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

Abstracts J Immunother Volume 33, Number 8, October 2010
that SGI-110 strongly up-regulated their constitutive levels of
expression in neoplastic cells of all investigated histotypes. This
latter observation was confirmed at protein level by flow cytometric
analysis of the intracytoplasmic levels of CTA, in melanoma cells.
Concomitantly, flow cytometric analyses revealed that treatment
with SGI-110 up-regulated the expression of HLA class I antigens,
HLA-A2 allospecificity and the co-stimulatory molecule ICAM-1.
Altogether, these preliminary in vitro experimental evidences
strongly suggest that SGI-110 may represent an attractive
therapeutic agent to comprehensively increase immunogenicity
and immune recognition of neoplastic cells from solid tumors, and
provide the scientific rationale for its clinical development to design
new and more effective combined chemo-immunotherapeutic
approaches in patients with solid malignancies.
4-1BB Activation Induces the Master-regulator Eomes and A
Broad-spectrum TH1 Phenotype Which Synergizes with
CTLA-4 Blockade to Reject B16 Melanoma
Michael A. Curran*, Myoung-joo Kim*, Aymen Al-Shamkhaniw,
James P. Allison*. *Howard Hughes Medical Institute, Department
of Immunology, Memorial Sloan-Kettering Cancer Center, New
York, NY; w Tenovus Research Laboratory, Southampton General
Hospital, Southampton, United Kingdom.
Antibodies which block the co-inhibitory receptor CTLA-4 or
which activate the co-stimulatory receptor 4-1BB can promote
the rejection of some murine tumors, but fail to cure poorly
immunogenic tumors like B16 melanoma. We find that combining
these two antibodies in the context of a Flt3-ligand, but not a GM-
CSF, based B16 melanoma vaccine promoted synergistic levels of
tumor rejection. 4-1BB activation elicited strong infiltration of CD8+
T cells into the tumor and drove the proliferation of these cells, while
CTLA-4 blockade did the same for CD4+ effector T cells. Anti-4-
1BB depressed regulatory T cell infiltration of tumors and this
effect was dominant over the tendency of aCTLA-4 to expand
them. 4-1BB activation strongly stimulated TH1-type inflammatory
cytokine production in the vaccine and tumor draining lymph
nodes as well as in the tumor itself. The addition of CTLA-4
blockade further increased IFN-g production from CD4+ effector
T cells in the vaccine draining node and the tumor.
A hallmark of 4-1BB agonist antibody treatment is the upregulation
of the lectin KLRG1 on tumor infiltrating CD8+ and CD4+
T cells. We find that these KLRG1+ T cells in the tumor express
high levels of multiple killing-associated genes and may be
responsible for the increased anti-tumor cytotoxicity which has
been attributed to a4-1BB treatment. Further investigation
revealed that formation of these cells is driven by high-level
expression of the master-regulatory transcription factor Eomesodermin
(Eomes) in both the CD8+ and CD4+ T cell compartments.
To determine the pathway leading from 4-1BB agonist
antibody to induction of Eomes expression, we have characterized
the direct effects of a4-1BB on cytokine production from antigen
presenting cells. Further, we have used a series of gene-specific
knockout mice to validate candidate cytokines and transcription
factors involved in this pathway. These findings reveal a previously
unappreciated role for Eomes in generating extremely potent
tumor-specific effector T cells which may be critically important for
understanding and augmenting the effects of TNF-receptor family
agonist antibodies as well as for T cell adoptive transfer therapies.
Clinical Efficacy of the Anti-Cytotoxic T Lymphocyte
Antigen-4 (CTLA-4) Monoclonal Antibody Ipilimumab in
Pretreated Metastatic Uveal Melanoma Patients
Riccardo Danielli*, Paola Queirolow, Alessandro Testoriz,
Ruth Plummery, Vanna Chiarion SileniJ, Maresa Altomonte*,
Luana Calabro´ *, Anna Maria Di Giacomo*, Ruggero Ridolfiz,
Michele Maio*. *Medical Oncology and Immunotherapy, University
Hospital-ITT, Siena; w Medical Oncology A, IST, Genoa;
zMelanoma and Sarcoma, IEO, Milan; JMedical Oncology, IOV,
Padua; zImmunotherapy and Somatic Cell Therapy, IRST, Meldola,
Italy; yNorthern Institute for Cancer Research, Newcastle University,
Newcastle upon Tyne, United Kingdom.
Background: The fully human anti-CTLA-4 monoclonal antibody
ipilimumab potentiates anti-tumor T cell responses. Ipilimumab
has improved overall survival (OS) of advanced cutaneous
melanoma patients (pts) in a phase III trial; however, no data are
available of its clinical effectiveness in uveal melanoma where no
effective treatment is available. We report the European experience
(6 Institutions) with ipilimumab in metastatic uveal melanoma pts.
Methods: Thirteen stage IV pts (8 male, 5 female), median age 57
(30 to 76) years, ECOG performance status 0 to 1, with uveal
melanoma progressing to 2 median (1 to 4) previous therapies
for metastatic disease received ipilimumab within an Expanded
Access Program. All pts had history (1) or evidence (12) of liver
metastases, 1 of brain metastases and 3 of elevated (>1 upper
limit of normal) LDH. In the induction phase (IF) pts received
ipilimumab (10 mg/Kg i.v.) q3 weeks (wk 4 cycles; after a 12
weeks rest, treatment was repeated q12 weeks in the maintainance
phase (MF) starting from week (wk) 24. Tumor assessment (TA)
per modified WHO criteria was evaluated at baseline, at weeks 12
and 24, then q12 weeks. Adverse Events (AE) and immune related
AE (irAE) were collected according to Common Terminology
Criteria for Adverse events version 3.0.
Results: All pts received at least one ipilimumab dose, 9/13
completed all IF cycles while the remaining 4 pts were prematurely
withdrawn for disease progression; 5 pts entered the MF. No
objective tumor responses were observed; however, TA at wks 12,
24 and 36 showed stable disease (SD) in 2/9, 3/6 and 1/4 pts,
respectively. As reported for metastatic cutaneous melanoma pts,
slow, steady tumor volume decline and appearance of new lesions
that subsequently shrunk was observed. No grade 3/4 AEs were
reported. Three pts (23%) had grade 3 IrAEs (1 trombocytopenia,
1 diarrhea, 1 ALT/AST elevation) that resolved after steroid
therapy. Median OS as of March 1, 2010 was 36 weeks (range 2 to
102 wk). One patient, maintaining SD at >2 years from initial
ipilimumab administration, is still on treatment.
Conclusions: Ipilimumab treatment of metastatic uveal melanoma
pts is feasible and safe. A sizeable proportion of pts experienced
prolonged SD and extended survival. These evidences, strongly
identify uveal melanoma as a promising indication for ipilimumab
treatment to be investigated in phase II trials.
Monoclonal IgE Targeting Prostate Specific Antigen (PSA)
or HER2/NEU (HER2) as a Tumor Specific Immunotherapeutic
Strategy
T. Daniels*, G. Helgueraw, R. Quintero*, E. Ortiz-Sánchez*,
J. Rodríguez*, B. Schultesz, M. Penichet*, C. Nicodemusz.
*UCLA, Los Angeles, CA; w CONICET & FFyB, University of
Buenos Aires, Buenos Aires, Argentina; zAdvanced Immune
Therapeutics, Charlestown, MA.
Biological treatments of both breast cancer (BCa) and prostate
cancer (PCa) have proven efficacy, however these malignancies
continue to be leading causes of cancer deaths worldwide. To
improve the treatment of BCa and PCa, we have developed two
monoclonal IgE antibodies specific for HER2 and PSA respectively.
HER2 is cell surface antigen over-expressed in 30 percent of
BCa and PSA is a secreted antigen that accumulates locally in
prostate tissue and PCa. Both antigens have been used for tumor
targeting and both are associated with circulating forms (secreted
PSA & shed extracellular domain of HER2 (ECDHER2)). We
hypothesized that an IgE mediated local acute inflammatory
response in the tumor microenvironment would result in tumor
destruction and that a subsequent adaptive anti-tumor immune
response that would lead to further elimination of disease. We also
hypothesized that IgE through interaction with Fce bearing antigen
presenting cells could facilitate antigen processing and cross
presentation of PSA or HER2 to enhance the adaptive cellular
immune response. To target HER2 we used the variable regions of
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