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

156s Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2557 General Poster Session (Board #3F), Mon, 8:00 AM-12:00 PM
First-in-human phase I and pharmacokinetic study of DTS-108 in patients
with advanced carcinomas. Presenting Author: Romain Coriat, Cochin
Teaching Hospital, AP-HP, Paris Descartes University, Paris, France
Background: DTS-108 is a soluble pro-drug of SN38, the active metabolite
of irinotecan, where the SN38 moiety is covalently linked to a 20AA
peptide through a specific cross-linker that releases SN38 by esterase bond
cleavage. DTS-108 was designed to achieve therapeutic levels of SN38,
while reducing diarrhea. Methods: This trial identified the pharmacokinetics,
the adverse event (AE) profile (NCI-CTCv3 criteria), the dose limiting
toxicities (DLT) at cycle 1, the maximum tolerated dose (MTD), and the
recommended phase II dose (RD) of intravenous DTS-108 (1-2 hours)
every two weeks (q2w) in patients (pts) with advanced/metastatic carcinomas,
ECOG:0-1, and adequate hepatic, marrow, and kidney functions.
Results: Forty-Two pts received DTS-108 across 14 dosing cohorts (range:
3-416 mg/m2). All grade AEs were asthenia (43%), nausea (43%),
diarrhea (41%), vomiting (33%), anemia (31%), rash (21%), anorexia
(21%), alopecia (19%), abdominal pain (19%), and neutropenia (19%).
Grade 3 diarrhea was only reported in two pts with either partial bowel
obstruction or recent history of a total colectomy. Neutropenia was the dose
limiting toxicity of DTS-108. Neutropenia started to be observed at doses
�56 mg/m2. At 416 mg/m2, 3/6 pts had grade 4 neutropenia. Infusion
related reactions (itching urticaria) were observed with increasing frequency
and severity at doses �75 mg/m2 and required antihistamine
premedications. At 313 mg/m2 and 416 mg/m2, infusion skin reactions
were 2/6 pts and 6/6 pts, respectively. Fluorescence HPLC was initially
used to quantify DTS-108 and its metabolites (SN-38 and SN-38G).
Sample stability analysis of this method showed that SN38 values were
inaccurate as DTS-108 degraded forming ex-vivo SN-38 during the blood
collection, plasma storage, and/or sample extraction. New processes and
analytical LC/MS/MS methods for testing SN-38 were implemented. At the
dose of 313 mg/m2, mean DTS-108, SN38, and SN38G AUCINF (CV%)
were 439293 (24%), 1992 (34%), and 4538 (46%) h*ng/mL. Tumor
stabilization (RECIST) was observed in 9 pts and confirmed in 6 pts.
Conclusions: DTS induced neutropenia and infusion skin reactions but no
dose-limiting diarrhea. The MTD was 416 mg/m2 and the RD was 313
mg/m2 q2w.
2559 General Poster Session (Board #3H), Mon, 8:00 AM-12:00 PM
Phase II trial of a GM-CSF-producing and CD40L-expressing cell line combined
with allogeneic tumor antigen as a novel vaccine for metastatic lung
adenocarcinoma. Presenting Author: Ben C. Creelan, H. Lee Moffitt Cancer
Center & Research Institute, Tampa, FL
Background: We created a vaccine in which irradiated allogeneic lung
adenocarcinoma cells are combined with a bystander K562 cell line
transfected with hCD40L and hGM-CSF. By recruiting and activating
dendritic cells, we hypothesized the vaccine would induce tumor regression
in metastatic lung adenocarcinoma. Methods: Intradermal vaccine was
given every 14 days x3, followed by monthly x3. Cyclophosphamide (300
mg/m2 IV) was administered before 1st and 4th vaccines to deplete
regulatory T-cells. All-trans retinoic acid was given (150/mg/m2/day) after
1st and 4th vaccines to enhance dendritic differentiation. Peripheral blood
mononuclear cells (PBMCs) were collected at baseline and after each
vaccination. T-cell activation profiles were analyzed by ELISpot assay and
tested by generalized Wilcoxon for correlation to survival. Results: 24
participants were accrued at a single center from 10/2006 to 6/2008, with
median age 64 and median of 3 previous lines of chemotherapy prior to
entry. 20 were former smokers and 4 had brain metastases. A total of 101
vaccines were administered. Common toxicities of any grade were joint pain
(79%) and fatigue (75%). Significant adverse events included a grade 3
hypotension and a grade 3 acute respiratory distress. No confirmed
complete or partial radiologic responses were observed. Median overall
survival (OS) was 8.0 mo (95% CI 3.5 – 12.5) and median time-toprogression
was 2.4 mo (95% CI 0.3 – 4.6). Presence of HLA-A2 conferred
reduced risk of progression (HR 0.37, 95% CI 0.14 -0.89, p�0.02) and
trend to improved OS (HR 0.59, p � 0.06). Of 14 participants with
evaluable PBMCs, 5 demonstrated sustained tumor peptide-specific T-cell
activation after vaccination. Ex vivo peptide immune response correlated
with improved OS compared to non-responders (23 vs. 7 mo, HR 0.48, p �
0.04). Conclusions: Vaccine administration was feasible and tolerable in a
heavily pretreated population of metastatic lung cancer. These data
suggest the vaccine has clinical activity in the subset with peptide-induced
T-cell immune responses and warrants further investigation. A randomized
trial of the vaccine is currently in development.
2558 General Poster Session (Board #3G), Mon, 8:00 AM-12:00 PM
Human papillomavirus type 16 (HPV16) E6/E7-specific cytotoxic T lymphocytes
(CTL) for immunotherapy of HPV-associated cancer (Ca). Presenting
Author: Carlos Almeida Ramos, Baylor College of Medicine, Houston, TX
Background: Vaccines prevent HPV-associated Ca, but their benefits in
established Ca are disappointing: although these tumors express viral E6
and E7 antigens (Ags) immune responses are limited even after vaccination,
likely due to negative environmental cues that block tumor recognition
and T cell (TC) activation in vivo. We postulated that ex vivo stimulation of
TCs in an immunologically favorable milieu would allow us to reactivate
tumor-directed CTLs from Ca patients and benefit the recipients on
reinfusion. Methods: We studied 68 patients with HPV� Ca. To detect
HPV16 E6/E7-specific TCs (HPV-TCs) in blood, we measured the IFN�
ELISpot responses of TCs stimulated by monocyte-derived dendritic cells
(DCs) loaded with pepmixes (peptide libraries of 15-mers overlapping by
11 aa) spanning E6/E7. Because HPV-TCs from these patients may be
anergized by their tumors, potent Ag presenting strategies might be
required for reactivation, and thus we stimulated these cells in the
presence of IL-6, -7, -12 and -15, as we have shown that these can induce
responses to poorly immunogenic Ags. Results: We successfully reactivated
HPV-TCs from 8/16 cervical and 33/52 oropharyngeal Ca patients. We
could expand these HPV-TCs to clinically useful numbers by using patient
B-cell blasts (BBs) as APCs. Stimulation of DC-stimulated HPV-TCs by
E6/E7 pepmix-loaded BBs further expanded (3.8 � 1.5�/round) HPV-TC
lines, which phenotypically are almost exclusively composed of TCs (98 �
3% CD3�), with a variable proportion of mostly effector memory (CD45RA–,
CD45RO�, CD62L– and CCR7–) CD4� and CD8� cells (37 � 28% and
49 � 27%, respectively). The viral/tumor associated epitopes recognized
mapped to E6 aa 49-71, 77-91 and 125-143, and E7 aa 1-19 and 73-87.
The expanded cells from patients killed E6/E7� targets (specific lysis up to
45-61% vs. 0-8% in controls, 40:1 E:T ratio). Conclusions: We have
developed a system that allows the robust generation of HPV-directed CTLs
from patients with HPV16� Ca, which recognize specific epitopes in
tumor-associated Ags. Our lines have the potential to be used for adoptive
cellular immunotherapy of HPV� Ca.
2560 General Poster Session (Board #4A), Mon, 8:00 AM-12:00 PM
Where to look for sentinel node in breast cancer? Presenting Author: Anton
J. Scharl, Klinikum St Marien, Amberg, Germany
Background: It has been observed, that the caudal Axilla on the border to
pectoralis muscle is predicive for the sentinel node. The sono-morphology
of lymph nodes has been the subject of multiple publications, usually
dealing with malignant melanoma. In the context of sentinel lymph node
biopsy (SLNB) in breast cancer patients, the following study examines the
feasibility of the sonographic differentiation of the Sentinel lymph node
(SLN) from neighboring non-SLNs and whether sentinel-ultrasound-needle
localization (SUN) is a useful addition or alternative to current methods of
“lymphatic mapping”. Methods: During a prospective study performed from
1/2003 to 9/2005 including 404 breast cancer patients (Tis-T4), the
SLNB was performed using patent blue�/- 99Tc-Nanocoll. In addition to
and independent of this method, the axilla was sonographically examined
for “reactive” lymph nodes n�180 pt. (Siemens Elegra 7.5 MHz). The
“reactivity” of the nodes was quantified using an index , which allowed the
comparison of adjacent nodes. The most “reactive” lymph node in the
caudal axilla was identified as the “Ultrasound-Sentinel-Node”(US-SLN)
and has been marked with a wire. Results: In 180 patients the SLN was
localized using the standard methods as well as (SUN). The was no
difference in detection rates of US-SLN and the standard methods in
tumor-free nodes(SLN-). However, for patients with axillary metastases
(SLN�) SUN provided superior detection rate (99,1%). The false-negativerate
was reduced from 10,7 % to 1,3%. This was attributed to the
embolization of lymph vessels afferent to the metastasized (SLN�) node
causing a bypass of the “lymphatic mapping” and inhibiting detection.
Conclusions: The SUN–Method is comparable to “lymphatic mapping” in
tumor free nodes (SLN -). If SLN is metastasized (SLN�) - SUN is superior
to the standard methods in sensitivity and specificity (80%) and the
false-negative-rate can be reduced. Systematic axilla sonography is an
effective method for the SLN-Localisation, and offers an excellent method
for quality control during SLNB.
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