Humoral immune response against nontargeted tumor antigens after treatment with sipuleucel-T and its association with improved clinical outcome

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

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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 <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). 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.

Original languageEnglish (US)
Pages (from-to)3619-3630
Number of pages12
JournalClinical Cancer Research
Volume21
Issue number16
DOIs
StatePublished - Aug 15 2015

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Neoplasm Antigens
Humoral Immunity
Immunoglobulin G
Galectin 3
Antigens
Castration
Prostate-Specific Antigen
Immunotherapy
Prostatic Neoplasms
Therapeutics
Survival
Galectin 1
Protein Array Analysis
sipuleucel-T
Autoantigens
L-Lactate Dehydrogenase
Proportional Hazards Models
Neoplasms
Research Design
Biomarkers

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Humoral immune response against nontargeted tumor antigens after treatment with sipuleucel-T and its association with improved clinical outcome. / Thakurta, Debraj Guha; 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; Bailey, Kate; Vu, Tuyen; Devries, Todd; Whitmore, James B.; Frohlich, Mark W.; Trager, James B.; Drake, Charles G.

In: Clinical Cancer Research, Vol. 21, No. 16, 15.08.2015, p. 3619-3630.

Research output: Contribution to journalArticle

Thakurta, DG, Sheikh, NA, Fan, LQ, Kandadi, H, Meagher, TC, Hall, SJ, Kantoff, PW, Higano, CS, Small, EJ, Gardner, T, Bailey, K, Vu, T, Devries, T, Whitmore, JB, Frohlich, MW, Trager, JB & Drake, CG 2015, 'Humoral immune response against nontargeted tumor antigens after treatment with sipuleucel-T and its association with improved clinical outcome', Clinical Cancer Research, vol. 21, no. 16, pp. 3619-3630. https://doi.org/10.1158/1078-0432.CCR-14-2334
Thakurta, Debraj Guha ; 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 ; Bailey, Kate ; Vu, Tuyen ; Devries, Todd ; Whitmore, James B. ; Frohlich, Mark W. ; Trager, James B. ; Drake, Charles G. / Humoral immune response against nontargeted tumor antigens after treatment with sipuleucel-T and its association with improved clinical outcome. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 16. pp. 3619-3630.
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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 <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). 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.",
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AU - Thakurta, Debraj Guha

AU - Sheikh, Nadeem A.

AU - Fan, Li Qun

AU - Kandadi, Harini

AU - Meagher, T. Craig

AU - Hall, Simon J.

AU - Kantoff, Philip W.

AU - Higano, Celestia S.

AU - Small, Eric J.

AU - Gardner, Thomas

AU - Bailey, Kate

AU - Vu, Tuyen

AU - Devries, Todd

AU - Whitmore, James B.

AU - Frohlich, Mark W.

AU - Trager, James B.

AU - Drake, Charles G.

PY - 2015/8/15

Y1 - 2015/8/15

N2 - 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 <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). 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.

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