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

Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2569 General Poster Session (Board #5B), Mon, 8:00 AM-12:00 PM
Patient-specific immunotherapy utilizing putative tumor stem cells in
patients with metastatic melanoma: A pooled analysis comparing tumor
cell and dendritic cell vaccines in two phase II trials and a randomized
phase II trial. Presenting Author: Robert Owen Dillman, Hoag Institute for
Research and Education and Hoag Family Cancer Institute, Newport
Beach, CA
Background: Metastatic melanoma is seldom cured, even in patients who
achieve a complete remission, because new sites of disease emerge. Autologous,
proliferating, self-renewing tumor cells (putative tumor stem cells and/or
early progenitor cells), are critical to establishment of new depots of metastatic
cancer, and may be excellent sources of antigen for vaccines. These trials
addressed the impact on survival from immunizing with antigens from such
cells. Methods: Data was pooled from 3 successive phase II trials, all of which
included patients with documented metastatic melanoma, who were treated in
protocols that utilized antigens from cell cultures of autologous tumor cells.
S.C. injections were given weekly for 3 weeks, then monthly for 5 months.
1992-2000: 74 patients were injected with irradiated tumor cells (TC).
2000-2006: 54 patients were injected with autologous dendritic cells (DC)
that had been co-cultured with irradiated autologous tumor cells (NCI-V01-
1646). 2007-2011: in a randomized phase II trial, 24 patients were injected
with TC, and 18 with DC (NCT00436930). Results: The table summarizes
overall survival (OS) in each trial. In the pooled analysis there were 98 TC and
72 DC patients. Characteristics were similar in terms of age (51, 52), male
gender (62%, 62%), no evidence of disease at the time of treatment (46%,
47%), and presence of M1c visceral disease at the time of treatment (13%,
14%). OS was longer in patients treated with DC (median 63.1 vs 20.2
months, 5-year OS 51% vs 26%, p�0.0002 Mantle-Cox log-rank test). The
difference in OS in the randomized trial is also significant (p�0.007).
Conclusions: Patient-specific DC vaccines primed with antigens from autologous
proliferating, self-renewing tumor cells are associated with encouraging
long-term survival rates, and are superior to patient-specific TC vaccines in
populations of patients who have been diagnosed with metastatic melanoma.
Vaccine # patients # deaths Median OS 2-yr OS 5-yr OS
TC 74 60 20.3 mos 45% 28%
DC 54 31 58.4 mos 72% 50%
TC 24 16 15.9 mos 31% ---
DC 18 5 Not reached 72% ---
2571 General Poster Session (Board #5D), Mon, 8:00 AM-12:00 PM
Correlation of interferon-g (IFN-�) response with survival in a phase II
hyperacute (HAL) immunotherapy trial for non-small cell lung cancer
(NSCLC). Presenting Author: John Charles Morris, University of Cincinnati,
Cincinnati, OH
Background: Lung cancer is the leading cause of cancer-related mortality.
Patients progressing after initial systemic therapy have a poor prognosis.
Thus, new therapies are needed. HAL immunotherapy exploits the hyperacute
rejection of a xenotransplant as defense mechanism to initiate
anti-tumor immune response by administering genetically modified allogeneic
tumor cells expressing the �Gal moieties on their cell surface. HAL
immunotherapy utilizes �Gal epitopes and natural human antibodies (Ab)
against these targets as the proposed mechanism for anti-tumor immunity.
Methods: We completed a phase II study of HAL immunotherapy in patients
with metastatic or recurrent NSCLC, age �18, ECOG PS �2, �2 prior
systemic therapies. Trial objectives were to determine response rate, safety
and immunological responses. Patients received 300 x 106 HAL cells every
2 weeks for 8 doses. Response was determined using RECIST and adverse
events were assessed using CTCAE v3. Immune responses were assessed
by changes in serum anti-�Gal titers and IFN-� response. Results: Twentyeight
patients were treated. Eight (29%) demonstrated stable disease (SD)
�16 wks including one patient that initially progressed and later regressed,
surviving over 40 months. Median overall survival (OS) was 11.3 months
(95% CI 3.8-21.9). Post vaccination, all patients responded by increasing
anti-�Gal Ab levels (2-100 fold) and 61% (11/18) of tested patients
showed increases in IFN-� levels (by ELISPOT). Interestingly, patients with
increased IFN-� responses after vaccination (�10-500 fold-increase
compared to baseline) had a median survival of 21.9 months compared to
5.5 months in patients with lesser IFN-� responses after vaccination
(p�0.001). In addition, patients with higher IFN-� responses showed
reactivity to a NSCLC cell line that was not a component of HAL, suggesting
cross-priming to shared tumor antigens. Conclusions: HAL immunotherapy
is safe and feasible. The median survival compared favorably to that
reported in patients receiving 2nd line chemotherapy for relapsed or
advanced NSCLC. The correlation between IFN-� response and survival is
highly encouraging.
2570 General Poster Session (Board #5C), Mon, 8:00 AM-12:00 PM
Effect of matrix metalloproteinase-2 on antitumor immunity. Presenting
Author: Emmanuelle Godefroy, New York University, New York, NY
Background: Cancer cells, including melanoma, can be highly resistant to
traditional treatments such as chemotherapy and radiotherapy. As a result,
a lot of effort has been put into developing immune therapies to treat
cancer patients. The main barrier to design effective immunotherapies is
the immunosuppression induced by the tumor. Matrix metalloproteinase-2
(MMP-2) is over-expressed in most cancers including melanoma, and its
expression is associated with increased dissemination and poorer survival/
prognosis. Here, we uncovered an immunosuppressive role of MMP-2 in
inducing ineffective/detrimental TH2 immune responses and its underlying
mechanisms. Methods: Human dendritic cells (DCs) were cultured in the
presence of MMP-2 or various TLR agonists. DCs responses were monitored
using immunostaining, ELISA or cytometric bead array methods. Autologous
CD4� T cells were stimulated using these conditioned tumorassociated
antigen (TAA)-pulsed DCs. TAA-specific CD4� T cells were
cloned and characterized using the same techniques as for DCs. Results:
Herewe showed that MMP-2-conditioned human DCs primed naïve CD4� T
cells into an inflammatory TH2 phenotype, i.e. mainly secreting TNF�, IL-4
and IL-13 and expressing GATA3. Accordingly, we detected MMP-2specific
CD4� T cells displaying the same inflammatory TH2 profile in
tumor-infiltrating lymphocytes from melanoma patients. We revealed the
underlying mechanisms: on the one hand, MMP-2 was found to degrade the
type-I IFN receptor IFNAR1, thereby preventing STAT1 phosphorylation,
which is necessary for IL-12 production. On the other hand, MMP-2
triggers the Toll-like receptor (TLR)-2 on DCs, which leads to NF-kB
activation and OX40L expression. Both lack of IL-12 and over-expression of
OX40L were found responsible for skewing T cell responses towards a
detrimental TH2 phenotype. Conclusions: MMP-2, therefore, acts as an
endogenous TH2 �conditioner� and may underlie the prevalence of detrimental
TH2 responses in cancer. Our findings also described the responsible
MMP-2-dependent mechanisms, which open the way to novel therapeutic
strategies and/or targets to skew anti-tumor CD4� T cell responses towards
a more efficient anti-tumor TH1 phenotype to treat cancer patients.
2572 General Poster Session (Board #5E), Mon, 8:00 AM-12:00 PM
Does the addition of molecular targeted therapy to standard treatments
lead to better or worse outcomes overall? A systematic review of EGFRtargeted
therapies used in combination with standard treatments. Presenting
Author: Jennifer Rauw, University of Toronto, Toronto, ON, Canada
Background: Combining novel targeted therapies with standard treatment is
a common strategy in drug development. The primary aim of this systematic
review was to provide a summary of the outcomes from studies combining
EGFR targeted therapy (ETT) with standard treatments. Methods: A PubMed
(1975-Jan, 2012) and ASCO (2005-2011) abstract database search was
performed. Eligible studies were RCTs that compared standard therapies
(chemotherapy, radiation therapy, or hormonal therapy) to standard therapy
plus an ETT. Efficacy outcomes: overall survival (OS), progression free
survival (PFS), objective response rate (ORR) time to progression (TTP),
clinical benefit rate (CBR), and toxicity (total and grade 3�) were recorded.
If any toxicity was significantly more frequent in one arm it was coded as
such. Results: 128 studies (60 manuscripts, 68 abstracts) met criteria.
Median study enrolment was 230 patients, with breast, lung, and colorectal
cancer as the main tumor sites. ETT, cetuximab (41%), trastuzumab
(19%), gefitinib (13%), erlotinib (13%), and lapatinib (16%), was combined
with platinums, 5FU, taxanes, nucleoside analogs; hormonal therapy
and/or radiation therapy. Refer to the table for efficacy results. Most
frequent toxicities (common and grade 3�) in the combined arm were rash,
diarrhea, hematological toxicity and fatigue. Conclusions: Despite enthusiasm
for combining standard treatments with targeted therapies, we have
demonstrated mixed efficacy results, with marginal benefit and worse
toxicity. Quality of life (Q of L) was rarely reported. A similar analysis is
underway for VEGFR, and mTor inhibitors, but raises the question of how
best to approach the question of combination therapy.
Outcome
Not
reported
Significantly
worse in
combined arm
No significant
difference
between arms
159s
Significantly
better in the
combined arm
OS 60 (51%) 1 (0.8%) 39 (31%) 23 (18%)
DFS 66 (52%) 1 (0.8%) 29 (23%) 32 (25%)
TTP 106 (83%) 0 10 (8%) 12 (9%)
CBR 108 (84%) 0 13 (10%) 7 (6%)
ORR 73 (57%) 0 29 (23%) 26 (20%)
Toxicity 58 (45%) 47 (36%) 22 (17%) 1 (0.8%)
QofL 110 (86%) 0 12 (9%) 6 (5%)
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