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

Abstracts J Immunother Volume 33, Number 8, October 2010
4/6 mice at day 35. Depletion experiments confirmed that the antitumor
response of IMQ was CD8 T cell mediated. Therefore, mice
were injected in both flanks with TSA cells, to assess systemic
tumor control. Local treatment with IMQ to one tumor resulted in
significant inhibition of a second placebo-treated tumor (P2) compared to placebo at cumulative radiation doses
1; P = 0.085) and prevention of ulcerative OM in 24% of
subjects up to 50 Gy, while all subjects on placebo had ulcerative
OM by 35 Gy. Cox regression analysis of time to initial occurrence
of ulcerative OM resulted in a 52% decrease in risk for subjects on
high dose SCV-07. This group also had 75% fewer unplanned
office- and emergency room visits, fewer RT interruptions due to
OM, and 14% fewer days when gastrostomy tubes were used vs.
placebo.
Conclusions: SCV-07 may be an effective intervention for the
development of OM in patients being treated for HNC. Additional
dose optimization studies are planned.
Checkpoint Blockade in Tumor Immunotherapy: New Insights
and Opportunities
James P. Allison*w. *Ludwig Center for Cancer Immunotherapy,
Memorial Sloan-Kettering Cancer Center; w Howard Hughes Medical
Institute, New York, NY.
Over the past several years it has become apparent that the
effectiveness of active immunologic strategies for cancer therapy
have been limited by cell intrinsic and extrinsic regulatory
pathways that act in concert to minimize harm to normal tissues.
The prototype of cell intrinsic ‘‘checkpoints’’ whose blockade
enhances anti-tumor responses is CTLA-4, which has been
extensively studied in a large number of animal models and shown
to be quite effective in achieving, either as a single agent or in
combination with other agents, complete tumor eradication and
long lasting tumor immunity.
Over 4000 patients have been treated with an antibody to human
CTLA-4 (Ipilimumab, Medarex and Bristol-Myers Squibb). Significant
responses, including complete remissions, have been
observed in about 15% of metastatic melanoma patients, with
about 40% of patients showing survival benefit. In a recent Phase
III trial, Ipilimumab was shown to prolong survival of stage IV
metastatic melanoma patients, with 25% alive and ongoing at 4
years. This is the first drug ever to show a survival benefit in
metastatic melanoma in a randomized trial. This has led to
considerable effort to identify biomarkers that would be useful in
determining the impact of CTLA-4 on human immune responses in
order to identify changes that might correlate with clinical
responses, as well as to address combinatorial strategies that might
enhance the effectiveness/frequency of clinical responses.
In both mouse and man, clinical benefit seems to correlate with an
increase in the ratio of Teff/Treg cells and with an increase in the
proportion of IFNg producing Teff cells that express high levels of
the CD28/CTLA-4 homolog ICOS. In human prostate and
melanoma patients clinical responses appear to correlate with
pre-existing or induced high titer antibody and polyfunctional CD4
T cells to the cancer testes antigen NY-ESO-1. In a presurgical
bladder cancer trial it has been shown that anti-CTLA-4 treatment
results in an increase in the ratio of IFNg producing effector cells
that express high levels of the CD28/CTLA-4 homolog ICOS. We
have confirmed this in ICOS high CD4 T cells in metastatic
melanoma and hormone refractory metastatic prostate cancer. In
melanoma, our data suggest that the duration of elevation of
ICOS high T cell numbers correlates with favorable clinical outcome.
We have begun to explore combinations of anti-CTLA-4 with
other agents.
We have found that with proper consideration of dosing and
timing, anti-CLTA-4 can synergize with standard chemotherapy,
cryoablation, and targeted therapies.
Increased Myeloid Derived Suppressor Cells in Advanced
Prostate Cancer
Nicola E. Annels, Mick Denyer, Hardev Pandha. Postgraduate
Medical School, University of Surrey, Guildford, United Kingdom.
Prostate cancer is one of the leading causes of death in adult men.
Whilst prostatectomy and radiotherapy are potentially curative for
organ-confined diseases, there is currently no effective treatment for
locally advanced and/or metastatic cancer. As prostate cancer
expresses several unique tumor-associated antigens, immunotherapy
affords a promising alternative approach to treat this disease.
However, although vaccination strategies tested in phase I trials
and a randomized phase III vaccine trial in prostate cancer showed
encouraging clinical results, they were still far from optimal. One
major explanation for this is the fact that many patients with
advanced cancer are immune suppressed and are unable to activate
tumor-reactive T cells. Recent studies have shown that myeloidderived
suppressor cells are major obstacles to effective cancer
immunotherapy as they are potent immune suppressive cells that
accumulate to high levels in response to tumor-secreted and proinflammatory
factors. Whilst there is now considerable evidence
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