Annual Meeting Proceedings Part 1 - American Society of Clinical ...

Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2561 General Poster Session (Board #4B), Mon, 8:00 AM-12:00 PM
A randomized pilot phase I study of modified carcinoembryonic antigen
(CEA) peptide (CAP1-6D)/montanide/GM-CSF-vaccine (CEA-vac) in patients
(pts) with pancreatic adenocarcinoma (PC). Presenting Author:
Daniel M. Geynisman, University of Chicago, Chicago, IL
Background: CEA is expressed in �90% of PC and may be an appropriate
immunotherapy target. CEA is poorly immunogenic due to immune tolerance;
CAP1-6D, an altered peptide ligand can help bypass tolerance. We
conducted a pilot randomized phase I trial in PC pts to determine the
appropriate CEA-vac peptide dose required to induce an optimal cytotoxic T
lymphocyte (CTL) response. Methods: Eligible pts, PS 0-1, expressed
HLA-A2 and had CEA-expressing, histologically-confirmed, previouslytreated
PC. Randomization: 10 �g (arm A), 100 �g (arm B) or 1000 �g
(arm C). CEA-vac was given Q 2 weeks until disease progression (amended
4/09 to a 24 dose maximum). Results: From 2/06-9/09 66 pts were
screened for HLA-A2; 19 pts randomized to Arms A/B/C 5/8/6 are evaluable
for toxicity; 14 pts (5/5/4) who received at least 3 doses of CEA-vac are
evaluable for the primary immunologic endpoint. Median age: 60 (range
27-86), female: 68%, PS 0: 58%. Disease stage: metastatic (M) 74%,
locally advanced (LA) 5%, resected (R) 21%. Cycles: median 4 (range
1-81). Mean CTL response by ELISPOT (spots per 104 CD8� cells, Arm
A/B/C): 37/126/248. (A vs. C, p�0.037). CTL responses developed in
20%/60%/100% of pts in Arms A/B/C. 1 LA pt in Arm C had a complete
radiologic response, a strong CTL response, and remains alive at 71 mo. 1
M pt in Arm B had SD for 11 mo, a strong CTL response, and is alive at 39
mo. Toxicity: no grade 3/4 toxicities, 58% grade 1/2 skin toxicity.
Conclusions: CTL response was dose-dependent in this randomized phase I
trial; the 1 mg peptide dose elicited the most robust CTL response. Clinical
activity was demonstrated at the higher doses. Further evaluation of 1 mg
CEA-vac with stronger adjuvants, combined with agents to overcome
immune inhibitory pathways, may be warranted in PC pts. Supported by
UCCCSG P30CA14599.
2563 General Poster Session (Board #4D), Mon, 8:00 AM-12:00 PM
Evaluation of immune activation following neoadjuvant sipuleucel-T in
subjects with localized prostate cancer. Presenting Author: Nadeem A.
Sheikh, Dendreon Corporation, Seattle, WA
Background: Sipuleucel-T is an FDA-approved autologous cellular immunotherapy
for men with asymptomatic or minimally symptomatic metastatic
castrate resistant prostate cancer (mCRPC). NeoACT (Study P07-1) was
undertaken to investigate neoadjuvant sipuleucel-T treatment in subjects
with localized prostate cancer. Methods: In this open-label, phase 2 study
(NCT00715104), subjects with localized prostate cancer received 3
infusions of sipuleucel-T at approximately 2-week intervals, beginning 6–7
weeks prior to radical prostatectomy (RP). Following RP, subjects were
randomized 1:1 to receive / not receive a sipuleucel-T booster infusion 12
weeks post-RP. Cellular composition, antigen presenting cell (APC) activation,
cytokines, and T and B cell activation were profiled before and after
each culture with PA2024, the fusion protein containing prostatic acid
phosphatase used to generate sipuleucel-T. Results: Of the 42 enrolled
subjects (median age: 61 years; 98% Caucasian), 38 received all 3
infusions of sipuleucel-T, and 15 subjects received a booster infusion.
Consistent with sipuleucel-T in mCRPC, CD54 upregulation (APC activation)
was greater at the second and third infusions relative to the first
(p�0.001). The expression of early T cell activation markers (CD134,
CD137, CD278 and CD279) were increased in pre-culture cells obtained
after the first infusion, and further increased after culture. Activated
mature B cells (CD20�CD27�IgD�CD86�) increased following culture
in all 3 products (p�0.01); memory B cells (CD20�CD27�IgD-CD86�)
were progressively increased following the first infusion (p�0.05 third vs.
first product). TNF-�, IFN-�, IL-2 were secreted at higher levels during
culture of the second and third products (all p�0.001). The observed
increases in CD54 upregulation, early T cell activation markers, and
memory and activated mature B cells were maintained at booster treatment.
Conclusions: Neoadjuvant sipuleucel-T resulted in robust immune
system activation that was consistent with boosting of an immune response
primed with the first infusion. Immune activation was maintained at the
booster infusion 3 months following initial sipuleucel-T treatment.
157s
2562 General Poster Session (Board #4C), Mon, 8:00 AM-12:00 PM
Lymphoid and myeloid biomarkers for clinical outcome of combined
immunotherapy with granulocyte-macrophage colony-stimulating factortranduced
allogeneic prostate cancer cells (GVAX) and ipilimumab in
castration-resistant prostate cancer patients. Presenting Author: Alfons
J. M. van den Eertwegh, VU University Medical Center Department of
Medical Oncology, Amsterdam, Netherlands
Background: In a phase-I dose escalation trial in patients with castrationresistant
prostate cancer we showed that GVAX and ipilimumab had an
acceptable safety profile. Moreover, we observed tumor responses and
prolonged survival as compared to the Halabi predicted overall survival
(OS). However, ipilimumab can also lead to severe immune-related adverse
events. To avoid unnecessary exposure to this risk, it is essential to identify
biomarkers that correlate with clinical activity. Methods: Patients had
castration-resistant prostate cancer and were chemotherapy-naïve. They
received bi-weekly GVAX for a 24 week period combined with monthly
intravenous administrations of ipilimumab. Each cohort of 3 patients
received an escalating dose of ipilimumab at 0·3, 1·0, 3·0 or 5·0 mg/kg. In
an expansion cohort 16 patients were treated with GVAX and 3·0 mg/kg
ipilimumab. Flowcytometric monitoring of lymphoid and myeloid subsets
in blood were performed. Results: We observed a significantly prolonged OS
for patients with high pre-treatment frequencies of CD4�CTLA-4�,
CD4�PD-1�, or differentiated CD8� T cells, or low pre-treatment frequencies
of differentiated CD4� T cells or CD4�CD25hiFoxP3� regulatory T
cells. In contrast, increased frequencies of granulocytic Myeloid-Derived
Suppressor Cells (MDSC) and high pre-treatment frequencies of monocytic
CD14�HLA-DRlo/- MDSC were associated with reduced OS. Treatmentinduced
CD4� T cell differentiation and CD4� and CD8� T cell activation
was associated with clinical benefit. Moreover, treatment-induced activation
of CD1c� conventional Dendritic Cells (cDC) and 6-sulfo LacNAc�
inflammatory DC were associated with significantly prolonged OS.
Conclusions: Together these data provide an immune profile to predict
clinical outcome. Importantly, cluster analysis revealed pre-treatment,
CRPC-associated expression of CTLA-4� by CD4� T cells to be a dominant
predictor for OS after GVAX/ipilimumab. This potentially biomarker for
patient selection should be validated in patients treated with ipilimumab.
2564 General Poster Session (Board #4E), Mon, 8:00 AM-12:00 PM
Neoadjuvant sipuleucel-T in localized prostate cancer: Effects on immune
cells within the prostate tumor microenvironment. Presenting Author:
Lawrence Fong, University of California, San Francisco, San Francisco, CA
Background: Sipuleucel-T is an FDA-approved autologous cellular immunotherapy
for patients with asymptomatic or minimally symptomatic metastatic
castrate resistant prostate cancer (mCRPC). To date, studies of
sipuleucel-T in patients with mCRPC have studied immune response in
peripheral blood. The effects of sipuleucel-T on prostate tumors are
unknown. Methods: NeoACT (P07-1; NCT00715104) is an open-label,
phase 2 study of patients with localized prostate cancer who received
sipuleucel-T prior to radical prostatectomy (RP) to examine the immunologic
effects of treatment on prostate tissue. Patients received 3 infusions
of sipuleucel-T at approximately 2-week intervals, beginning 6-7 weeks
prior to RP. The primary endpoint was the change in the frequency of
lymphocytes between prostate biopsies (pre-treatment) and RP tissue
(post-treatment), as assessed by immunohistochemistry (IHC). Results: The
median age of the 42 enrolled patients was 61 years, and all had an ECOG
performance status of 0. Thirty-eight patients received all 3 pre-RP
sipuleucel-T infusions. To date, tissue IHC analysis has been completed on
32 patients. Treatment-related AEs were manageable and transient.
Sipuleucel-T did not appear to impact surgery, as judged by operative
complications, procedure time, and estimated blood loss. Frequent events
that occurred �1 day after infusion (�10% of patients) were fatigue,
headache, and myalgia. Significant increases (�3 fold) in CD3� and
CD4� T cell populations were observed at the tumor interface (where
benign and malignant glands interface), compared with the pre-treatment
biopsy, benign RP tissue, and tumor RP tissue (ANOVA post hoc Newman-
Keuls test: p�0.0001 for each comparison). FoxP3� CD4� T cells were
also increased (p�0.0005) at the tumor interface, but represented a small
fraction of the observed CD4� T cells. Conclusions: Neoadjuvant sipuleucel-T
treatment is associated with an increased frequency of T cells in
prostate cancer tissue at the interface of the benign and malignant glands.
These data suggest that sipuleucel-T can modulate the presence of
lymphocytes at the prostate tumor site. Work is ongoing to more fully
characterize the immune response.
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