Annual Meeting Proceedings Part 1 - American Society of Clinical ...

Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2521 Poster Discussion Session (Board #9), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
The immunological impact of the RAF inhibitor BMS908662: Preclinical
and early clinical experience in combination with CTLA-4 blockade.
Presenting Author: Margaret Callahan, Memorial Sloan-Kettering Cancer
Center, New York, NY
Background: Two new approaches to treat advanced melanoma have
transformed the standard of care: the CTLA-4 blocking antibody, ipilimumab,
and the targeted inhibitor of mutated BRAF, vemurafenib. These
agents are mechanistically unique and combination therapy is a promising
next step. We evaluated the combination of BMS908662 (662), a pan RAF
inhibitor, with CTLA-4 blockade in preclinical studies and report first-inhuman
clinical experience with this combination. Methods: 1) We tested
the impact of 662 on T cells in vitro, using cultured human T cells, and in
vivo, using OT-1 transgenic mice. T cell activation and MAPK pathway
signaling were assessed in parallel. 2) Preclinical studies measuring the
anti-tumor activity of combination therapy were performed in CT-26 and
SA1N tumor models. 3) Three pts with BRAF mutant stage IV melanoma
were treated at MSKCC on CA206005, an IRB-approved protocol, receiving
ipilimumab (3 mg/kg) and 662 (25 mg bid) (NCT01245556). Two pts
consented to an IRB-approved protocol permitting immune monitoring.
Results: 1) In vitro studies demonstrate that 662 can potentiate T cell
activation after stimulation. This corresponds with increased MAPK pathway
signaling, consistent with paradoxical activation of the MAPK pathway
in wild type cells, a class effect of RAF inhibitors. In vivo, enhanced
expansion of OT-1 cells after ovalbumin challenge was seen in mice treated
with 662. T cell expansion was greatest in mice treated with a combination
of CTLA-4 blockade and 662 (p�0.05). 2) Both preclinical models
demonstrate superior anti-tumor activity with combination therapy compared
to monotherapy (p�0.05). 3) All pts treated on protocol CA206005
tolerated combination therapy. New keratoacanthomas and SCCs, likely
related to 662, were identified. One pt has an ongoing response at 10 mos
(-85%), one had stable disease for 24 wks (-19%) and a third had disease
progression. Enhanced MAPK signaling in PBMCs after treatment with 662
was detected ex vivo. Conclusions: RAF inhibitors may potentiate T cell
activation in vitro and in vivo, offering one explanation for the enhanced
anti-tumor activity seen in combination with CTLA-4 blockade in preclinical
models.
2523 Poster Discussion Session (Board #11), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Cyclin-A1 expression in acute myeloid leukemia stem cells and its
representation as an immunogenic antigen that can be targeted by
cytotoxic T cells. Presenting Author: Sebastian Ochsenreither, Department
of Hematology and Medical Oncology, Charité, CBF, Berlin, Germany
Background: Targeted T-cell therapy represents a more specific and less
toxic alternative to allogeneic stem cell transplantation for providing a
cytotoxic anti-leukemic response to eliminate the leukemic stem cell (LSC)
compartment in acute myeloid leukemia (AML). The aim of this study was
to identify a leukemia-associated antigen that is both immunogenic and
exhibits selective high expression in AML LSCs. Methods: Expression
microarrays of leukemic and normal cells were used to identify suitable
candidate genes. Cyclin-A1 appeared to be differentially expressed, and
was further analyzed by quantitative RT-PCR, intracellular FACS staining,
and immunofluorescence microscopy. T-cell clones specific for cyclin-A1
were generated by stimulation in vitro with an overlapping peptide library,
followed by cloning of responding cells. Specificity of the clones was
documented by intracellular IFNg and tetramer staining. Cytotoxicity was
determined by chromium release and caspase-3 cleavage assays. Results:
To identify target candidates with a suitable expression pattern, microarray
data from LSCs, hematopoietic cells and healthy tissues were compared.
Cyclin-A1 was found to be selectively expressed in LSCs of �50% of AML
patients, but minimally expressed in normal tissues with exception of
testis. Using dendritic cells and monocytes pulsed with a cyclin-A1 peptide
library, T-cells were generated against eight cyclin-A1 oligopeptides. Two
HLA A2-restricted epitopes were further characterized, and specific T-cell
clones recognized both peptide-pulsed target cells and the HLA A2-positive
AML line THP-1. Furthermore, cyclin-A1-specific CD8 T-cells lysed primary
AML cells. Conclusions: Cyclin-A1, known to be important in meiosis,
is expressed in AML LSCs and testis and can be targeted by T-cells. Thus,
cyclin-A1 is the first prototypic LSC-associated leukemia-testis-antigen.
Cyclin-A1 already has been shown to be leukemogenic in mice and to
promote proliferation and survival in AML blasts. This pro-oncogenic
activity, together with high expression levels and a multitude of immunogenic
epitopes, make it a promising target for T-cell based therapy
approaches.
147s
2522 Poster Discussion Session (Board #10), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Immune responses and association with clinical outcome of advanced
colorectal cancer patients treated with the multi-peptide vaccine IMA910.
Presenting Author: Sabrina Kuttruff, Immatics Biotechnologies GmbH,
Tuebingen, Germany
Background: IMA910 is a novel multi-peptide cancer vaccine consisting of
10 HLA class I and 3class II tumor-associated peptides (TUMAPs), which
were selected based on natural presentation on colorectal tumors by the
XPRESIDENT antigen discovery platform. Methods: 92 HLA-A*02� advanced
colorectal cancer (aCRC) patients (pts) with stable or responding
disease after 12 weeks of first-line oxaliplatin-based therapy were enrolled
in this phase I/II trial. After pre-treatment with cyclophosphamide (300
mg/m2 ), patients were immunized intradermally with IMA910 plus the
immune modulator GM-CSF without (cohort 1; n�66) or with (cohort 2;
n�26) topically applied imiquimod, another immune modulator acting via
toll-like receptor 7 on antigen presenting cells. T-cell responses to
individual IMA910 peptides were analyzed by HLA multimer and intracellular
cytokine staining (ICS) assays. Results: IMA910 elicited immune
responses towards multiple class I (43%) and class II TUMAPs (65%).
34% of pts responded to multiple class I and class II TUMAPs. Pts that
received imiquimod were more often multi-peptide class I responders in the
ICS assay (p�0.016) and showed an approx. 2x higher frequency of T-cell
response (p�0.12). Responses to multiple class I and class II TUMAPs
were associated with higher disease control rate at all time points (all
p�0.02), increased time to progression (p�0.006), progression-free
survival (p�0.009) and OS (p�0.088, HR�0.53). Baseline characteristics
of multi vs. non-multi responders were overall well comparable. In a
prospectively defined, blinded matched-pair analysis with patients in arm C
of the COIN trial, multi-peptide responder patients showed a prolonged
survival vs. corresponding COIN patients (p�0.04), while the non-multi
responder patients had comparable survival. Conclusions: IMA910 is
immunogenic. Imiquimod increases the quality of immune responses.
Responses to multiple TUMAPs are associated with better clinical outcome.
Several observations indicate that this association is not a reflection
of better prognosis of the immunologically responding subset of patients.
These results suggest further development of IMA910.
2524 Poster Discussion Session (Board #12), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Adjuvant dendritic cell (DC)-based vaccine therapy of melanoma patients.
Presenting Author: Natalia N. Petenko, N. N. Blokhin Cancer Research
Center, Russian Academy of Medical Sciences, Moscow, Russia
Background: Earlier DC vaccine therapy demonstrated clinical benefit in
some patients (pts) with advanced melanoma although the effect was seen
only in pts with minimal tumor burden (ASCO2007 abstract No: 3077). As
there is no effective treatment for high risk resected melanoma we
conducted an exploratory trial to assess the effectiveness of DC vaccine in
stage III and IV melanoma pts after radical surgery in comparison with
observation. Methods: 108 stage III and IV melanoma pts were enrolled in
two comparative arms. The arms were well balanced in respect with
demographic and prognostic factors. The vaccine was based on mature
autologous monocyte-derived DC primed with autologous tumor lysate,
administered intradermally every 2-6 weeks until the disease progression.
Disease free survival (DFS) and overall survival (OS) were evaluated with
Kaplan-Meier method and compared between the two arms using the log
rank test. Safety of DC vaccine was also monitored. Results: The vaccine
arm included 56 pts (stage III – 46, stage IV – 10 pts) who were surgically
rendered free of disease and treated with DC vaccine. 52 pts were enrolled
in the control arm (stage III – 47, stage IV – 5 pts), they were treated
surgically and observed afterwards. At a median follow-up of 22 months,
the HR (DC vs observation) for DFS was 0.45 (p � 0.05; 95%CI
0.29-0.69) and for OS was 0.71 (p�0.23; 95%CI 0.40-1.25). 60% of pts
in the DC arm remained alive at this time point. Risk reduction significantly
correlated with the strong delayed type hypersensitivity reaction induced by
vaccine in 31 (55%) out of 56 vaccinated pts. The vaccine was safe and
well tolerated although vitiligo was registered in 4 cases which was
associated with more durable time to progression and OS. Conclusions: The
immunotherapy with DC vaccine is safe and significantly improves DFS
compared with observation in the adjuvant treatment of stage III and IV
melanoma.
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