Abstract Book 2010 - CIMT Annual Meeting

021 Santegoets | Immune monitoring
Immune and clinical response monitoring in patients with metastatic
hormone-refractory prostate cancer receiving combined
Prostate GVAX and anti-CTLA4 immunotherapy
Saskia J.A.M. Santegoets 1 , A.J.M. van den Eertwegh 1 , A.G.M. Stam 2 , R.J. Scheper 2 , S.M.
Lougheed 1 , P.E.T. Scholten 2 , B.M.E. von Blomberg 2 , H. Gall 1 , K. Jooss 3 , N. Sacks 3 , T. Harding
3 , K. Hege 3 , I. Lowy 4 , W.R. Gerritsen 1 , and T.D. de Gruijl 1
1 Department of Medical Oncology, VU University medical center, Amsterdam, The Netherlands
2 Department of Pathology, VU University medical center, Amsterdam, The Netherlands
3 Cell Genesys Inc., South San Francisco, CA, USA
4 Medarex In.c, Bloomsbury, NJ, USA
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The effects of a GM-CSF-secreting allogeneic pro-
state cancer vaccine (Prostate GVAX) and the anti-
CTLA4 antibody Ipilimumab were investigated in
a Phase I dose escalation/expansion trial of patients
with metastatic, hormone-refractory prostate
cancer (mHRPC). Patients received a 500 million
cell GVAX priming dose on day 1 followed by 12 biweekly
intradermal administrations of 300 million
cells, while Ipilimumab was administered every 4
wks from day 1 for a total of 6 times. Initially, 12 patients
were enrolled in cohorts of 3 and each cohort
was assigned an escalating dose of Ipilimumab at
0.3, 1, 3 or 5 mg/kg. 16 additional patients were
enrolled in the expansion cohort of 3 mg/kg Ipilimumab.
PSA declines of more than 50% (Partial
Response, PR) were observed in 5 of 22 patients
in the 3-5 mg/kg Ipilimumab dose cohorts, and
were associated with Autoimmune Breakthrough
Events (ABE), including Grade 2 or 3 hypophysitis
and Grade 3 alveolitis. PSA stabilizations (Stable
Disease, SD) were observed in 1/3 patients in lower
(0.3 and 1 mg/kg), and in 7 of 22 in the higher (3-5
mg/kg) dose levels. Moreover, regressing bone and
lymph node metastases were observed in 2/5 PR
patients.
Immune response monitoring was performed to
identify changes that might predict or correlate
with clinical efficacy. Significant increases in frequencies
of activated and effector CD4+ and CD8+
T cells were observed by HLA-DR and ICOS expression
upon administration of high (3 and 5 mg/kg)
but not of low (0.3 and 1 mg/kg) Ipilimumab doses;
a relation to clinical behaviour was only observed
for HLA-DR with earlier and more pronounced increases
in patients with PR or SD. As an indication
of tumor-specific responsiveness HLA-Tetramer
(Tm) and seroreactivity to NY-ESO and PSMA were
tested. For NY-ESO, therapy-induced increased seroreactivity
was observed in 6/28 patients, which in
2 patients was confirmed to coincide with increased
Tm reactivity. PSMA seroconversions were observed
in a total of 12/28 patients (and, of note, in
4/5 PR), but no Tm positivity at any time was found
in a total of 15 patients tested. PSMA seroconversion
in the higher dose levels was associated with
increased overall survival (P=0.062). In addition,
significantly increased ex vivo levels of IL-4 in both
CD4+ and CD8+ T cells were observed in patients
with PR or SD (P