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

Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2585 General Poster Session (Board #7B), Mon, 8:00 AM-12:00 PM
Effect of the vaccine Ad5 [E1-, E2b-]-CEA(6D) on CEA-directed CMI
responses in patients with advanced CEA-expressing malignancies in a
phase I/II clinical trial. Presenting Author: Michael Morse, Duke University
Medical Center, Durham, NC
Background: Adenovirus (Ad) vectors are promising platforms for use as
cancer vaccines because of their substantial immunogenicity; however,
Ad-specific neutralizing antibodies, present due to natural infection, limit
their use. We created a new vector containing additional deletions of the
E2b gene and observed that this Ad5 [E1-, E2b-] vector, engineered to
express carcinoembryonic antigen (CEA(6D)), could induce antitumor
immune responses in mice despite pre-existing Ad5 immunity. The
purpose of the current translational study was to evaluate the immunologic
effect of increasing doses of Ad5 [E1-, E2b-]-CEA(6D) in mice and then to
extended these pre-clinical observations into a phase I/II study. Methods:
Ad5 naïve female C57Bl/6 mice, 4-6 weeks old, were immunized subcutaneously
3 times at 2 week intervals with doses of 1.4X107 viral particles
(vp) up to1.4X109 vp of Ad5 [E1-, E2b-]-CEA(6D). Two weeks after the last
immunization, splenocytes were harvested for immune determinations.
Cohorts of patients (n�25 total) with advanced colorectal cancer, refractory
to prior therapies, received escalating doses of Ad5 [E1-, E2B-]-
CEA(6D) (109 to 1011 vp) subcutaneously every 3 weeks for 3
immunizations.CEA-specific cell mediated immunity was measured by
ELISPOT. Results: Increasing doses of Ad5 [E1-, E2b-]-CEA(6D) in mice
induced increasing CEA-specifc CMI responses. Similarly, patients who
received the highest dose of Ad5 [E1-, E2b-]-CEA(6D) exhibited the
highest levels of CEA-specific CMI responses. The induction of CEAspecific
CMI responses increased over the course of the 3 injections despite
the presence of pre-existing Ad5 immunity in the majority (75%) of
patients. There were no drug related grade 3/4 toxicities.Two patients with
stable disease remained so during the study. All other patients experienced
progressive disease; however, 1-year survival was 54%. Conclusions:
Multiple homologous doses of Ad5 [E1-, E2b-]-CEA(6D) could break
tolerance and generate CEA-specific CMI responses in the setting of Ad
specific immunity in colorectal cancer patients.
2587 General Poster Session (Board #7D), Mon, 8:00 AM-12:00 PM
Development of an assay based on SOMAmer affinity reagents that detects
drug-unbound serum EGFR in the presence of cetuximab and panitumumab.
Presenting Author: Noh Jin Park, Quest Diagnostics, San Juan
Capistrano, CA
Background: EGFR is an oncogene product whose extracellular domain
(ECD) can be either up-regulated or down-regulated in serum of patients
with various cancers. In colon cancer patients with positive tissue EGFR
expression, 2 EGFR ECD-targeting monoclonal antibody drugs, cetuximab
(Erbitux) and panitumumab (Vectibix), are widely used chemotherapeutic
agents. Patient responses to these drugs vary, and the mechanism of this
variability remains unelucidated. Methods: A Slow Off-Rate Modified
Aptamer (SOMAmer) targeting the EGFR ECD was selected via Systematic
Evolution of Ligands by Exponential Enrichment (SELEX). Using this
SOMAmer as a capturing reagent and based on published studies ( Gold et
al. PLoS ONE; Dec 7, 2010:10.1371/journal.pone.0015004), we developed
a quantitative serum EGFR assay to reliably quantify EGFR in serum.
Results: Recovery tests using various amounts of purified EGFR spiked into
serum demonstrated a full level of EGFR. Intra and inter assay variability
were tested and showed minimum variability. The detection range is 0.95
ng/ml to 600 ng/ml. Interestingly, when serum samples from patients
taking cetuximab or panitumumab at the time of blood collection were
tested, we observed markedly lower levels of EGFR-captured SOMAmer.
ELISA assays from 2 different vendors showed normal to high levels of
EGFR in these samples. We further showed that pretreatment of normal
serum with either cetuximab or panitumumab can dose-dependently
reduce the EGFR SOMAmer signal. The data suggest that our EGFR
SOMAmer assay detects serum EGFR molecules that are unbound by
cetuximab or panitumumab. Some treated patient samples had more
drastic reductions in circulating serum EGFR than others. Conclusions:
Various assay development parameters such as accuracy, detection range,
and intra and inter assay variability showed that a SOMAmer-based assay
detecting serum EGFR can be used in a clinical setting. Our data suggest
that this assay can accurately measure drug-unbound EGFR in patients,
which may serve as a surrogate drug efficacy indicator, and this may help
physicians to adjust the drug dosage. Further studies will be necessary to
investigate this possibility.
163s
2586 General Poster Session (Board #7C), Mon, 8:00 AM-12:00 PM
Effect of modulation of the hostile tumor microenvironment through
adoptive transfer of IL-12 expressing MUC-16 targeted T cells on ovarian
tumors in vivo. Presenting Author: Alena A. Chekmasova, Memorial
Sloan-Kettering Cancer Center, New York, NY
Background: T cells may be genetically modified to recognize tumor
associated antigens (TAAs) through the introduction of genes encoding
artificial T cell receptors termed chimeric antigen receptors (CARs).
MUC16 (CA125) is an antigen over-expressed on ovarian carcinomas and a
serum marker for the diagnosis of ovarian cancer. We have previously
demonstrated enhanced antitumor efficacy of CAR � T cells further modified
to secrete IL-12. We therefore tested whether MUC-16 targeted T cells
further modified to express IL-12 would exhibit an enhanced antitumor
efficacy in a syngeneic immunocompetent tumor model of ovarian cancer.
Methods: We have constructed SFG retroviral vectors encoding the second
(4H11m28mz) generation CARs as well as IL-12 modified CAR
(4H11m28mz/mIL12) targeted to the retained extra-cellular domain of
MUC16, termed MUC-CD. We demonstrated an antitumor efficacy of these
T cells in a syngeneic tumor model using the C57BL6 (B6) mice
intraperitoneally (i.p.) injected with ID8(MUC-CD) tumor cells. Results: In
our studies treatment of mice bearing established ID8(MUC-CD) ovarian
tumor with MUC-CD specific T cells expressing IL-12 gene, in contrast to T
cells targeted to MUC-CD alone, fully eradicate highly advanced intraperitoneal
ovarian tumors. Significantly, we found that mice treated with
4H11m28mz/mIL12 T cells had increased number of modified T cells in
the peritoneum at day 4 and 7 with increased recruitment of endogenous T
cells to the site of the tumor when compared to controls and mice treated
with 4H11m28mz T cells. The observed antitumor effect did not required
prior lymphodepletion and was well tolerated in treated mice. Conclusions:
CAR modified T cells targeted to the MUC-16 antigen efficiently eradicate
orthotopic ovarian cancer in syngeneic immunocompetent mice with
markedly enhanced antitumor efficacy seen in those mice treated with
CAR � T cells further modified to secrete IL-12. These data support future
clinical trials utilizing adoptive T cell therapy in patients with relapsed
ovarian cancer.
2588 General Poster Session (Board #7E), Mon, 8:00 AM-12:00 PM
Effect of the novel therapeutic cancer vaccine formulation DPX-0907 on
multifunctional T-cell responses in ovarian, breast, and prostate cancer
patients. Presenting Author: Neil Lorne Berinstein, Odette Cancer Centre,
Toronto, ON, Canada
Background: To increase the efficacy of peptide cancer vaccines, we
developed a novel vaccine platform called DepoVax, an adjuvanted waterfree
depot formulation with the ability to generate enhanced immune
responses. Naturally processed HLA-A2 restricted peptides that are selectively
presented by breast, ovarian and prostate cancer cell lines, but not by
normal HLA-A2� cells, were used as antigens with a proprietary adjuvant
and a T helper peptide epitope to create a therapeutic cancer vaccine,
DPX-0907. Methods: A phase I clinical study was designed to examine the
safety and immune activating potential of DPX-0907 in advanced stage
breast, ovarian and prostate cancer patients. A total of 23 late stage cancer
patients were recruited and were divided into two dose volume cohorts in a
three immunization clinical protocol. Results: DPX-0907 proved to be safe
with no serious adverse effects related to the vaccine reported. Of those
evaluable for immunogenicity, all breast cancer patients (3/3), most of
ovarian (5/6) and one third of prostate (3/9) cancer patients demonstrated
immune response to one or more of seven antigenic peptides, resulting in a
61% response rate. Immune responses correlated with achievement of CR,
PR or SD to last treatment. No difference in immune response rate or
magnitude was seen between the two dose groups. DPX-0907 displayed
strong immune induction potential, with 73% of immune responders
showing responses with just one dose of vaccine. In 83% of responders,
immune responses were detected at �2 time points post vaccination and
64% had a persistent immune response at one month post last vaccination.
Immune monitoring showed peptide-specific CD8 T cells, and these T cells
were able to secrete multiple Th1 cytokines indicating their multifunctionality,
a feature attributable to cells that mediate protective responses.
Conclusions: These data support the ability of DPX-0907 to elicit Th1
dominated, specific immunity and support the rationale for further testing
in immunologically competent cancer patients. The novel DepoVax formulation
may promote multifunctional memory responses with peptides from
other tumor associated antigens.
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