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

148s Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2525 Poster Discussion Session (Board #13), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
CD40 ligand/interferon-� matured DC immunization with gp100 antigen
HLA class I A *0201 restricted peptides in patients with newly diagnosed
metastatic melanoma. Presenting Author: Gerald P. Linette, Washington
University, St. Louis, MO
Background: CD40L/IFN-� matured Dendritic Cells (DCs) produce IL-12
and are potent antigen-presenting cells for naïve resting T cells. We sought
to determine the magnitude and kinetics of CD8� T cell growth in patients
receiving autologous CD40L/IFN-� matured DC and identify biomarkers
associated with clinical outcome. Methods: A phase I clinical trial
(NCT00683670) incorporating CD40L/IFN-� for the ex vivo maturation of
autologous DCs pulsed with three well characterized gp100 melanoma
antigen derived peptides (G154, G209-2M, G280-9V) was initiated with
enrollment from 2008-11 at a single center. HLA-A*0201� individuals
with treatment naïve metastatic melanoma were immunized every 3 weeks
by intravenous infusion for six doses after a single dose of cyclophosphamide
(300 mg/m2 iv). CT imaging was performed at baseline, week 9
and 18 for clinical assessment using RECIST. Responding patients were
eligible for maintenance doses every 2-4 months. PBMC were taken weekly
for immune monitoring by tetramer analysis and functional assays. DC
preparations were characterized to assess for biomarkers of response.
Results: 10 patients were screened. Among the 7 treated patients, there
were 3 confirmed responses (independently verified), including one durable
CR �3 years and 2 PR. Three patients had rapid disease progression
and received only 3 doses. Four patients (1 CR, 2 PR, 1 PD) received 6 or
more vaccine doses. No SAEs were noted. There was no correlation between
tumor volume and response. Using pre-specified immune response criteria,
6 (86%) treated patients developed CD8� T cell immunity to all three
peptides as assessed by tetramer analysis. The vaccine-induced T cells
from all 6 individuals were polyfunctional and killed gp100�, HLA-A2�
human melanoma targets in a standard 51Cr release assay. IL-12 production
by DCs correlated with TTP (p�0.0198, likelihood ratio test) but not
OS (p�0.08). Conclusions: Weekly immune monitoring reveals the rapid
onset of CD8� T cell immunity against gp100 among the responder
patients. This is the first DC vaccine clinical trial in melanoma to
demonstrate a correlation of IL-12 production and TTP.
2527 Poster Discussion Session (Board #15), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
EGF-based cancer vaccine for advanced NSCLC: Results from a phase III
trial. Presenting Author: Tania Crombet Ramos, Center of Molecular
Immunology, Havana, Cuba
Background: The prognosis of patients with advanced non small cell lung
cancer (NSCLC) remains dismal. Epidermal Growth Factor Receptor
(EGFR) is overexpressed in epithelial tumors and its role in the development
of NSCLC is widely proven. The EGF vaccine is a therapeutic cancer
vaccine composed by recombinant Epidermal Growth Factor (EGF) conjugated
to a carrier protein, P64K from Neisseria Meningitides and Montanide,
as adjuvant. The vaccine is intended to induce antibodies against
self EGF that would block EGF-EGFR interaction. Methods: A multicentric,
randomized Phase III trial was designed to assess the efficacy, immunogenicity
and safety of the EGF cancer vaccine in advanced NSCLC patients.
Patients older than 18 years with histology or cytology proven NSCLC at
stage IIIB and IV were enrolled in the trial. All patients received no less than
4 platinum-based cycles and achieved at least stable disease, before
entering the trial. A low-dose of cyclophosphamide was administered 3
days before the first immunization. Then, patients received 4 quarterly
immunizations followed by monthly re-immunizations. Control patients
received best supportive care. Results: In total, 405 patients bearing stage
IIIB/IV NSCLC were recruited in 21 sites. The vaccine was very well
tolerated. The most frequent adverse events consisted in grade 1/2
injection site pain, fever, headache, vomiting and chills. The vaccine was
immunogenic. Antibody titers against EGF significantly increased with
vaccination and on the contrary, EGF concentration in sera showed a fast
reduction after immunization. There was an inverse correlation between the
anti-EGF antibody titers and the EGF concentration in sera. Baseline EGF
concentration was a worse prognostic factor for the control patients and a
predictive factor for vaccinated subjects. The overall survival was significantly
better for vaccinated patients as compared to controls. There was a
direct correlation between the antibody titers and survival. Conclusions: The
EGF cancer vaccine was very well tolerated and significantly increased
overall survival of the vaccinated patients. Baseline EGF concentration
predicted survival benefit. The EGF vaccine is a new therapeutic option for
advanced NSCLC patients.
2526 Poster Discussion Session (Board #14), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Interim analysis of a phase II randomized clinical trial of samrium-153
(Sm-153) with or without PSA-TRICOM vaccine in metastatic castrationresistant
prostate cancer after docetaxel. Presenting Author: Christopher
Ryan Heery, Medical Oncology Branch, National Cancer Institute, National
Institutes of Health, Bethesda, MD
Background: A prior randomized, placebo-controlled, multi-center phase 2
trial of PSA-TRICOM (PROSTVAC) demonstrated an overall survival benefit.
Sm-153 is a radiopharmaceutical that targets osteoblastic bone lesions.
Preclinical data indicated that Sm-153 could alter tumor phenotype,
causing upregulation of Fas, MHC Class I, and tumor-associated antigens,
making tumor cells more amenable to immune-mediated killing. Methods:
This is a phase 2 multi-center trial design intended to randomize 68
patients (pts) to Sm-153 with or without PROSTVAC. Eligibility included
castrate resistant prostate cancer bone metastases, no visceral disease,
prior docetaxel, ECOG �2, and normal organ function. Sm-153 was given
at 1mCi/kg IV on day 8 and then every 12 weeks. PROSTVAC was given on
days 1, 15, 29, then every 4 weeks. The 1° endpoint is a comparison of
progression-free survival at 4 months (mo) utilizing PCCWG, but not PSA
criteria. 68 patients will provide 80% power to detect a difference of 15%
vs. 40% without progression at 4 mo with a one-tailed alpha � 0.10
assuming Fisher’s exact test comparing these fractions as the primary
method of analysis. 2° endpoints are OS, ORR, PSA changes, immunologic,
toxicity, and palliation. Reported here is the result of a pre-specified
interim analysis, which required �20% conditional power to detect 15%
vs. 40% without progression at 4 months for the trial to continue. Results:
Of 37 enrolled pts, 3 were not evaluable for PFS. PFS and PSA findings are
found below. Hematologic toxicities (anemia, thrombocytopenia, neutropenia,
or lymphocytopenia) are most common, with grade 3 or 4 thrombocytopenia
occurring in 22% and 26% of treatment cycles on Arms A and B,
respectively. The conditional power for the comparison of fractions without
progression at 4 mo is 77%. Conclusions: This interim analysis suggests the
combination of PROSTVAC and Sm-153 is well tolerated with similar
toxicity profile to Sm-153 alone. The early indication of improved TTP
warrants continued study accrual.
Sm-153
(A)
Sm-153 � PROSTVAC
(B)
PFS
At4mo 2/17 (11.8%) 5/17 (29.4%)
Median PFS days 60 117
Pt # confirmed PSA decline
> 30% 0 4
> 50% 0 2
2528 Poster Discussion Session (Board #16), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Association of idiotype vaccine-induced T-cell response with improved
survival and time-to-next treatment (TTNT) in untreated mantle cell
lymphoma (MCL). Presenting Author: Kieron Dunleavy, Metabolism Branch,
National Cancer Institute, National Institutes of Health, Bethesda, MD
Background: Murine models show Id-vaccines induce antitumor responses,
possibly through Th1/Tc1 cytokines. We report an 11-year follow-up of
Id-vaccine following DA-EPOCH-Rituximab in 26 untreated MCL patients.
Methods: DA-EPOCH-R was administered q3 weeks � 6, followed 12 weeks
later by 5 cycles of Id-vaccine. Id protein was made by hybridoma
technology, conjugated to keyhole limpet hemocyanin (KLH) and administered
with GM-CSF. Pre- and post-vaccine immune responses (IR) were
tested in parallel: anti-Id and anti-KLH humoral responses (ELISA);
anti-KLH cellular responses (intracellular cytokine assay); and anti-tumor
cellular responses (cytokine induction, IFN� ELISPOT). Results: Characteristics:
median age 57 (r 22-73), blastoid variant 15%, and MIPI (low-65%;
intermediate-16%; high-19%). With 122 mo median follow-up (r 111-
132), the median PFS is 24 mo and OS is 104 mo. MIPI was associated
with OS (p�0.0002); median OS: low (not reached), intermediate (84 mo)
and high (44 mo). We found no association between OS and anti-KLH IR,
anti-Id humoral response, IFN� ELISPOT, or antitumor TNF� or IFN�
responses. Normalized antitumor T-cell GM-CSF response (median �4.3
vs. �4.3) was associated with OS of 79 mo vs. not reached, respectively
(p�0.015 (unadj.) and p�0.045 (adj.)). MIPI (p�0.02) and GM-CSF
(p�0.057) were independently associated with OS. TTNT (based on
disease activity), correlated with antitumor GM-CSF response (p�0.018)
but not MIPI and was independent of MIPI (GM-CSF; p�0.041). Correlation
of pre-and post-treatment GM-CSF production suggested a priming
effect. Tumor proliferation by GEP did not correlate with OS (n�14).
Conclusions: Antitumor GM-CSF response was significantly associated with
OS and TTNT, suggesting antitumor cellular immune response significantly
delayed tumor growth. Antitumor GM-CSF response may serve as a
surrogate biomarker for vaccine efficacy. Our results are consistent with
recent data that T-cell GM-CSF production is required for breaking
tolerance against self-antigens. Id vaccines may prolong survival of MCL
following rituximab-based chemotherapy and should be further evaluated.
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