Thi s art i cl e w as dow nl oaded by: [175. 153. 40. 131]
On: 26 August 2015, At : 16:17
Publ i sher: Tayl or & Franci s
Inf orm a Lt d Regi st ered i n Engl and and W al es Regi st ered Num ber: 1072954 Regi st ered of f i ce: 5 How i ck Pl ace,
London, SW 1P 1W G
Hum an Vacci nes & I m m unot her apeut i cs
Publ i cat i on det ai l s, i ncl udi ng i nst r uct i ons f or aut hor s and subscr i pt i on i nf or m at i on:
ht t p: //www. t andf onl i ne. com /l oi /khvi 20
An overvi ew of si pul eucel - T: Aut ol ogous cel l ul ar
i m m unot her apy f or prost at e cancer
Johnna W esl eya, Jam es W hi t m or ea, Jam es Tr agera & Nadeem Shei kha
a Dendr eon Cor por at i on, Resear ch; Seat t l e, WA USA
Publ i shed onl i ne: 28 Feb 2012.
To ci t e t hi s art i cl e: Johnna W esl ey , Jam es W hi t m or e, Jam es Tr ager & Nadeem Shei kh ( 2012) An over vi ew of si pul eucel - T:
Aut ol ogous cel l ul ar i m m unot her apy f or pr ost at e cancer , Hum an Vacci nes & I m m unot her apeut i cs, 8: 4, 520- 527, DOI : 10. 4161/
hv . 18769
To l i nk t o t hi s art i cl e: ht t p: //dx. doi . or g/10. 4161/hv . 18769
PLEASE SCROLL DOW N FOR ARTICLE
Tayl or & Franci s m akes every ef f ort t o ensure t he accuracy of al l t he i nf orm at i on (t he “Cont ent ”) cont ai ned
i n t he publ i cat i ons on our pl at f orm . How ever , Tayl or & Franci s, our agent s, and our l i censors m ake no
represent at i ons or w arrant i es w hat soever as t o t he accuracy, com pl et eness, or sui t abi l i t y f or any purpose of t he
Cont ent . Any opi ni ons and vi ew s expressed i n t hi s publ i cat i on are t he opi ni ons and vi ew s of t he aut hors, and
are not t he vi ew s of or endorsed by Tayl or & Franci s. The accuracy of t he Cont ent shoul d not be rel i ed upon and
shoul d be i ndependent l y veri f i ed w i t h pri m ary sources of i nf orm at i on. Tayl or and Franci s shal l not be l i abl e f or
any l osses, act i ons, cl ai m s, proceedi ngs, dem ands, cost s, expenses, dam ages, and ot her l i abi l i t i es w hat soever
or how soever caused ari si ng di rect l y or i ndi rect l y i n connect i on w i t h, i n rel at i on t o or ari si ng out of t he use of
t he Cont ent .
Thi s art i cl e m ay be used f or research, t eachi ng, and pri vat e st udy purposes. Any subst ant i al or syst em at i c
reproduct i on, redi st ri but i on, resel l i ng, l oan, sub-l i censi ng, syst em at i c suppl y, or di st ri but i on i n any
f orm t o anyone i s expressl y f orbi dden. Term s & Condi t i ons of access and use can be f ound at ht t p://
w w w. t andf onl i ne. com /page/t erm s-and-condi t i ons
© 2012 Landes Bioscience.
Do not distribute.
response, and, consequently, a survival benefit in subjects with
asymptomatic or minimally symptomatic metastatic castrate
resistant prostate cancer. adverse events are generally mild to
moderate and resolve within 2 d. Serious adverse events occur
at a low rate. as the first autologous cellular immunotherapy
to demonstrate a survival benefit, sipuleucel-T is a novel
oncologic therapeutic that warrants the reassessment of the
current prostate cancer treatment paradigm.
Special FocuS Review
Human vaccines & immunotherapeutics 8:4, 520-527; april 2012; © 2012 landes Bioscience
An overview of sipuleucel-T
Autologous cellular immunotherapy for prostate cancer
520 Human vaccines & immunotherapeutics volume 8 issue 4
Prostate cancer treatment paradigm. Prostate cancer is the
second leading cause of cancer deaths among males in most
western countries, and is predicted to result in over 33,000 deaths
in the US in 2011.1 Initial therapy for prostate cancer depends
on patient age and prognostic factors. In patients with localized
cancer, and in whom active surveillance is not an option, surgery
or radiation therapy can cure the disease. Up to 30% of patients,
however, will experience disease recurrence, often evidenced
by a progressive rise in serum prostate-specific antigen (PSA).
While disease recurrence can be temporarily controlled with
hormone therapy, recurrent prostate cancer inevitably progresses
to metastatic castrate resistant prostate cancer (mCRPC).
*Correspondence to: Nadeem Sheikh; firstname.lastname@example.org
Submitted: 10/08/11; Accepted: 11/15/11
Sipuleucel-T, the first autologous active cellular immunotherapy
approved by the uS Food and Drug administration, is
designed to stimulate an immune response to prostate
cancer. Sipuleucel-T is manufactured by culturing a patient’s
peripheral blood mononuclear cells (including antigen
presenting cells) with a recombinant protein comprising a
tumor-associated antigen (prostatic acid phosphatase) and
granulocyte-macrophage colony stimulating factor. Treatment
consists of three infusions at approximately 2-week intervals,
resulting in a prime-boost pattern of immune activation,
a robust antigen-specific cellular and humoral immune
Johnna D. wesley, James whitmore, James Trager and Nadeem Sheikh*
Dendreon corporation, Research; Seattle, wa uSa
Keywords: sipuleucel-T, active cellular therapy, prostate cancer, immunotherapy, autologous cellular therapy
Abbreviations: AE, adverse event; APC, antigen presenting cells; ECOG, eastern cooperative oncology group; ELISPOT,
enzyme-linked immunosorbent spot; GM-CSF, granulocyte-macrophage colony stimulating factor; IL, interleukin; IMPACT,
immunotherapy for prostate adenocarcinoma treatment (clinical trial); LAK, lymphokine activated killer cells; mCRPC, metastatic
castrate resistant prostate cancer; OS, overall survival; PAP, prostatic acid phosphatase; PBMC, peripheral blood mononuclear cells;
PROTECT, Provenge treatment and early cancer treatment trial (clinical trial); PSA, prostate-specific antigen; IFN, interferon;
SAE, serious adverse event; TNF, tumor necrosis factor
Treatment options for mCRPC patients have been limited.
Docetaxel was approved in 2004 after demonstrating a survival
benefit, but treatment is associated with significant toxicity.
Although new treatments have been approved since 2004 (e.g.,
cabazitaxel, abiraterone), they are currently only approved for use
in patients previously treated with docetaxel, and do not address
the need for less toxic therapies in patients without cancer-related
pain who elect not to pursue chemotherapy. Manipulation of
the immune system, or specific immune components, has been
regarded as a potentially more effective and less toxic therapeutic
option for these patients. Indeed, multiple lines of evidence have
demonstrated that the immune response plays an important
role in controlling tumor growth.2 Moreover, reported cases
of spontaneous tumor regression may be mediated by an anti-
tumor immune response.3,4 The development of immune-based
treatments has proven difficult, however, due to the variability
of a tumor’s antigenic profile and its ability to otherwise evade or
suppress a normal anti-tumor immune response.2
Cancer immunotherapy. Passive immunotherapies have
been utilized for decades in an attempt to treat cancer. These
therapies vary widely in type, ranging from introduction of
simple inflammatory agents to the transfer of purified active
humoral or cellular components of a normal immune response.
Early passive immunotherapies were non-specific in nature, and
included bacterial lipopolysaccharides and glycoproteins (e.g.,
Bacillus-Calmette-Guerin) as well as cytokines (e.g., interferonα
[IFNα], interleukin-2 [IL-2]).5 These types of therapies may
promote or enhance immune responses and inflammation but
are not directed at a specific target or antigen; thus, they are often
used as adjuvant therapies. Given the non-specific nature of these
treatments, care must be taken in the choice of these agents and
the clinical setting in which they are used.
Adoptive transfer therapies, which utilize isolated effec-
tor components of the immune system to more directly target
tumor cells, have become a major area of research in recent
years.6-9 Such therapies are based on the isolation, ex vivo cul-
ture/enhancement, and reintroduction of a large number of
anti-tumor immune components into the patient. Examples of
Downloaded by [184.108.40.206] at 16:17 26 August 2015
© 2012 Landes Bioscience.
Do not distribute.
34. Butterfield LH, Disis ML, Khleif SN, Balwit JM,
Marincola FM. Immuno-oncology biomarkers 2010
and beyond: perspectives from the iSBTc/SITC
biomarker task force. J Transl Med 2010; 8:130;
35. Stewart FP, Dela Rosa C, Sheikh NA, McNeel DG,
Frohlich MW, Urdal DL, et al. Correlation between
product parameters and overall survival in three
trials of sipuleucel-T, an autologous active cellular
immunotherapy for the treatment of prostate cancer.
[abstract 4552]. J Clin Oncol 2010; 28.
36. Sheikh NA, Dela Rosa C, Kuan LY, Stewart FP,
Frohlich MW, Urdal DL, et al. Sipuleucel-T generates
robust and persistent cellular and humoral immune
responses—results from the IMPACT trial [abstract].
AACR. Washington DC 2010.
37. Beer TM, Bernstein GT, Corman JM, Glode LM, Hall
SJ, Poll WL, et al. Randomized trial of autologous
cellular immunotherapy with sipuleucel-T in
androgen-dependent prostate cancer. Clin Cancer Res
2011; 17:4558-67; PMID:21558406; http://dx.doi.
38. Augustin H, Freibauer C, Bayer L, Lunglmayr G,
Tschurlovich F, Kuber W, et al. Molecular markers
and their prognostic impact in patients with advanced
prostate cancer undergoing intermittent androgen
suppression. Prostate Cancer Prostatic Dis 2006; 9:279-
83; PMID:16702984; http://dx.doi.org/10.1038/
39. Akyol F, Ozyigit G, Selek U, Karabulut E. PSA
bouncing after short term androgen deprivation and
3D-conformal radiotherapy for localized prostate
adenocarcinoma and the relationship with the
kinetics of testosterone. Eur Urol 2005; 48:40-5;
www.landesbioscience.com Human vaccines & immunotherapeutics 527
40. Bates AT, Pickles T, Paltiel C. PSA doubling time
kinetics during prostate cancer biochemical relapse
after external beam radiation therapy. Int J Radiat
Oncol Biol Phys 2005; 62:148-53; PMID:15850915;
41. Scher HI, Halabi S, Tannock I, Morris M, Sternberg
CN, Carducci MA, et al.; Prostate Cancer Clinical
Trials Working Group. Design and end points of clinical
trials for patients with progressive prostate cancer and
castrate levels of testosterone: recommendations of the
Prostate Cancer Clinical Trials Working Group. J Clin
Oncol 2008; 26:1148-59; PMID:18309951; http://
42. Scher HI, Warren M, Heller G. The association
between measures of progression and survival in
castrate-metastatic prostate cancer. Clin Cancer Res
2007; 13:1488-92; PMID:17332293; http://dx.doi.
43. Kantoff PW, Schuetz TJ, Blumenstein BA, Glode
LM, Bilhartz DL, Wyand M, et al. Overall survival
analysis of a phase II randomized controlled trial
of a Poxviral-based PSA-targeted immunotherapy in
metastatic castration-resistant prostate cancer. J Clin
Oncol 2010; 28:1099-105; PMID:20100959; http://
44. Stein WD, Gulley JL, Schlom J, Madan RA, Dahut
W, Figg WD, et al. Tumor regression and growth rates
determined in five intramural NCI prostate cancer
trials: the growth rate constant as an indicator of
therapeutic efficacy. Clin Cancer Res 2011; 17:907-17;
45. Gulley JL, Drake CG. Immunotherapy for prostate
cancer: recent advances, lessons learned and areas for
further research. Clin Cancer Res 2011; 17:3884-91;
46. Madan RA, Gulley JL, Fojo T, Dahut WL.
Therapeutic cancer vaccines in prostate cancer: the
paradox of improved survival without changes in
time to progression. Oncologist 2010; 15:969-75;
47. Tuma RS. Immunotherapies in clinical trials: do they
demand different evaluation tools? J Natl Cancer
Inst 2011; 103:780-1; PMID:21551417; http://dx.doi.
48. Kudo-Saito C, Schlom J, Hodge JW. Induction
of an antigen cascade by diversified subcutaneous/
intratumoral vaccination is associated with antitumor
responses. Clin Cancer Res 2005; 11:2416-26;
49. Small EJ, Higano CS, Kantoff PW, Whitmore JB,
Frohlich MW, Petrylak DP. Time to disease-related
pain after sipuleucel-T in asymptomatic patients with
metastatic castrate-resistant prostate cancer (mCRPC):
Results from three randomized phase III trials. J Clin
Oncol 2011; 29.
50. Hall SJ, Klotz L, Pantuck AJ, George DJ, Whitmore
JB, Frohlich MW, et al. Integrated safety data from
4 randomized, double-blind, controlled trials of
autologous cellular immunotherapy with sipuleucel-T
in patients with prostate cancer. J Urol 2011; 186:877-
81; PMID:21788048; http://dx.doi.org/10.1016/j.
51. Flanigan R, Price T, Whitmore J, Holman J. Safety
of leukapheresis in prostate cancer patients receiving
sipuleucel-T. J Urol 2011; 185:261; http://dx.doi.
52. Sims RB. Development of sipuleucel-T: Autologous
cellular immunotherapy for the treatment of metastatic
castrate resistant prostate cancer. Vaccine 2011; In
press; PMID:22122856; http://dx.doi.org/10.1016/j.
26. Sheikh NA, Dela Rosa C, Frohlich MW, Urdal
DL, Provost NM. Sipuleucel-T treatment results in
sequential ex vivo activation of APCs and T cells during
the culture step—evidence for in vivo immunological
priming [abstract]. AACR. Washington DC 2010.
27. Wesley JD, Chadwick E, Kuan LY, Dela Rosa C,
Frohlich M, Urdal D, et al. Characterization of antigen
specific T cell activation and cytokine expression induced
by sipuleucel-T. J Immunother 2010; 33:912-3.
28. Sheikh NA, Wesley JD, Chadwick E, Perdue N, Dela
Rosa C, Frohlich MW, et al. Characterization of antigen
specifric T-cell activation and cytokine expression
induced by sipuleucel-T. J Clin Oncol 2011; 29.
29. Burch PA, Breen JK, Buckner JC, Gastineau DA,
Kaur JA, Laus RL, et al. Priming tissue-specific cellular
immunity in a phase I trial of autologous dendritic cells
for prostate cancer. Clin Cancer Res 2000; 6:2175-82;
30. Small EJ, Fratesi P, Reese DM, Strang G, Laus R, Peshwa
MV, et al. Immunotherapy of hormone-refractory
prostate cancer with antigen-loaded dendritic cells. J
Clin Oncol 2000; 18:3894-903; PMID:11099318.
31. Rini BI, Weinberg V, Fong L, Conry S, Hershberg RM,
Small EJ. Combination immunotherapy with prostatic
acid phosphatase pulsed antigen-presenting cells
(provenge) plus bevacizumab in patients with serologic
progression of prostate cancer after definitive local
therapy. Cancer 2006; 107:67-74; PMID:16736512;
32. Beinart G, Rini BI, Weinberg V, Small EJ. Antigen-
presenting cells 8015 (Provenge) in patients with
prostate cancer. Clin Prostate Cancer 2005; 4:55-60;
33. Small EJ, Schellhammer PF, Higano CS, Redfern
CH, Nemunaitis JJ, Valone FH, et al. Placebo-
controlled phase III trial of immunologic therapy with
sipuleucel-T (APC8015) in patients with metastatic,
asymptomatic hormone refractory prostate cancer.
J Clin Oncol 2006; 24:3089-94; PMID:16809734;
Berger C, Turtle CJ, Jensen MC, Riddell SR. Adoptive
transfer of virus-specific and tumor-specific T cell
immunity. Curr Opin Immunol 2009; 21:224-32;
10. Chames P, Van Regenmortel M, Weiss E, Baty D.
Therapeutic antibodies: successes, limitations and
hopes for the future. Br J Pharmacol 2009; 157:220-
33; PMID:19459844; http://dx.doi.org/10.1111/
11. Riddell SR. Finding a place for tumor-specific T cells
in targeted cancer therapy. J Exp Med 2004; 200:1533-
7; PMID:15611285; http://dx.doi.org/10.1084/
12. Riddell SR. Engineering antitumor immunity by
T-cell adoptive immunotherapy. Hematology Am Soc
Hematol Educ Program 2007; 250-6; PMID:18024637;
13. Le DT, Pardoll DM, Jaffee EM. Cellular vaccine
14. Palena C, Abrams SI, Schlom J, Hodge JW. Cancer
vaccines: preclinical studies and novel strategies. Adv
Cancer Res 2006; 95:115-45; PMID:16860657;
15. Weide B, Garbe C, Rammensee HG, Pascolo S.
Plasmid DNA- and messenger RNA-based anti-
cancer vaccination. Immunol Lett 2008; 115:33-
42; PMID:18006079; http://dx.doi.org/10.1016/j.
16. Eager RM, Nemunaitis J. Clinical development
directions in oncolytic viral therapy. Cancer Gene Ther
2011; 18:305-17; PMID:21436867; http://dx.doi.
17. Loisel-Meyer S, Foley R, Medin JA. Immuno-gene
threapy approaches for cancer: from in vitro studies
to clinical trials. Front Biosci 2008; 1:3202-14; http://
18. Higano CS, Schellhammer PF, Small EJ, Burch PA,
Nemunaitis J, Yuh L, et al. Integrated data from
2 randomized, double-blind, placebo-controlled,
phase 3 trials of active cellular immunotherapy with
sipuleucel-T in advanced prostate cancer. Cancer
2009; 115:3670-9; PMID:19536890; http://dx.doi.
19. Kantoff PW, Higano CS, Shore ND, Berger ER, Small
EJ, Penson DF, et al.; IMPACT Study Investigators.
Sipuleucel-T immunotherapy for castration-resistant
prostate cancer. N Engl J Med 2010; 363:411-22;
20. Graddis TJ, McMahan CJ, Tamman J, Page KJ,
Trager JB. Prostatic acid phosphatase expression in
human tissues. Int J Clin Exp Pathol 2011; 4:295-306;
21. Laus R, Yang DM, Ruegg CL, Shapero MH, Slagle
PH, Small EJ, et al. Dendritic cell immunotherapy of
prostate cancer: Preclinical models and early clinical
experience. Cancer Research Therapy and Control
22. Alberts B, Johnson A, Lewis J, Raff M, Roberts K,
Walter P. Molecular Biology of the Cell. Garland
23. Dustin ML, Rothlein R, Bhan AK, Dinarello CA,
Springer TA. Induction by IL 1 and interferon-gamma:
tissue distribution, biochemistry and function of a
natural adherence molecule (ICAM-1). J Immunol
1986; 137:245-54; PMID:3086451.
24. Sheikh NA, Jones LA. CD54 is a surrogate marker of
antigen presenting cell activation. Cancer Immunol
Immunother 2008; 57:1381-90; PMID:18297282;
25. FDA/CBER. Guidance for Industry: Potency Tests for
Cellular and Gene Therapy Products 2011 January.
J 2010; 16:304-10;
Downloaded by [220.127.116.11] at 16:17 26 August 2015