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Annals of Oncology
942P ANTIGEN PRESENTING CELL (APC) ACTIVATION IN
SIPULEUCEL-T: IS ACTIVATION INCREASED IN EARLIER
PROSTATE CANCER DISEASE STATES?
E.J. Small1 , J.D. Wesley2 , D.I. Quinn3 , C. Higano4 , D. Lin5 , H. Haynes2 ,
F. Stewart6 , J.B. Trager2 , N. Sheikh7 1
Medicine/urology, University of California, San Francisco, San Francisco, CA,
UNITED STATES OF AMERICA, 2 Clinical Immunology, Dendreon, Seattle, WA,
UNITED STATES OF AMERICA, 3 USC Norris Comprehensive Cancer Center,
University of Southern California, Keck School of Medicine, Los Angeles, CA,
UNITED STATES OF AMERICA, 4 Seattle Cancer Care Alliance, University of
Washington, Seattle, WA, UNITED STATES OF AMERICA, 5 School of Medicine,
University of Washington, Seattle, WA, UNITED STATES OF AMERICA,
6
Biometrics, Dendreon Corporation, Seattle, WA, UNITED STATES OF AMERICA,
7
Clinical Immunology, Dendreon Corporation, Seattle, WA, UNITED STATES OF
AMERICA
Background: Sipuleucel-T is an autologous cellular immunotherapy approved by the
US FDA for the treatment of asymptomatic or minimally symptomatic metastatic
castrate resistant prostate cancer (mCRPC). In the Phase 3 mCRPC trials, APC
activation in the sipuleucel-T product correlated with overall survival. In this analysis,
sipuleucel-T product characteristics were compared across a range of disease states.
Methods: Sipuleucel-T product parameters were assessed in 4 trials of the following
treatment settings: neoadjuvant, n = 42; serologic progression following local therapy,
n = 12; asymptomatic or minimally symptomatic mCRPC, n = 341; and mCRPC
(asymptomatic and symptomatic), n = 104. Cellular composition and APC activation
(CD54 upregulation) were evaluated for all 3 sipuleucel-T doses; cumulative CD54
upregulation was calculated for each patient. In some studies, cytokines and T cell
and B cell activation markers were assessed during sipuleucel-T manufacture.
Results: Baseline demographics were generally representative of each disease state:
patients in the neoadjuvant setting were younger with lower disease burden; those
with mCRPC had the highest disease burden and more patients had received prior
chemotherapy. APC activation patterns were similar among trials, with increased
CD54 upregulation at the second and third treatment. The median cumulative fold
increase in CD54 upregulation in patients with earlier disease (neoadjuvant: 35.5,
serological progression: 43.5) was significantly greater than in patients with
asymptomatic or minimally symptomatic mCRPC (28.7) and mCRPC (21.8) (p <
0.0001). During sipuleucel-T manufacture, lymphocyte activation and cytokine
profiles were similar across disease states, with consistently enhanced expression at
the second and third doses.
Conclusion: The process of manufacturing sipuleucel-T activates APCs in both early
and late disease states, and generates similar T and B cell activation and cytokine
profiles consistent with immunological prime-boost. However, APC activation was
more robust in earlier disease states, raising the possibility that patients with less
advanced disease may derive greater benefit.
Disclosure: E.J. Small: Honoraria from Dendreon. J.D. Wesley: Employee and
Stockholder of Dendreon. D.I. Quinn: Consultant/Advisor to Dendreon, Pfizer,
Bayer, Novartis, Genentech, C. Higano: Consultant/advisory role, honoraria, and
research funding from Dendreon, D. Lin: Honoraria from Dendreon. H. Haynes:
Employee and Stockholder of Dendreon. F. Stewart: Employee and Stockholder of
Dendreon. J.B. Trager: Employee and Stockholder of Dendreon. N. Sheikh: Employee
and Stockholder of Dendreon.
943P OPENACT: PHASE 2, OPEN-LABEL STUDY OF SIPULEUCEL-T
IN METASTATIC CASTRATE-RESISTANT PROSTATE CANCER
(MCRPC)
J. Corman 1 , N. Dawson 2 , S. Hall 3 , C. Nabhan 4 , A. Ferrari 5 , A.J. Armstrong 6 ,
M.I. Murdock 7 , F. Stewart 8 , N. Sheikh 9 , D.P. Petrylak 10
1 Surgery, Virginia Mason Medical Center, Seattle, WA, UNITED STATES OF
AMERICA, 2 Medical Oncology, Georgetown University, Washington, WA,
UNITED STATES OF AMERICA, 3 Urology, Mount Sinai School of Medicine,
New York, NY, UNITED STATES OF AMERICA, 4 Hematology and Medical
Oncolgoy, Advocate Lutheran General Hospital, Park Ridge, IL, UNITED STATES
OF AMERICA, 5 Medicine, New York University Cancer Center, New York, NY,
UNITED STATES OF AMERICA, 6 Medical Oncology, Duke Cancer Institute, Duke
University, Durham, NC, UNITED STATES OF AMERICA, 7 Urology, Murdock
Urology Associates, Greenbelt, MD, UNITED STATES OF AMERICA,
8 Biometrics, Dendreon Corporation, Seattle, WA, UNITED STATES OF AMERICA,
9 Clinical Immunology, Dendreon Corporation, Seattle, WA, UNITED STATES OF
AMERICA, 10 Medical Oncology, Columbia University Medical Center, New York,
NY, UNITED STATES OF AMERICA
Background: Sipuleucel-T is an FDA-approved autologous cellular immunotherapy
for the treatment of asymptomatic or minimally symptomatic mCRPC. In the Phase
3 IMPACT trial, sipuleucel-T showed a 22% reduction in risk of death (p = 0.032)
and a 4.1-month median OS improvement (25.8 vs 21.7 months) compared with
control. OpenACT (P09-1; NCT00901342) is a Phase 2 open-label study to further
evaluate the safety and immune responses of sipuleucel-T in patients (pts) with
mCRPC.
Methods: Pts received sipuleucel-T at 2-week (wk) intervals for a total of 3 infusions.
Sipuleucel-T is manufactured from autologous PBMCs isolated by leukapheresis at
wks 0, 2 and 4, and activated with PA2024 (a recombinant fusion protein composed
of prostatic acid phosphatase [PAP] linked to GM-CSF). Cell activation is measured
by upregulation of the costimulatory molecule CD54. The primary endpoint was to
evaluate the magnitude of immune responses to sipuleucel-T treatment.
Results: From October 2009–June 2010, 104 pts were enrolled; 101 pts received ≥1
leukapheresis and 98 pts received ≥1 infusion (safety population). Pts who had
received prior docetaxel (D; 29.3% of enrolled pts) had a higher baseline
prostate-specific antigen (90 vs 40ng/mL) and a greater proportion with a time from
diagnosis of ≥6 years (93.5% vs 68.7%) compared with pts with no prior D exposure.
Consistent with previous studies, CD54 upregulation and post-culture cytokine levels
were significantly greater at wk2 and wk4 compared with wk0 (p < 0.05). At wk 6,
PAP2024 and PAP-specific humoral and T cell proliferative responses were
significantly increased from baseline. Pts without prior exposure to D had higher
CD54 cell counts and total nucleated cell count (TNC) than pts who had received
prior D. The most common AEs were infusion-related: fatigue (30.6%), nausea
(18.4%) and chills (17.3%).
Discussion: Sipuleucel-T generates antigen-specific immune responses in patients
with and without prior D exposure. However, product characteristics suggest that
patients without prior D may generate sip-T products with higher TNC, which has
previously been shown to correlate with prolonged survival, supporting earlier use in
the mCRPC treatment paradigm.
Disclosure: J. Corman: On the Board of Directors for Benaroya Research Institute
and employee of Virginia Mason Medical Center, N. Dawson: Corporate sponsored
research for Dendreon Corporation, and participation in Speakers Bureau also for
Dendreon Corporation, S. Hall: Corporate sponsored research for Dendreon and
Medivation, C. Nabhan: Participation in corporate sponsored research and speakers
bureau, A. Ferrari: Participation in advisory boards, A.J. Armstrong: Advisory boards
for Bristol Myers Squibb, Bayer, Amgen; sponsored research for Dendreon, Sanofi
Aventis, Medivation, Eli Lilly, Pfizer, Novartis, Janssen Biotech, Kanglaite Active
Biotech/Ipsen; speaker for Dendreon, Sanofi Aventis, Amgen, Pfizer, F. Stewart:
Employee and stock ownership in Dendreon Corporation, N. Sheikh: Employee of
and stock ownership in Dendreon Corporation, D.P. Petrylak: Advisory boards for
Amgen, Bayer, Pfizer, Ferring, Millenium, Novartis, Dendreon, Johnson and
Johnson, GlaxoSmithKline; sponsored research Celgene, Dendreon, Sanofi, Pfizer,
AstraZeneca, GlaxoSmithKline, Rogesen Institute, Boheringer Ingelheim, All other
authors have declared no conflicts of interest.
944P COMPARATIVE EVALUATION OF RADIATION-INDUCED
DAMAGES IN PROSTATE CANCER PATIENTS AFTER
INTRATISSUE RADIATION THERAPY USING I-125 SEEDS
AND EXTERNAL BEAM RADIATION THERAPY
I.N. Boyko, A. Ulyanov, V. Pasov, O. Terekhov
Radiation-Induced Damages, Medical Radiological Research Center of the RF
Health and Social Development Ministry, Obninsk, RUSSIAN FEDERATION
Purpose: To compare complications of external beam radiation therapy (EBRT) and
brachytherapy for prostate cancer.
Materials and methods: We performed a comparative evaluation of
radiation-induced damages of the small pelvis organs in 46 patients with prostate
cancer. The first group consisted of 24 patients who received EBRT to a total tumor
dose of 65-72 Gy. In the second group (22 patients), standard brachytherapy
procedures were carried out.
Results: The patients were distributed according to the type of radiation-induced
complications (Table 1). Table 1 Distribution of patients according to the type of
radiation-induced complications.
Group No. Cystitis
Bladder
ulcer Rectitis
Rectal
ulcer
Combined damages
(rectitis, rectal
ulcer)
Group 1 (24) 8 (33.3%) 2 (8.3%) 7 (29.2%) 3 (12.5%) 4 (16.7%)
Group 2 (22) 4 (18.2%) 0 13 (59%) 2 (9.1%) 3 (13.7%)
Thus, the rate of rectal complications was higher in the brachytherapy group
compared with the EBRT group. Radiation cystitis occurred more frequently in
patients with bladder lesions of group 1. It is worth noting that the severity of
radiation-induced damage appeared to be more marked in group
2. Radiation-induced strictures of the posterior urethra were detected in 2 (8.3%)
patients of group 1 and in 5 (22.7%) patients of group 2. More serious complications
associated with functional disturbances of organs (microcystitis, rectovesical fistula,
rectal stricture) occurred only in patients who had undergone external beam
radiation therapy.
Conclusions: Our study suggests that radiation-induced damages of the rectum and
posterior urethra occur more often after brachytherapy. EBRT can result in radiation
cystitis. It should be pointed out that EBRT can produce more severe lesions of the
pelvic organs including complications associated with physical disability.
Disclosure: All authors have declared no conflicts of interest.
Volume 23 | Supplement 9 | September 2012 doi:10.1093/annonc/mds400 | ix311