Abstracts for the 25th Annual Scientific Meeting of the International ...

J Immunother Volume 33, Number 8, October 2010
Abstracts
Results: 17 of 28 patients (60%) achieved SD after 6 vaccinations
and 8 of these (29%) maintained SD after 10 vaccines (4 mo). One
patient has ongoing SD for 20 vaccines (13 mo). No objective
responses were seen. Two patients were excluded prior to the first
evaluation due to progression and 1 was excluded after 4 vaccines
due to anemia and refusal of blood transfusion. One patient did not
receive any vaccines due to rapid progression and death and is not
included in the results. The treatment was associated with a marked
increase in the proportion of Tregs from baseline to the 4th vaccine
followed by a decrease from the 4th to the 6th vaccine although not
to the baseline values.
Conclusion: The combination of DC vaccination and Cy was well
tolerated. The induction of Tregs was not decreased by adding Cy,
on the contrary a higher Treg level was maintained. However, the
fraction of patients who achieved SD was more than doubled as
compared to a comparable cohort of patients treated with DC
vaccination without Cy. The fact that there is no concordance
between the increase in Tregs and the beneficial outcome, outline
the complexity of the in vivo immunology. Evaluations of vaccine
specific immune responses are ongoing.
Dendritic Cell Vaccination in Cancer: Achievements,
Obstacles and Future Perspectives
Carl G. Figdor, Jolanda de Vries, Karlijn Bol, Erik Aarntzen,
Joost Lesterhuis, Gosse Adema, Kees Punt. Tumor Immunology,
Radboud University Medical Centre, Nijmegen, Netherlands.
We exploit dendritic cells (DCs) to vaccinate melanoma patients. We
recently demonstrated a statistical significant correlation between
favorable clinical outcome and the presence of vaccine-related tumor
antigen specific T cells in delayed type hypersensitivity (DTH) skin
biopsies. While we find immunological responses in 30% to 50% of
the patients, favorable clinical outcome is only observed in a minority
of the treated patients. Therefore, it is obvious that current DC-based
protocols need to be improved to increase clinical efficacy. For this
reason, we study in small proof of principle trials the fate,
interactions and effectiveness of the injected DCs.
We compared DC loaded with tumor antigen specific MHC class I
binding peptides alone, in combination with MHC class II binding
peptides or with defined tumor antigen mRNA (gp100 and
tyrosinase). The results show that the presence of supplementary
tumor antigen-specific MHC class II epitopes result in an T helper
response that might be beneficial for the clinical outcome in these
patients. Furthermore, comparing different routes of administration
we observed that intranodal injection is not always successful
(MRI) and that only a small proportion of the intradermally
administered DCs reach the lymph nodes (scintigraphy). Our data
clearly indicate that the cells that reach the lymph nodes are fully
mature DCs that are able to induce an immune response in vivo.
We have begun to explore the potency of DC subsets in the
peripheral blood. Recently we have completed a phase I trial with
plasmacytoid DCs. Results will be discussed as well as the potency of
other DC subsets.
This work was supported by grants 1999 to 1950, 2000 to 2301, 2003 to
2893, 2003 to 2917 and 2004 to 3127 from the Dutch Cancer Society,
and EU projects DC-THERA, and CANCER IMMUNOTHER-
APY, NWO- Spinoza, the TIL-foundation and the NOTK.
Combined Intraprostatic Autologous Dendritic Cell Injection with
Radiation Therapy in Localized, High Risk Prostate Cancer:
Serial Assessment of Apoptosis and Lymphocyte Infiltrates
Steven E. Finkelstein, Dmitry Gabrilovich, Francisco Rodriguez,
Mary-Jane Farmello, Renee Smilee, William Janssen, Tian Chuang,
Loveleen Kang, Javier Torres-Roca, Randy Heysek, Ravi Shankar,
Matthew Biagioli, John Seigne, Julio Pow-Sang, Scott Antonia,
Mayer Fishman. Moffitt Cancer Center, Tampa, FL.
Previous work in murine models suggested combining local
radiotherapy (XRT) with intratumoral syngeneic dendritic cell
(DC) injection could result in apoptosis/cell death mediated
effective induction of cytotoxic T lymphocytes (CTL) based antitumor
immunity. However, the presence, timing, and effectiveness
of effector cell infiltrates prior, during, and following combined
XRT/intratumoral DC injection in humans is unknown. Herein, we
report the feasibility and tolerability of intraprostatic autologous
dendritic cell injection; five HLA-A2+, high risk localized prostate
cancer patients were treated on an investigational protocol using
androgen suppression therapy, external beam radiation therapy
(EBRT, 45 Gy) followed by brachytherapy permanent interstitial
implant with addition of experimental autologous intraprostatic
DC injections during EBRT, after fractions 5, 15, and 25 of 25.
Multiple serial prostate biopsies were collected before initiation
of treatment, during EBRT and at 3, 12, 24 & 36 months after
completion of treatment. Biopsies were stained for hematoxylin
and eosin, CD4, CD8, and cleaved caspase 3, and evaluated in a
blinded manner. The specific anti-tumor immunity was assessed via
ELISpot interferon gamma production by lymphocytes stimulated
by HLA-A2 peptides derived from sequences of proteins associated
with prostate cancer. Apheresis, intraprostatic DC injections, and
biopsies were well tolerated. The pattern of distribution of CD8+
cells was consistent with prostate cancer antigen targeting, rather
than non-specific organ infiltration. There was no immediate
obvious intraprostratic infiltrate by effector cells after DC injection
in vivo, in humans. Measurable, induced increases in ELISpot
titers in peripheral blood CTL were observed for some subjects, for
some antigens, but non-specific immunity also fluctuated. This
initial translational experience demonstrates safety of intraprostatic
injection of autologous DC injection coordinated combined
modality hormone suppression and radiation. Design of future
trials employing combination XRT and intratumoral DC injection
should consider appropriate timing concerns to match therapyinduced
apoptosis with the timing of dendritic cell injections.
Dendritic Cell and Myeloid Derived Suppressor Changes
with Interleukin-2 Therapeutic Administration
Steven E. Finkelstein, Dmitry Gabrilovich, Timothy Carey, Ingo
Fricke, Daohai Yu, Mary Dunn, Adil Daud, Ronald DeConti,
Scott Antonia, Mayer Fishman. Moffitt Cancer Center, Tampa, FL.
High-dose intravenous interleukin-2 (IL-2) therapy (14 doses/course,
2 courses/cycle) for metastatic melanoma or kidney cancer (RCC)
can induce major responses; subcutaneous IL-2 has been also used in
RCC therapy. In three concurrent clinical trials, we evaluated
(N = 45) the effect of IL-2 on dendritic cell (DC) and myeloid derived
suppressor cells (MDSC). The first intervention employed a new
schedule (dose of 600,000 IU/kg, 8 h between doses, 5 doses/course, 4
courses at weekly intervals per cycle) of high-dose IL-2; the second
used all trans retinoic acid (ATRA) followed by subcutaneous IL-2 in
RCC; and the third used intravenous bevacizumab followed by subcutaneous
IL-2 in RCC. Herein, we report a hypothesis-generating
observation that the patients treated with high dose IL-2, who had
most favorable outcomes had high (88.8, median) pre-treatment DCto-MDSC
ratios, similar to the pattern in healthy individuals.
However, the DC-to-MDSC ratio, even in those for whom it was
favorable at the outset declined (20.1, median). A general decline of
DC-to-MDSC ratio also was observed on low dose IL2 combination
regimens (N = 29). Thus, changes induced by IL-2 in the MDSC
number and the DC-to-MDSC ratio merit further detailed clinical
and laboratory evaluation; pretreatment assessment of DC phenotypic
status may be a starting point for patient selection in high-dose
IL-2 immunotherapy.
IFN-Gamma is Central to Both Immunogenic and Tolerogenic
Properties of Dendritic Cells After IL-12 and GM-CSF
Microsphere Treatment
Jamie L. Harden, Tao Gu, Mehmet O. Kilinc, Lauren P. Virtuoso,
Nejat K. Egilmez. Microbiology and Immunology, University at
Buffalo, Buffalo, NY.
A single intra-tumoral injection of IL-12 and GM-CSF microspheres
results in tumor regression and initiation of an anti-tumor
immune response. Activation of NK cells and CD8+ T-cells along
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