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

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156s Developmental Therapeutics—<strong>Clinical</strong> Pharmacology and Immunotherapy<br />

2557 General Poster Session (Board #3F), Mon, 8:00 AM-12:00 PM<br />

First-in-human phase I and pharmacokinetic study <strong>of</strong> DTS-108 in patients<br />

with advanced carcinomas. Presenting Author: Romain Coriat, Cochin<br />

Teaching Hospital, AP-HP, Paris Descartes University, Paris, France<br />

Background: DTS-108 is a soluble pro-drug <strong>of</strong> SN38, the active metabolite<br />

<strong>of</strong> irinotecan, where the SN38 moiety is covalently linked to a 20AA<br />

peptide through a specific cross-linker that releases SN38 by esterase bond<br />

cleavage. DTS-108 was designed to achieve therapeutic levels <strong>of</strong> SN38,<br />

while reducing diarrhea. Methods: This trial identified the pharmacokinetics,<br />

the adverse event (AE) pr<strong>of</strong>ile (NCI-CTCv3 criteria), the dose limiting<br />

toxicities (DLT) at cycle 1, the maximum tolerated dose (MTD), and the<br />

recommended phase II dose (RD) <strong>of</strong> intravenous DTS-108 (1-2 hours)<br />

every two weeks (q2w) in patients (pts) with advanced/metastatic carcinomas,<br />

ECOG:0-1, and adequate hepatic, marrow, and kidney functions.<br />

Results: Forty-Two pts received DTS-108 across 14 dosing cohorts (range:<br />

3-416 mg/m2). All grade AEs were asthenia (43%), nausea (43%),<br />

diarrhea (41%), vomiting (33%), anemia (31%), rash (21%), anorexia<br />

(21%), alopecia (19%), abdominal pain (19%), and neutropenia (19%).<br />

Grade 3 diarrhea was only reported in two pts with either partial bowel<br />

obstruction or recent history <strong>of</strong> a total colectomy. Neutropenia was the dose<br />

limiting toxicity <strong>of</strong> DTS-108. Neutropenia started to be observed at doses<br />

�56 mg/m2. At 416 mg/m2, 3/6 pts had grade 4 neutropenia. Infusion<br />

related reactions (itching urticaria) were observed with increasing frequency<br />

and severity at doses �75 mg/m2 and required antihistamine<br />

premedications. At 313 mg/m2 and 416 mg/m2, infusion skin reactions<br />

were 2/6 pts and 6/6 pts, respectively. Fluorescence HPLC was initially<br />

used to quantify DTS-108 and its metabolites (SN-38 and SN-38G).<br />

Sample stability analysis <strong>of</strong> this method showed that SN38 values were<br />

inaccurate as DTS-108 degraded forming ex-vivo SN-38 during the blood<br />

collection, plasma storage, and/or sample extraction. New processes and<br />

analytical LC/MS/MS methods for testing SN-38 were implemented. At the<br />

dose <strong>of</strong> 313 mg/m2, mean DTS-108, SN38, and SN38G AUCINF (CV%)<br />

were 439293 (24%), 1992 (34%), and 4538 (46%) h*ng/mL. Tumor<br />

stabilization (RECIST) was observed in 9 pts and confirmed in 6 pts.<br />

Conclusions: DTS induced neutropenia and infusion skin reactions but no<br />

dose-limiting diarrhea. The MTD was 416 mg/m2 and the RD was 313<br />

mg/m2 q2w.<br />

2559 General Poster Session (Board #3H), Mon, 8:00 AM-12:00 PM<br />

Phase II trial <strong>of</strong> a GM-CSF-producing and CD40L-expressing cell line combined<br />

with allogeneic tumor antigen as a novel vaccine for metastatic lung<br />

adenocarcinoma. Presenting Author: Ben C. Creelan, H. Lee M<strong>of</strong>fitt Cancer<br />

Center & Research Institute, Tampa, FL<br />

Background: We created a vaccine in which irradiated allogeneic lung<br />

adenocarcinoma cells are combined with a bystander K562 cell line<br />

transfected with hCD40L and hGM-CSF. By recruiting and activating<br />

dendritic cells, we hypothesized the vaccine would induce tumor regression<br />

in metastatic lung adenocarcinoma. Methods: Intradermal vaccine was<br />

given every 14 days x3, followed by monthly x3. Cyclophosphamide (300<br />

mg/m2 IV) was administered before 1st and 4th vaccines to deplete<br />

regulatory T-cells. All-trans retinoic acid was given (150/mg/m2/day) after<br />

1st and 4th vaccines to enhance dendritic differentiation. Peripheral blood<br />

mononuclear cells (PBMCs) were collected at baseline and after each<br />

vaccination. T-cell activation pr<strong>of</strong>iles were analyzed by ELISpot assay and<br />

tested by generalized Wilcoxon for correlation to survival. Results: 24<br />

participants were accrued at a single center from 10/2006 to 6/2008, with<br />

median age 64 and median <strong>of</strong> 3 previous lines <strong>of</strong> chemotherapy prior to<br />

entry. 20 were former smokers and 4 had brain metastases. A total <strong>of</strong> 101<br />

vaccines were administered. Common toxicities <strong>of</strong> any grade were joint pain<br />

(79%) and fatigue (75%). Significant adverse events included a grade 3<br />

hypotension and a grade 3 acute respiratory distress. No confirmed<br />

complete or partial radiologic responses were observed. Median overall<br />

survival (OS) was 8.0 mo (95% CI 3.5 – 12.5) and median time-toprogression<br />

was 2.4 mo (95% CI 0.3 – 4.6). Presence <strong>of</strong> HLA-A2 conferred<br />

reduced risk <strong>of</strong> progression (HR 0.37, 95% CI 0.14 -0.89, p�0.02) and<br />

trend to improved OS (HR 0.59, p � 0.06). Of 14 participants with<br />

evaluable PBMCs, 5 demonstrated sustained tumor peptide-specific T-cell<br />

activation after vaccination. Ex vivo peptide immune response correlated<br />

with improved OS compared to non-responders (23 vs. 7 mo, HR 0.48, p �<br />

0.04). Conclusions: Vaccine administration was feasible and tolerable in a<br />

heavily pretreated population <strong>of</strong> metastatic lung cancer. These data<br />

suggest the vaccine has clinical activity in the subset with peptide-induced<br />

T-cell immune responses and warrants further investigation. A randomized<br />

trial <strong>of</strong> the vaccine is currently in development.<br />

2558 General Poster Session (Board #3G), Mon, 8:00 AM-12:00 PM<br />

Human papillomavirus type 16 (HPV16) E6/E7-specific cytotoxic T lymphocytes<br />

(CTL) for immunotherapy <strong>of</strong> HPV-associated cancer (Ca). Presenting<br />

Author: Carlos Almeida Ramos, Baylor College <strong>of</strong> Medicine, Houston, TX<br />

Background: Vaccines prevent HPV-associated Ca, but their benefits in<br />

established Ca are disappointing: although these tumors express viral E6<br />

and E7 antigens (Ags) immune responses are limited even after vaccination,<br />

likely due to negative environmental cues that block tumor recognition<br />

and T cell (TC) activation in vivo. We postulated that ex vivo stimulation <strong>of</strong><br />

TCs in an immunologically favorable milieu would allow us to reactivate<br />

tumor-directed CTLs from Ca patients and benefit the recipients on<br />

reinfusion. Methods: We studied 68 patients with HPV� Ca. To detect<br />

HPV16 E6/E7-specific TCs (HPV-TCs) in blood, we measured the IFN�<br />

ELISpot responses <strong>of</strong> TCs stimulated by monocyte-derived dendritic cells<br />

(DCs) loaded with pepmixes (peptide libraries <strong>of</strong> 15-mers overlapping by<br />

11 aa) spanning E6/E7. Because HPV-TCs from these patients may be<br />

anergized by their tumors, potent Ag presenting strategies might be<br />

required for reactivation, and thus we stimulated these cells in the<br />

presence <strong>of</strong> IL-6, -7, -12 and -15, as we have shown that these can induce<br />

responses to poorly immunogenic Ags. Results: We successfully reactivated<br />

HPV-TCs from 8/16 cervical and 33/52 oropharyngeal Ca patients. We<br />

could expand these HPV-TCs to clinically useful numbers by using patient<br />

B-cell blasts (BBs) as APCs. Stimulation <strong>of</strong> DC-stimulated HPV-TCs by<br />

E6/E7 pepmix-loaded BBs further expanded (3.8 � 1.5�/round) HPV-TC<br />

lines, which phenotypically are almost exclusively composed <strong>of</strong> TCs (98 �<br />

3% CD3�), with a variable proportion <strong>of</strong> mostly effector memory (CD45RA–,<br />

CD45RO�, CD62L– and CCR7–) CD4� and CD8� cells (37 � 28% and<br />

49 � 27%, respectively). The viral/tumor associated epitopes recognized<br />

mapped to E6 aa 49-71, 77-91 and 125-143, and E7 aa 1-19 and 73-87.<br />

The expanded cells from patients killed E6/E7� targets (specific lysis up to<br />

45-61% vs. 0-8% in controls, 40:1 E:T ratio). Conclusions: We have<br />

developed a system that allows the robust generation <strong>of</strong> HPV-directed CTLs<br />

from patients with HPV16� Ca, which recognize specific epitopes in<br />

tumor-associated Ags. Our lines have the potential to be used for adoptive<br />

cellular immunotherapy <strong>of</strong> HPV� Ca.<br />

2560 General Poster Session (Board #4A), Mon, 8:00 AM-12:00 PM<br />

Where to look for sentinel node in breast cancer? Presenting Author: Anton<br />

J. Scharl, Klinikum St Marien, Amberg, Germany<br />

Background: It has been observed, that the caudal Axilla on the border to<br />

pectoralis muscle is predicive for the sentinel node. The sono-morphology<br />

<strong>of</strong> lymph nodes has been the subject <strong>of</strong> multiple publications, usually<br />

dealing with malignant melanoma. In the context <strong>of</strong> sentinel lymph node<br />

biopsy (SLNB) in breast cancer patients, the following study examines the<br />

feasibility <strong>of</strong> the sonographic differentiation <strong>of</strong> the Sentinel lymph node<br />

(SLN) from neighboring non-SLNs and whether sentinel-ultrasound-needle<br />

localization (SUN) is a useful addition or alternative to current methods <strong>of</strong><br />

“lymphatic mapping”. Methods: During a prospective study performed from<br />

1/2003 to 9/2005 including 404 breast cancer patients (Tis-T4), the<br />

SLNB was performed using patent blue�/- 99Tc-Nanocoll. In addition to<br />

and independent <strong>of</strong> this method, the axilla was sonographically examined<br />

for “reactive” lymph nodes n�180 pt. (Siemens Elegra 7.5 MHz). The<br />

“reactivity” <strong>of</strong> the nodes was quantified using an index , which allowed the<br />

comparison <strong>of</strong> adjacent nodes. The most “reactive” lymph node in the<br />

caudal axilla was identified as the “Ultrasound-Sentinel-Node”(US-SLN)<br />

and has been marked with a wire. Results: In 180 patients the SLN was<br />

localized using the standard methods as well as (SUN). The was no<br />

difference in detection rates <strong>of</strong> US-SLN and the standard methods in<br />

tumor-free nodes(SLN-). However, for patients with axillary metastases<br />

(SLN�) SUN provided superior detection rate (99,1%). The false-negativerate<br />

was reduced from 10,7 % to 1,3%. This was attributed to the<br />

embolization <strong>of</strong> lymph vessels afferent to the metastasized (SLN�) node<br />

causing a bypass <strong>of</strong> the “lymphatic mapping” and inhibiting detection.<br />

Conclusions: The SUN–Method is comparable to “lymphatic mapping” in<br />

tumor free nodes (SLN -). If SLN is metastasized (SLN�) - SUN is superior<br />

to the standard methods in sensitivity and specificity (80%) and the<br />

false-negative-rate can be reduced. Systematic axilla sonography is an<br />

effective method for the SLN-Localisation, and <strong>of</strong>fers an excellent method<br />

for quality control during SLNB.<br />

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