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

Abstracts J Immunother Volume 33, Number 8, October 2010
17/19 (89%) and 13/19 (68%) generated an NY-ESO-1-specific
CD4+ and CD8+ T cell response, respectively. NY-ESO-1
seropositive patients who generated NY-ESO-1-specific interferon-gamma
(IFNg)+ CD8+ T cells experienced significantly more
frequent clinical benefit (10/13; 77%) than those who did not
mount this immune response (1/7; 14%), P = 0.017. No association
was found between an NY-ESO-1-specific IFNg+ CD4+ T cell
responses and clinical outcome (P = 0.16). Furthermore, all
detectable CD4+ or CD8+ IFNg+ T cell responses showed
polyfunctionality for TNFa, MIP-1b and/or CD107a. Finally,
Being NY-ESO-1 seropositive with a CD8+ T cell response
demonstrated a significant survival advantage compared to the
general population (median survival not reached vs. 8 mo,
P = 0.0158).
Conclusion: NY-ESO-1 seropositive patients may or may not
develop NY-ESO-1 specific CD8+ T cell responses. Those who
develop both antibody and CD8+ T cell responses may be more
likely to experience clinical benefit. Further understanding the
significance of this association could have prognostic or predictive
value and may support future studies in patients previously
immune to NY-ESO-1 or other relevant antigens.
Immunotherapy of Adenocarcinomas with Gc Protein-Derived
Macrophage Activating Factor, GcMAF
Nobuto Yamamoto, Masumi Ueda, Kazuya Hashinaka. Socrates
Institute for Theapeutic Immunology, Philadelphia, PA.
Intratumor BCG administration eradicates local as well as
metastasized tumors. Administration of BCG into noncancerous
tissues, however, results in no effect on the tumors. Inflammation
induced by BCG in normal tissues releases lysophospholipids that
activate macrophages. Because cancerous tissues contain alkylphospholipids,
BCG-induced inflammation of cancerous tissues
produces alkyl-lysophospholipids and alkylglycerols that activate
macrophages approximately 400 times more effective than lysophospholipids,
implying that highly activated macrophages are
tumoricidal. Inflammation-primed macrophage activation is the
principal macrophage activation process that requires hydrolysis of
serum Gc protein (known as vitamin D-binding protein) with an
inducible b-galactosidase of inflammatory B cells and the Neu-1
sialidase of T cells to yield the macrophage activating factor
(MAF). Thus, Gc protein is the precursor for MAF. However, the
MAF precursor activity of serum Gc protein of cancer patients was
lost or reduced because Gc protein is deglycosylated by serum
a-N-acetylgalactosaminidase (Nagalase) secreted from cancerous
cells but not from healthy cells. Thus, serum Nagalase activity is
proportional to tumor burden and serves as an excellent prognostic
index. Deglycosylated serum Gc protein can not be converted to
MAF, leading to immunosuppression. Stepwise treatment of
purified Gc protein with immobilized b-galactosidase and sialidase
generates the most potent MAF (GcMAF) that produces no side
effect in humans. In vitro treatment of macrophages/monocytes
with 10 pg GcMAF activates macrophages at maximal level with
200-fold increased ingestion index and 30-fold increased superoxide
generating capacity in 3 hours. Both in vivo and in vitro GcMAF
activated macrophages developed an enormous variation of
receptors that recognize cell surface abnormality of malignant
cells and become tumoricidal to a variety of cancers indiscriminately.
GcMAF also has a potent mitogenic activity on myeloid
progenitor cells that generate systemically 40-fold increase in the
activated macrophages in 4 days. When adenocarcinoma (metastatic
breast, prostate and colorectal cancers) patients were
intramuscularly administered with 100 ng GcMAF/wk, their
tumors were eradicated in 16 to 25 weeks. These patients were
tumor free for more than six years after GcMAF therapy. Since
intravenous administration of GcMAF allows rapid interaction of
GcMAF with myeloid progenitor cells in bone marrow, the
systemic cell counts of the activated macrophages increased to
more than 200-fold in 2 days. Weekly intravenous administration
of 100 ng GcMAF to adenocarcinoma patients eradicates tumors in
11 to 16 weeks.
Anti-Tumor Action and Tolerance of Oral SHP-1 Inhibitor
TPI-1a4 in Mouse Models
Taolin Yi, Mingli Cao, Keke Fan, Dan Lindner, Ralph Tuthill,
Ernest Borden. Cleveland Clinic, Cleveland, OH.
Cancer therapeutic efficacy via targeting negative immune regulators
has been demonstrated by ipilimumab, which extends overall
survival in advanced melanoma. Protein tyrosine phosphatase
SHP-1 is a key negative regulator in anti-tumor immune cells and
might be targeted as a novel cancer therapeutic strategy. Indeed,
tyrosine phosphatase inhibitor-1a4 (TPI-1a4) was identified recently
as a novel small molecule inhibitor for SHP-1 and exhibited
pre-clinical anti-tumors in mice. Its translational potential has been
further investigated in the current study.
TPI-1a4 as a single oral agent inhibited the growth of murine
K1735 melanoma tumors in a dose-dependent manner. The growth
of 4-day established K1735 tumors (s.c.) in syngeneic C3H/HeJ
mice was inhibited 44% (P60 mg/kg
in CD-1 mice during a 50-day period (5 d/wk, po). Moreover, oral
TPI-1a4 at 3 mg/kg was tolerated by Balb/c mice for 4 months with
no apparent side effects. Consistent with a low toxicity and high
efficiency in activating immune cells, TPI-1a4 at 1 to 30 mg/mL
showed escalating activities in inducing mouse splenic IFNg+ cells
in vitro whereas its parental compound was less effective. Novel
analogs of TPI-1a4 were synthesized and evaluated, leading to the
identification of a new anti-tumor agent.
These data provide further evidences designate TPI-1a4 as an
attractive platform for developing novel immunotherapeutic agents
and support SHP-1 as a cancer therapeutic target.
A Flow Cytometry Method to Quantitate Internalized
Immunotoxins In Vivo Explains Taxol and Immunotoxin
Synergy
Yujian Zhang, Johanna K. Hansen, Laiman Xiang, Seiji Kawa,
Masanori Onda, Mitchell Ho, Raffit Hassan, Ira Pastan. Laboratory
of Molecular Biology, National Cancer Institute/NIH, Bethesda,
MD.
Cancer cells within solid tumors live in a unique microenvironment
containing barriers impairing the penetration of antibodies,
immunoconjugates and immunotoxins. SS1P is an immunotoxin
composed of the Fv portion of a mesothelin specific antibody fused
to a bacterial toxin and is now undergoing Phase II testing in
mesothelioma. We describe a new approach to study the targeting
process of SS1P in tumors. A flow cytometry-based method (FC
method) was developed to quantify the uptake of SS1P by
individual tumor cells, and a gel filtration assay was developed to
study shed mesothelin (sMSLN), a barrier for SS1P therapy. The
cellular uptake of SS1P in tumor cells peaked several hours after
blood SS1P was cleared, reflecting the underlining intra-tumor
distribution process of SS1P independent of its blood supply. With
this approach, we demonstrated Taxol improved the penetration of
SS1P in the tumor, associated with a reduced sMSLN barrier in
tumor extracellular fluid. Our study provides a mechanistic basis
for the combined use of SS1P with cytotoxic drugs and helps
explain the increased antitumor activity when chemotherapy and
antibody-based therapies are combined. We also showed that the
FC method can quantify the tumor cell uptake of Herceptin and an
immunotoxin targeting HER2/neu. This method has the advantage
in quantifying drug penetration process and the ability to study
drug distribution among cellular components of solid tumor. This
study provided an alternative approach to study drug penetration
in solid tumor.
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