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

146s Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2517 Poster Discussion Session (Board #5), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
A phase I safety study of NPC-1C: A novel, therapeutic antibody to treat
pancreas and colorectal cancers. Presenting Author: Philip M. Arlen,
Neogenix Oncology, Rockville, MD
Background: NPC-1C (NEO-101; Ensituximab) is a chimeric monoclonal
antibody being developed as a novel biological treatment for pancreatic and
colorectal cancers. This antibody was selected from a panel of hybridomas
generated from mice immunized with semi-purified membrane-associated
proteins derived from biologically screened, pooled human allogeneic colon
cancer tissues. The NPC-1C target appears to be a variant of MUC5AC that
is expressed specifically by human colon and pancreatic tumors with
minimal cross-reactivity to normal GI tract tissues. Methods: A phase I open
label, multi-center dose escalation clinical trial with NPC-1C has completed
accrual of subjects with advanced pancreatic and colorectal cancer
refractory to standard therapy. The primary objectives are to determine
safety and tolerability of escalating doses of NPC-1C and to assess
pharmacokinetics (PK) and select immune responses to the antibody at
each dose level. Secondary objectives are to evaluate evidence of clinical
benefit and to explore immunologic correlates Results: Three cohorts of
subjects have been treated with NPC-1C at escalating dose levels of 1, 1.5,
and 2 mg/kg IV every two weeks. All 15 subjects (10 colorectal, 5
pancreatic) have enrolled on study (5/15 non-evaluable). No DLT was noted
at the 1mg/kg dose level with 2 of 3 patients showing stable disease at
completion of Course 1. At the 2 mg/kg dose level, one patient demonstrated
stable disease after course 1. At escalating rates of infusion, 3
subjects experienced mild to moderate hemolysis that resolved without
intervention. All 6 patients who have received 1.5 mg/kg at a constant rate
of infusion have been evaluated, with no dose limiting toxicity. One of 5
patients re-staged thus far in the 1.5 mg/kg cohort showed stable disease
on scans after completing the first course of treatment (4 doses), and
continued to receive additional doses. Preliminary data show no drug
induced antibody responses in treated subjects. PK, HAMA and cytokine
evaluation is ongoing. Conclusions: NPC-1C is tolerated well at the current
dose level of 1.5 mg/kg every 2 weeks without producing any DLT We plan
to continue accrual in the Phase 2A to evaluate clinical responses and
additional safety data.
2519 Poster Discussion Session (Board #7), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Assessment of a novel immunological biomarker SNP panel from a phase
III trial of Bacillus Calmette-Guérin (BCG) adjuvant treatment in stage III
melanoma patients. Presenting Author: Connie Ging Ting Chiu, Department
of Molecular Oncology and Division of Surgical Oncology, John Wayne
Cancer Institute, Santa Monica, CA
Background: Melanoma is an immunogenic cancer, whereby immunotherapy
in stage III patients has shown some success. However, there are no
effective immune biomarker tests to identify patients most likely to benefit
from immunotherapy. BCG (Bacillus Calmette-Guérin) therapy is a form of
immunomodulation. The objective was to assess the predictive clinical
effect of a single nucleotide polymorphism(SNP) immune biomarker panel
in stage III resected melanoma patients treated with BCG. Methods:
MMAIT-III was a phase III prospective randomized international multicenter
trial of BCG�melanoma vaccine vs BCG�placebo after complete
resection of stage III melanoma patients (NIH #NCT00052130). 120/292
patients with palpable disease treated with resection and BCG�placebo
had lymphocytes(PBL) from USA sites available for analysis. Endpoints
were overall survival(OS) and disease-free survival(DFS), with a 10-yr
follow-up. PBL DNA was assessed by MassARRAY MALDI-TOF for 28 SNPs
associated with macrophage/monocyte-related immune response pathways
to BCG/tuberculosis. A pilot study(n�34) from phase II BCG trial confirmed
presence of the SNPs. A logistic regression determined a SNP score,
and a cutoff was identified by ROC and used as a predictor in a Cox
proportional hazard model in a verification study(n�120). Results: 9 SNPs
in 6 genes had prognostic value: NRAMP1 and CD14, 18, 195, 209, 282.
The 9-SNP panel distinguished patients in 2 survival groups(OS median
4.9-yrs vs 1.5-yrs, p�0.0008), AUC�0.77. SNP biomarker positivity
demonstrates significant association with 10-yr OS (59.7% vs 15.7%; HR
1.97, CI 1.11-3.50, p�0.018) and DFS (47.2% vs 12.3%; HR 2.35, CI
1.43-3.92, p�0.0007). In Cox model, the SNP panel was a significant
predictor of OS(HR 2.69, CI 1.56-9.00, p�0.0052) and DFS(HR 2.33, CI
1.49-5.16, p�0.0003) independent of known melanoma prognostic
factors. Conclusions: The 9-SNP panel identified patients with an exceptionally
favourable disease outcome, and may represent a stratifying predictive
SNP panel for identifying patients that are inherently responsive to BCG
therapy and potentially other immunomodulating agents in melanoma.
2518 Poster Discussion Session (Board #6), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Myeloid-derived suppressor cell quantity prior to treatment with ipilimumab
at 10mg/kg to predict for overall survival in patients with metastatic
melanoma. Presenting Author: Shigehisa Kitano, Memorial Sloan-
Kettering Cancer Center, New York, NY
Background: Ipilimumab, an antibody that blocks the function of the
immune inhibitory molecule cytotoxic T lymphocyte antigen 4 (CTLA-4),
significantly prolongs survival in patients with metastatic melanoma.
Approximately 30% of patients derive clinical benefit from therapy.
Defining biomarkers of response to ipilimumab therapy would enable
selection of patients more likely to respond and is relevant for both
practicing clinicians and for clinical trial design. We performed a pilot
correlative study evaluating myeloid derived suppressor cells (MDSC), a
population of immune suppressive monocytic cells, as a biomarker of
clinical outcome. Methods: Peripheral blood from 26 patients with stage IV
melanoma treated with ipilimumab 10mg/kg every 3 weeks for 4 doses at
our center, as part of an expanded access program (BMS CA184-045) was
assessed for MDSC quantity (%CD14� ,HLA-DRlow/- cells) pre-treatment, at
week 7, week 12, and week 24 by flow cytometry. MDSC ability to inhibit T
cell proliferation was tested using an in vitro suppression assay. Results: We
found that lower MDSC quantity pre-treatment predicted for improved
overall survival (Hazard ratio 1.07 (1.03, 1.11) p�0.002) and trended
toward associating with clinical benefit measured at week 24 imaging
(p�0.09). This effect was independent of pre-treatment or week 7 absolute
lymphocyte counts (ALC) and pre-treatment LDH when evaluated in a
multivariate model with ALC and MDSC quantity HR 1.10; 95% CI 1.04,
1.17 p�0.0006 and LDH and MDSC quantity HR 1.06; 95% CI 1.01,
1.11 p � 0.013. Furthermore, a general trend of increasing MDSC number
by week 24 from the pre-treatment baseline was associated with patients
that did not achieve clinical benefit. MDSC suppressed peripheral blood T
cell proliferation as measured by CFSE dilution in response to anti-CD3
antibody stimulation. Conclusions: Pre-treatment MDSC quantity may
predict clinical response following ipilimumab therapy. Further studies
evaluating MDSC as a biomarker of ipilimumab therapy are warranted both
retrospectively and prospectively in a broader group of patients.
2520^ Poster Discussion Session (Board #8), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Investigating genes and pathways that play a role in immune responses
mediated by anti-CTLA-4 therapy. Presenting Author: Jianjun Gao, University
of Texas M. D. Anderson Cancer Center, Houston, TX
Background: Blockade of the inhibitory T cell molecule CTLA-4 with a
monoclonal antibody has led to enhanced anti-tumor immune responses
and clinical benefit. Ipilimumab, an anti-CTLA-4 antibody (BMS), was
recently FDA-approved for the treatment of metastatic melanoma. Only a
subset of patients benefit from anti-CTLA-4. In order to identify genes and
pathways that are induced by anti-CTLA-4, which may be used in future
studies for potential correlation with clinical outcomes or provide additional
targets for therapy, we purified and analyzed CD4 T cells from
patients treated with anti-CTLA-4 for changes in gene expression profile.
We also obtained tumor tissues from treated patients for similar studies.
Methods: On an IRB-approved Phase Ia pre-surgical clinical trial, 6 patients
with localized bladder cancer were treated with two doses of Ipilimumab at
10 mg/kg at weeks 1 and 4. Blood was collected pre-therapy and
post-therapy (3 weeks after each dose). CD4 T cells were enriched from
peripheral blood by using the CD4 T cell isolation kit from Miltenyi Biotec
(Auburn, CA). Total RNA was isolated from purified CD4 T cells using
Qiagen RNeasy kit for Affymetrix microarray analyses. Microarray data were
then analyzed using Ingenuity iReport (Redwood City, CA). RT-PCR, RPPA
and Western blot were used to confirm significant changes in genes or
pathways identified in microarray analyses. Results: Ipilimumab treatment
resulted in modulation of differentially expressed genes (DEGs). After dose
#1, Ipilimumab only modulated 16 DEGs �2-fold (p�0.05) in CD4 T cells.
After two doses of treatment, Ipilimumab significantly changed expression
of a total of 100 DEGs. Further pathway analyses indicated that Ipilimumab
induced a variety of pathways involved in cell cycle control, cell proliferation,
apoptosis, and immune modulation. Specifically, these pathways
include PI3K/AKT, MAP/ERK, IFN/JAK-STAT, granzyme, and protein
ubiquination. Conclusions: Ipilimumab treatment results in modulation of
multiple genes and pathways, which likely play important roles in antitumor
immune responses and need to be considered for future optimization
of anti-CTLA-4 therapy and design of combination immunotherapy strategies.
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