FINAL PROGRAM - Society for Immunotherapy of Cancer

Oral Presentation Abstracts
that use pox viral vectors.
Key Word: Prostate cancer.
SEROMICS: MEASURING ANTIGEN-SPECIFIC SERUM
ANTIBODY RESPONSES DURING ANTICANCER
IMMUNOTHERAPIES FOR CORRELATION WITH
CLINICAL EVENTS
Sacha Gnjatic
Branch at Memorial Sloan-Kettering Cancer Center, Ludwig Institute for
Cancer Research, New York, NY
The immune system recognizes antigens expressed in cancer
cells, thereby generating antibody and T cell responses that can be
measured from peripheral blood and tumor sites. By knowing the
nature and quality of immune responses generated in an antigenspecific
manner to cancer as well as immunoregulatory processes
involved, one can design immunotherapeutic strategies to affect the
clinical course of cancer using vaccines and immunomodulators.
To this end, antibody responses occurring either spontaneously or
as a result of immunotherapy were analyzed by ELISA for model
cancer/testis antigen NY-ESO-1, and linked to CD8 and CD4 T cell
responses as well as to antigen expression. Serological analyses were
then extended to 35+ known tumor antigens, to establish a general
immunogenicity profile. Finally, humoral immune responses were
characterized in a comprehensive manner using protein microarrays
for antibody profiling of >8000 antigens. This strategy was used for
monitoring immunological events during CTLA-4 blockade.
Blockade of CTLA-4, a molecule that acts as a natural break to
prevent immune responses from going into overdrive following
T-cell activation, with monoclonal antibodies such as ipilimumab
has shown durable clinical activity and improved overall survival in
advanced melanoma patients (N Engl J Med 2010;363:711-23). This
activity is likely linked to the prolongation of immune responses
directed against tumor cells; however, the exact immune responses
targeted by anti-CTLA-4 therapy remain unclear, as does the
reason why only some patients benefit from the drug.
Autoantibody responses were measured before and after
treatment with ipilimumab to provide further insight into the
mechanism of action of such immunotherapy and identify factors
that help to predict patients who are most likely to derive clinical
benefit from treatment. Changes were detected in autoantibody
levels in treated patients relative to samples prior to treatment
and to controls, suggesting that some targets may have been “hit”
by the immune system as potential interesting rejection antigens
that help explain the mechanism of action of the drug. Extended
serological analyses are also useful to identify preexisting antibody
signatures associated with clinical response to anti-CTLA-4 and
other therapies, to define the subset of patients most likely to
experience clinical benefit
These approaches provide a broader scope of immune responses
occurring in cancer, and may be useful for finding new targets of
cancer vaccines and selecting biomarkers with predictive value for
therapeutic treatments, as well as for establishing correlations with
tumor characteristics and with clinical events.
Key Words: B cell, Ipilimumab, Melanoma.
PRESIDENTIAL ABSTRACT SESSION
IMMUNOTRANSPLANT FOR MANTLE CELL
LYMPHOMA: A PHASE I/II STUDY DEMONSTRATING
AMPLIFICATION OF TUMOR-REACTIVE T CELLS
J. Brody 1 , D. Czerwinski 1 , V. Carlton 2 , M. Moorhead 2 , J. Zheng 2 , M.
Klinger 2 , M. Faham 2 , R. Levy 1
1
Stanford University, Stanford, CA
2
Sequenta Inc, San Francisco, CA
Mantle cell lymphoma (MCL) has a poor prognosis. Though
autologous transplant prolongs survival, novel therapies are needed
to target residual, myeloablation-resistant tumor cells that result in
relapse.
Trials of CpG-based vaccines for low-grade lymphoma have
shown induction of anti-tumor T cells and clinical responses
[Brody et al, JCO 2010]. In a pre-clinical model, we developed
‘immunotransplant’, combining: 1) CpG-based vaccination, 2)
vaccine-primed T cell harvest, 3) myeloablation with stem cell
rescue, and 4) T cell re-infusion. Immunotransplant amplifies the
proportion of anti-tumor T cells by an order of magnitude and
cures even bulky, systemic lymphoma [Brody et al, Blood 2009].
Methods: We initiated a phase I/II study of immunotransplant
for newly diagnosed MCL patients to test the hypothesis that
immunotransplant amplifies anti-tumor T cells as seen preclinically.
Tumor-reactive T cells are assessed by co-culturing
autologous tumor with peripheral blood T cells and measuring
their production of: IFN TNF, IL2, CD137, perforin and granzyme
by multiplex surface and intracellular flow cytometry. Using highthroughput
sequencing, we have initiated assessment of the
peripheral blood TCR repertoire, obtaining at least 1e6 sequence
reads per time point.
Results: Accrual has been rapid with 24 patients enrolled in 22
months and 13 patients completing the complete protocol so far.
Flow-cytometric immune response testing has demonstrated that
immunotransplant amplifies the proportion of tumor-reactive T
cells in 83% of patients thus far. Notably, we have observed some
patients with primarily CD8 T cell responses, some with CD4
T cell responses, and some with a combination. In some cases,
tumor-reactive T cells have been tested for reactivity to autologous,
non-malignant B cells and have demonstrated that a significant
proportion are tumor-specific. High throughput sequencing of
TCR repertoires have also demonstrated instances of significant
clonal amplification after immunotransplantation, up to two orders
of magnitude. In extreme cases, these have yielded dominant
clones comprising as much as 50% of a patient’s entire peripheral
blood T cell repertoire post-transplant.
Conclusions: Pre-clinically, amplification of anti-tumor T cells
correlates with cure of myeloablation-resistant disease. The
ABSTRACTS AND
POSTER LISTINGS
FINAL PROGRAM • SITC 26 TH ANNUAL MEETING
November 4-6, 2011 • North Bethesda, MD • www.sitcancer.org
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