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

Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2504 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
A phase I study of EpCAM/CD3-bispecific antibody (MT110) in patients
with advanced solid tumors. Presenting Author: Walter M. Fiedler, Medical
Clinic II, University Medical Center Hamburg-Eppendorf, Center of Oncology
(Hubertus Wald Tumorzentrum), Hamburg, Germany
Background: MT110 is a bispecific T cell engaging antibody construct
(BiTE) that directs CD3 expressing T cells to kill target cells that express
EpCAM, which is widely found on solid tumors. Methods: Safety, tolerability,
pharmacokinetics and anti-tumor activity of MT110 in patients (pts)
with advanced solid tumors were studied using a 3�3 design. Continuous
IV infusions for at least 28 days of doses ranging from 1 to 48 �g/d have
been tested. Stepwise intra-patient dose escalations within cycle 1 or at
start of cycle 2 have been explored. Results: 51 pts (6 gastric cancers, 32
CRC, 2 SCLC, 5 NSCLC, 3 HRPC, 1 ovarian cancer) have been treated in
12 dose cohorts. The maximally administered dose includes day 1 dose of 3
�g/d escalated up to 48 �g/d. The maximum tolerable dose (MTD) has not
yet been established. Diarrhea and elevations in liver function tests have
been reported as dose limiting toxicity (DLT) for individual patients.
Transaminase elevations were fully reversible and mitigated by dexamethasone
at initiation or escalation of dose. Other adverse events of grade 3 or
higher included transient lymphopenia, increase in lipase or amylase,
nausea, vomiting, and hypoalbuminaemia. No CNS safety signal was
observed. The mean serum half-life of MT110 was 4.5 hours. Mean steady
state serum concentrations of MT110 were linear with dose across
treatment cycles. At 48 �g/d, the mean Css was 3.2 ng/mL. This compares
to preclinical EC90 of 1.35 – 3.85 ng/ml in CRC cell lines. Sixteen pts who
received a dose of � 24 �g/d were evaluable for anti-tumor response. Best
response of SD was reported in 38%; median duration was 155 days (95%
CI 92; 161). Anti-tumor activity was demonstrated on biopsy of liver
metastases in one patient. Following at least 1 week of MT110 treatment at
48 �g/d, a decrease in circulating tumor cells was observed with a median
nadir 74% below baseline. Conclusions: The use of stepwise dose escalation
and concomitant dexamethasone resulted in improved tolerability. A
dose of 48 �g/d appears tolerable. Tumor biopsy evaluation on treatment
and pharmacodynamic evidence of anti-tumor activity are encouraging.
Additional dose cohorts will seek to identify the recommended phase II
dose and further evidence of anti-tumor activity.
2506 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
WT1-targeted dendritic cell vaccination as a postremission treatment to
prevent or delay relapse in acute myeloid leukemia. Presenting Author: Zwi
N. Berneman, Antwerp University Hospital, Edegem, Belgium
Background: Vaccination with tumor antigen-loaded dendritic cells (DC)
holds promise for the adjuvant treatment of cancer. Methods: In a phase I/II
trial, we investigated the effect of autologous DC vaccination in 17 patients
with acute myeloid leukemia (AML) in remission but at very high risk of full
relapse. Wilms’ tumor 1 protein (WT1) was chosen as immunotherapeutic
target and introduced into the DC by mRNA electroporation. We are
continuing a phase II trial, which is still recruiting. Results: Two out of 3
patients, who were in partial remission with chemotherapy-refractory
disease, were brought into complete remission following 4 biweekly
intradermal injections of WT1 mRNA-electroporated DC. In those 2
patients as well as in 6 other patients who were in complete remission but
who had molecularly demonstrable residual disease, there was a return to
normal of the AML-associated WT1 mRNA tumor marker following DC
vaccination, compatible with reaching clinical and molecular remission in
8/17 patients. Among the 8 responders, there have been 2 relapses and 2
deaths. Of the 9 non-responders, 8 have relapsed and 7 have died. Of the 2
patients in partial remission who were brought into complete remission by
DC vaccination, 1 has died following relapse. Median overall survival was 6
months in non-responders and 52 months in responders (p�0.0007).
Median relapse-free survival was 3 months in non-responders as compared
to 47 months in responders (p�0.0001). Clinical responses overall were
correlated with elevated levels of activated natural killer (NK) cells
post-vaccination. Long-term clinical responses, lasting for at least 3 years,
were significantly correlated with an increase in polyepitope WT1-specific
tetramer� CD8� T-cell frequencies. Conclusions: DC-based immunotherapy
elicits both innate (NK) and adaptive (T cells) cellular responses
correlated with clinical benefit. WT1 mRNA-transfected DC emerge as a
feasible and effective strategy to control residual disease in AML, in
particular as a post-remission treatment to prevent full relapse.
143s
2505 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
Anti-CD3 immunotoxin to induce remissions in cutaneous T-cell lymphoma
patients. Presenting Author: Arthur E. Frankel, Scott and White Hospital,
Temple, TX
Background: The anti-CD3 immunotoxin, AdmDT390bisFv(UCHT1), composed
of the catalytic and translocation domains of diphtheria toxin
(DT390) fused to two anti-CD3 sFvs showed selective cytotoxicity to normal
and malignant human T cells in vitro and in vivo and was prepared for a
phase I clinical study (Woo, Protein Exp Purif 58, 1, 2008). FDA approval
(BB IND#100712), and IRB approval was obtained. Methods: Nineteen T
cell lymphoma patients were screened, and 12 patients treated. Median
age was 62 years (range, 39-84 years) with 6 males and 6 females. Disease
was previously treated with one (6), two (3), three (1) or four (2) systemic
therapies. One patient had stage IV PTCL and the other patients had CTCL
(stage IB in 5, IIB in 4, IIIB in 1, and IV in 1). Six patients were treated with
2.5�g/kg x 8; five patients were treated with 5�g/kgx5-8andonepatient
treated with 7.5�g/kg x 8. Results: Drug-related toxicities were mild in
11/12 patients and were not dose dependent with transient fevers, chills,
lymphopenia, transaminasemia, CMV and/or EBV viremia, and hypoalbuminemia.
One 69 year old male with pre-existing heart failure treated at the
5�g/kg x 5 suffered severe vascular leak syndrome and heart failure.
Immunotoxin Cmax was 1 – 60ng/mL, and mean half-life was 42min. Four
patients had pre-treatment anti-immunotoxin titers �10�g/mL, and the
others had lower pre-treatment antibody levels. All evaluable patients
except two had increases of antibody titer between day 12 to 30 of 4 –
2000-fold. Among 10 evaluable patients, there were 2 complete remissions
(CRs) of 17 and 41� months durations and 4 partial remissions (PRs)
of 1� -32�months. Conclusions: The immunotoxin has exciting clinical
efficacy in this heavily pretreated group of patients. Dose escalation is
proceeding.
2507 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
Phase IB study on combined intradermal (ID) and intravenous (IV)
administration of autologous mRNA electroporated dendritic cells (DC) as a
single-agent cellular immunotherapy or combined with ipilimumab. Presenting
Author: Bart Neyns, UZ Brussel, Brussels, Belgium
Background: Autologous monocyte-derived DC electroporated with synthetic
mRNA encoding CD40 ligand, a constitutively active TLR4, and
CD70 (TriMix-DC) have superior T-cell stimulatory capacity. In a pilot
clinical trial, ID administration of TriMixDC-MEL (a mixture of TriMix-DC
co-electroporated with mRNA encoding a fusion of DC.LAMP and 1 of 4
melanoma associated antigens) was immunogenic but resulted in limited
anti-tumor activity in patients (pts) with advanced melanoma. Ipilimumab
(IPI) is a CTLA-4 blocking mAb with established activity in pts with
advanced melanoma. Methods: TriMixDC-MEL by the IV and ID-route was
investigated as a single-agent or in combination with IPI (10 mg/kg q3wks
x4, allowing for maintenance with IPI-alone q12wks in pts PFS at �24
wks). Ratio of ID/IV administered DC: Cohort-1: 20.106 /4.106 DC [2pts],
-2: 12.106 /12.106 DC [3pts], -3: 4.106 /20.106 [6pts], and -4: 0/24.106 DC [4pts]; DC were administered 4x q2w, and a 5th administration on w16.
in cohort-5, DC (4.106-ID/20.106-IV) were first administered alone and 2w
thereafter in combination with IPI for a total of 4 administrations [6pts].
Results: Local skin reactions (gr1-2) were observed in all pts receiving DC
ID, flu-like symptoms (� gr2) were observed in 12/21 pts, post IV-infusion
chills (gr2) in 7/21 pts. Cytokines release (including a �2-fold rise in the
serum levels of IL-1RA, IL-6, IL-8, IL-17, G-CSF, IFN-g, MIP-1a, MIP-1b,
TNF-a) was documented during chills. Best objective tumor response: 2x
PR � 2x CR (by RECIST) out of 15 pts (27%) treated with DC-only (ongoing
after 10�, 14�, 19�, and 20� mths) and 3 PR out of 6 pts (all stage
IV-M1c) treated with DC�IPI (ongoing after 5�,5�,6�mths). Conclusions:
ID/IV-administration of TriMixDC-MEL as a single-agent cellular immunotherapy
or combined with IPI is associated with distinct but manageable
side-effects and has clinical activity against pretreated advanced melanoma.
Activity compares favorably with TriMixDC-MEL by ID-administrationonly.
Combined ID/IV administration of TriMixDC-MEL with IPI is currently
under further evaluation in a phase II trial.
Visit abstract.asco.org and search by abstract for the full list of abstract authors and their disclosure information.