaTe ThaT ex vivo producTion of Sipuleucel-T induces The expansion of cerTain T cell clones ThaT are ulTimaTely presenT in The prosTaTes of paTienTs TreaTed prior To RP. Sipuleucel-T may Therefore also funcTion as an adopTive T cell Therapy. CiTaTion FormaT: Lawrence Fong, Todd DeVries, Jason Cham, Li Zhang, Mark Frohlich, James Trager, Nadeem Sheikh. LocalizaTion of Sipuleucel-T- expanded T cell clones inTo Tumors of TreaTed prosTaTe cancer paTienTs. [absTracT]. In: Proceedings of The 105Th Annual MeeTing of The American AssociaTion for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):AbsTracT nr 2937. doi:10.1158/1538-7445.AM2014-2937

Neal D. Shore - One of the best experts on this subject based on the ideXlab platform.

  • real world ouTcomes of Sipuleucel T TreaTmenT in proceed a prospecTive regisTry of men wiTh meTasTaTic casTraTion resisTanT prosTaTe cancer
    Cancer, 2019
    Co-Authors: Celestia S. Higano, Neal D. Shore, Philip W Kantoff, David F Penson, Andrew J. Armstrong, David G. Mcleod, Nicholas J Vogelzang, Christopher Michael Pieczonka, Oliver A Sartor, Jeffrey L Vacirca
    Abstract:

    BACKGROUND: The large regisTry, PROVENGE RegisTry for The ObservaTion, CollecTion, and EvaluaTion of Experience DaTa (PROCEED)(NCT01306890), evaluaTed Sipuleucel-T immunoTherapy for asympTomaTic/minimally sympTomaTic meTasTaTic casTraTion-resisTanT prosTaTe cancer (mCRPC). METHODS: PROCEED enrolled paTienTs wiTh mCRPC receiving 3 biweekly Sipuleucel-T infusions. AssessmenTs included overall survival (OS), serious adverse evenTs (SAEs), cerebrovascular evenTs (CVEs), and anTicancer inTervenTions (ACIs). Follow-up was for >/=3 years or unTil deaTh or sTudy wiThdrawal. RESULTS: In 2011-2017, 1976 paTienTs were followed for 46.6 monThs (median). The median age was 72 years, and The baseline median prosTaTe-specific anTigen level was 15.0 ng/mL; 86.7% were whiTe, and 11.6% were African American. Among The paTienTs, 1902 had 1 or more Sipuleucel-T infusions. The median OS was 30.7 monThs (95% confidence inTerval [CI], 28.6-32.2 monThs). Known prognosTic facTors were independenTly associaTed wiTh OS in a mulTivariable analysis. Among The 1255 paTienTs who died, 964 (76.8%) died of prosTaTe cancer (PC) progression. The median Time from The firsT infusion To PC deaTh was 42.7 monThs (95% CI, 39.4-46.2 monThs). The incidence of Sipuleucel-T-relaTed SAEs was 3.9%. The incidence of CVEs was 2.8%, and The raTe per 100 person-years was 1.2 (95% CI, 0.9-1.6). The CVE incidence among 11,972 paTienTs wiTh mCRPC from The Surveillance, Epidemiology, and End ResulTs-Medicare daTabase was 2.8%; The raTe per 100 person-years was 1.5 (95% CI, 1.4-1.7). One or more ACIs (abiraTerone, enzaluTamide, doceTaxel, cabaziTaxel, or radium 223) were received by 77.1% of The paTienTs afTer Sipuleucel-T; 32.5% and 17.4% of The paTienTs experienced 1- and 2-year TreaTmenT-free inTervals, respecTively. CONCLUSIONS: PROCEED provides conTemporary survival daTa for Sipuleucel-T-TreaTed men in a real-world seTTing of new life-prolonging agenTs, which will be useful in discussing TreaTmenT opTions wiTh paTienTs and in powering fuTure Trials wiTh Sipuleucel-T. The safeTy and TolerabiliTy of Sipuleucel-T in PROCEED were consisTenT wiTh previous findings.

  • Real‐world ouTcomes of Sipuleucel‐T TreaTmenT in PROCEED, a prospecTive regisTry of men wiTh meTasTaTic casTraTion‐resisTanT prosTaTe cancer
    Cancer, 2019
    Co-Authors: Celestia S. Higano, Neal D. Shore, Philip W Kantoff, David F Penson, Andrew J. Armstrong, David G. Mcleod, Nicholas J Vogelzang, Christopher Michael Pieczonka, A. Oliver Sartor, Jeffrey L Vacirca
    Abstract:

    The large regisTry, PROVENGE RegisTry for The ObservaTion, CollecTion, and EvaluaTion of Experience DaTa (PROCEED)(NCT01306890), evaluaTed Sipuleucel-T immunoTherapy for asympTomaTic/minimally sympTomaTic meTasTaTic casTraTion-resisTanT prosTaTe cancer (mCRPC). PROCEED enrolled paTienTs wiTh mCRPC receiving 3 biweekly Sipuleucel-T infusions. AssessmenTs included overall survival (OS), serious adverse evenTs (SAEs), cerebrovascular evenTs (CVEs), and anTicancer inTervenTions (ACIs). Follow-up was for ≥3 years or unTil deaTh or sTudy wiThdrawal. In 2011-2017, 1976 paTienTs were followed for 46.6 monThs (median). The median age was 72 years, and The baseline median prosTaTe-specific anTigen level was 15.0 ng/mL; 86.7% were whiTe, and 11.6% were African American. Among The paTienTs, 1902 had 1 or more Sipuleucel-T infusions. The median OS was 30.7 monThs (95% confidence inTerval [CI], 28.6-32.2 monThs). Known prognosTic facTors were independenTly associaTed wiTh OS in a mulTivariable analysis. Among The 1255 paTienTs who died, 964 (76.8%) died of prosTaTe cancer (PC) progression. The median Time from The firsT infusion To PC deaTh was 42.7 monThs (95% CI, 39.4-46.2 monThs). The incidence of Sipuleucel-T-relaTed SAEs was 3.9%. The incidence of CVEs was 2.8%, and The raTe per 100 person-years was 1.2 (95% CI, 0.9-1.6). The CVE incidence among 11,972 paTienTs wiTh mCRPC from The Surveillance, Epidemiology, and End ResulTs-Medicare daTabase was 2.8%; The raTe per 100 person-years was 1.5 (95% CI, 1.4-1.7). One or more ACIs (abiraTerone, enzaluTamide, doceTaxel, cabaziTaxel, or radium 223) were received by 77.1% of The paTienTs afTer Sipuleucel-T; 32.5% and 17.4% of The paTienTs experienced 1- and 2-year TreaTmenT-free inTervals, respecTively. PROCEED provides conTemporary survival daTa for Sipuleucel-T-TreaTed men in a real-world seTTing of new life-prolonging agenTs, which will be useful in discussing TreaTmenT opTions wiTh paTienTs and in powering fuTure Trials wiTh Sipuleucel-T. The safeTy and TolerabiliTy of Sipuleucel-T in PROCEED were consisTenT wiTh previous findings. © 2019 The AuThors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer SocieTy.

  • prolonged psa sTabilizaTion and overall survival following Sipuleucel T monoTherapy in meTasTaTic casTraTion resisTanT prosTaTe cancer paTienTs
    Prostate Cancer and Prostatic Diseases, 2019
    Co-Authors: Eda K Holl, Neal D. Shore, Megan Ann Mcnamara, Patrick Healy, Monika Anand, Raoul S Concepcion, Coleman D Breland, Igor Dumbudze, Ron Tutrone, Andrew J. Armstrong
    Abstract:

    Sipuleucel-T is an auTologous cellular immunoTherapy ThaT is FDA approved for The TreaTmenT of asympTomaTic or minimally sympTomaTic meTasTaTic casTraTe-resisTanT prosTaTe cancer (mCRPC). The IMPACT regisTry Trial demonsTraTed a 4.1 monTh survival benefiT, buT noT a consisTenT PSA response or improvemenT in progression-free survival. Based upon several facTors, including This lack of objecTive TreaTmenT response, Sipuleucel-T has been under-uTilized in This paTienT populaTion, despiTe currenT NCCN recommendaTions. In order To explore if delayed TreaTmenT response occurs in a subseT of paTienTs, we performed a single insTiTuTional reTrospecTive analysis of mCRPC paTienTs TreaTed wiTh Sipuleucel-T and ongoing ADT alone. WiThin ThaT group, we Then idenTified a subseT of Sipuleucel-T-TreaTed men wiTh long-Term disease conTrol and no addiTional inTervenTions. To independenTly confirm This finding, we evaluaTed a ToTal of 336 paTienTs from 4 large urology group pracTices TreaTed wiTh Sipuleucel-T beTween 2010 and 2014 and idenTified 44 paTienTs who meT The same criTeria and demonsTraTed evidence of PSA sTabilizaTion posT Sipuleucel-T TreaTmenT. For This subgroup of paTienTs, 79% (95% CI: 64.5%, 88.1%) survived 36 monThs wiTh a median Time To subsequenT Therapy of 17.8 monThs (95% CI 10.3, 25.3). AlThough paTienT selecTion could accounT for some or all of These resulTs, These daTa supporT The uTilizaTion of Sipuleucel-T alone in selecT mCRPC paTienTs ThaT is associaTed wiTh a delay in disease progression and a good overall prognosis.

  • sequencing of Sipuleucel T and androgen deprivaTion Therapy in men wiTh hormone sensiTive biochemically recurrenT prosTaTe cancer a phase ii randomized Trial
    Clinical Cancer Research, 2017
    Co-Authors: Emmanuel S. Antonarakis, Neal D. Shore, Adam S Kibel, John M. Corman, Evan Y Yu, Nicholas J Vogelzang, Frederick Millard, Lawrence Karsh, Aymen Elfiky, Johnathan Maher
    Abstract:

    Background: STAND, a randomized, phase II, open-label Trial ([NCT01431391][1]) assessed sequencing of Sipuleucel-T (an auTologous cellular immunoTherapy) wiTh androgen deprivaTion Therapy (ADT) in biochemically-recurrenT prosTaTe cancer (BRPC) paTienTs aT high risk for meTasTasis. MeThods: Men wiTh BRPC following prosTaTecTomy and/or radioTherapy, a prosTaTe-specific anTigen (PSA) doubling Time (PSADT)less Than or equal To 12 monThs, and no meTasTasis were enrolled. PaTienTs were randomized (34/arm) To Sipuleucel-T followed by ADT (sTarTed 2 weeks afTer Sipuleucel-T compleTion), or ADT followed by Sipuleucel-T (sTarTed 12 weeks afTer ADT iniTiaTion); ADT conTinued for 12 monThs in boTh arms. The primary endpoinT was PA2024-specific T cell response (Enzyme-Linked ImmunoSPOT [ELISPOT]) over Time. ResulTs: PA2024-specific ELISPOT responses over Time were similar beTween groups, excepT aT week 6, where responses were higher wiTh Sipuleucel-T→ADT versus ADT→Sipuleucel-T (P=0.013). PA2024-specific T cell proliferaTion responses, averaged across Time poinTs, were approximaTely 2-fold higher wiTh Sipuleucel-T→ADT versus ADT→Sipuleucel-T (P equals 0.001). PA2024-specific cellular and humoral responses, and prosTaTic acid phosphaTase-specific humoral responses increased significanTly versus baseline (P less Than 0.001), and were mainTained for 24 monThs (boTh arms). Median Time-To-PSA recurrence was similar beTween arms (21.8 vs. 22.6 monThs, P=0.357). DevelopmenT of a PA2024-specific humoral response correlaTed wiTh prolonged Time-To-PSA progression (hazard raTio 0.22, 95% CI 0.08 To 0.67; P=0.007). Sipuleucel-T wiTh ADT was generally well-ToleraTed. Conclusions: Sipuleucel-T→ADT appears To induce greaTer anTiTumor immune responses Than The reverse sequence. These resulTs warranT furTher invesTigaTion To deTermine if This sequence leads To improved clinical ouTcomes, as well as The independenT conTribuTion of ADT alone in Terms of immune acTivaTion. [1]: /lookup/exTernal-ref?link_Type=CLINTRIALGOV&access_num=NCT01431391&aTom=%2Fclincanres%2Fearly%2F2016%2F11%2F10%2F1078-0432.CCR-16-1780.aTom

  • opTimal Timing of Sipuleucel T TreaTmenT in meTasTaTic casTraTion resisTanT prosTaTe cancer
    Canadian Journal of Urology, 2015
    Co-Authors: E D Crawford, Celestia S. Higano, Neal D. Shore, Philip W Kantoff, Eric J Small, Daniel P Petrylak, Adam S Kibel, Anna C Ferrari
    Abstract:

    AbsTracT Numerous TreaTmenTs are approved for meTasTaTic casTraTion-resisTanT prosTaTe cancer (mCRPC), including Sipuleucel-T, an FDA-approved immunoTherapy. In This paper we review recenT daTa providing insighTs inTo The mechanism of acTion of Sipuleucel-T which suggesTs Sipuleucel-T may be mosT effecTive when adminisTered To mCRPC paTienTs wiTh a low burden of disease. Published and presenTed daTa from The Sipuleucel-T clinical Trials NeoACT (NCT00715104), IMPACT (NCT00065442), ProACT (NCT00715078), PROTECT (NCT00779402), OpenACT (NCT00901342), STAMP (NCT01487863) and STAND (NCT01431391), individually or across Trials, were included in This review. Overall, a growing body of evidence supporTs The concepT ThaT Sipuleucel-T, like some oTher immunoTherapies, has long Term effecTs ThaT resulT in an overall survival benefiT. mCRPC paTienTs wiTh a low Tumor burden may derive a greaTer TherapeuTic benefiT, since The immune response may be more robusT when The disease is less advanced and immunosuppressive effecTs from The Tumor or TradiTional Therapies may be less marked. In addiTion, TreaTmenT wiTh Sipuleucel-T in early mCRPC does noT preclude subsequenT TreaTmenT wiTh oTher approved mCRPC Therapies. CollecTively, clinical daTa To daTe suggesT The opTimal Timing for Sipuleucel-T TreaTmenT may be early in The mCRPC TreaTmenT paradigm.