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

160s Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2573^ General Poster Session (Board #5F), Mon, 8:00 AM-12:00 PM
Messenger RNA vaccination and B-cell responses in NSCLC patients.
Presenting Author: Martin Sebastian, Medizinische Klinik II Hämatologie/
Onkologie, Rheumatologie, Infektiologie, HIV Klinikum der J.W. Goethe-
Universität Frankfurt, Frankfurt am Main, Germany
Background: Vaccination with mRNA is a novel technology in cancer
immunotherapy. CV9201 consists of self-adjuvanted mRNA molecules
(RNActive) coding for five non small cell lung cancer (NSCLC)-associated
tumor antigens (MAGE-C1, MAGE-C2, NY-ESO-1, BIRC5, 5T4). We report
final results of a phase I/IIa trial of CV9201 in patients (pts.) with NSCLC.
Methods: Pts. with stage IIIB/IV NSCLC with a response or stable disease
after first-line chemotherapy or chemoradiation were eligible. Cohorts of 3
pts. were treated at three dose levels (400�g, 800�g and 1600�g
CV9201) and observed for DLTs to select the highest tolerated dose for
phase IIa. Primary endpoint was safety and tolerability; secondary endpoints
were immune response, clinical efficacy and survival. Pts. received
up to five vaccinations of CV9201 within 15 weeks. Antigen-specific
immune responses against each of the 5 antigens were measured at
baseline, and two weeks after the 3rd and 5th vaccination. Frequency of
lymphocyte subsets and expression of activation and maturation markers
were measured and retrospectively correlated with immunological and
clinical parameters. Results: 46 pts. were included (9 phase I; 37 phase
IIa); No DLTs occurred, and the 1600 �g dose was investigated in phase
IIa. The most frequent related adverse events were mild to moderate
injection site reactions and flu-like symptoms. 3 patients (7%) had
potentially related grade 3 AEs (fatigue, injection site granuloma, asthma
attack) and no related SAEs were reported. There were no objective
responses. Data on PFS and survival will be presented. Antigen specific
immune responses against at least one antigen were induced in 65% of pts.
(39% cellular and 49% humoral). Consistently, a significant �2 fold
increase of pre germinal center B cells (pGCB) was observed in 61% of pts.
This increase of pGCB correlated significantly (p�0.0028) with increase of
total CD4 effector T cells. Frequency of CD 4 T Reg cells did not increase
during treatment. Conclusions: Vaccination with CV9201 has a favorable
safety profile and induces T and B cell responses against all included
antigens. Vaccine-induced increase of pGCB is a new finding and might be
used as a biomarker in cancer immunotherapy.
2575 General Poster Session (Board #5H), Mon, 8:00 AM-12:00 PM
Bispecific Fynomer-antibody fusion proteins targeting two epitopes on
HER2. Presenting Author: Frederic Mourlane, Covagen AG, Zurich-
Schlieren, Switzerland
Background: Fynomers are small binding proteins (7 kDa) derived from the
SH3 domain of Fyn kinase. They can be engineered to yield specific and
high-affinity binding domains to target proteins of interest. In the past, we
have isolated Fynomers with excellent physico-chemical properties binding
to 16 different antigens. One important application of the Fynomer
technology represents the genetic fusion of a Fynomer to an antibody to
provide bispecific fusion proteins. Methods: Using phage display technology
we have isolated Fynomers binding to tumor-associated antigens. After
genetic fusion of these Fynomers to antibodies of interest the resulting
bispecific proteins were evaluated in vitro and in vivo for their antitumoral
activity. Results: The fusion of Fynomers to the antibodies of interest did not
alter the favorable biophysical properties of the antibodies. First, the
Fynomer-antibody fusion proteins could be purified with the same high
yields from the supernatant of transiently transfected CHO cells as the
unmodified antibodies (in the range of 100 mg/L). Second, the purified
fusion proteins were monomeric and showed no signs of aggregation even
after four months of storage at 4 °C or -20 °C in PBS as determined by size
exclusion chromatography. Third, the Fc-mediated effector functions of
antibodies were not altered by their fusion with Fynomers. Antibodydependent
cellular cytotoxicity (ADCC) was maintained, and the affinity to
the neonatal Fc-receptor (FcRn) was similar as observed for the unmodified
antibody. In addition, the bispecific Fynomer-antibody fusion proteins
demonstrated excellent growth inhibition of tumor cells in vitro and high
efficacy in vivo in tumor xenograft mouse models. Conclusions: These
encouraging preclinical results indicate that the bispecific Fynomerantibody
fusions have highly promising properties with a great potential for
further preclinical and clinical development.
2574 General Poster Session (Board #5G), Mon, 8:00 AM-12:00 PM
Adoptive cell therapy for melanoma patients using tumor-infiltrating
lymphocytes, lymphodepleting chemotherapy, and low-dose interleukin-2.
Presenting Author: Eva Ellebaek, Department of Oncology and Center for
Cancer ImmuneTherapy, Department of Hematology, Copenhagen University
Hospital Herlev, Herlev, Denmark
Background: Adoptive T cell therapy is based on isolation of tumor
infiltrating lymphocytes (TIL) from autologous tumor, in vitro activation and
expansion, and the reinfusion of these cells into a lymphodepleted patient.
Together with high-dose interleukin (IL)-2 this treatment has in a few other
countries successively been given to patients with advanced malignant
melanoma and an impressive 50% response rate has been observed. Here
we report the experience from a Danish Translational Research Center
using low-dose subcutaneous IL-2 injections. Methods: A pilot trial including
patients with metastatic melanoma, PS �1, age �70, measurable and
progressive disease, and no CNS involvement. Six patients were treated
with lymphodepleting chemotherapy, TIL infusion, and 14 days of low-dose
IL-2, 2 MIU/day. Results: Low-dose IL-2 considerably decreased the
toxicity of the treatment with no grade 3-4 events related to this drug. Two
of the 6 treated patients have an ongoing complete response (30� and 7�
months), 2 patients had stable disease (4.5 and 5 months) and 2 patients
progressed shortly after treatment. Five patients went through surgery but
were not treated because of rapid disease progression (2), development of
brain metastases (2) or the inability to grow cells (1). Tumor-reactivity of
the infused cells and peripheral monocytes before and after therapy were
analyzed. High tumor responses in the infusion products were correlated to
clinical response and also an induction of tumor reactive T cells were seen
in the peripheral blood for 1 patient in complete response. Conclusions:
Complete and durable responses are induced after treatment with adoptive
cell transfer in combination with low-dose IL-2 questioning the need for
high and toxic doses of IL-2.
2576 General Poster Session (Board #6A), Mon, 8:00 AM-12:00 PM
A phase I study of the safety and pharmacodynamic effects of everolimus in
combination with lenalidomide in patients with advanced solid malignancies.
Presenting Author: Taofeek Kunle Owonikoko, Winship Cancer Institute,
Emory University, Atlanta, GA
Background: Everolimus (E), an mTOR inhibitor, and Lenalidomide (L) are
both potent anti cancer agents with immunomodulatory effects. Preclinical
evidence of enhanced cytotoxicity of the combination of an mTOR inhibitor
and lenalidomide provided the rationale for this phase I study. Methods:
Patients with advanced solid malignancies, ECOG performance status (PS)
0-2 and adequate organ function were eligible. Using standard 3�3 dose
escalation schema, patients were treated in cohorts of three with increasing
doses of E (5mg, 10mg) and L (10, 15, 20, 25mg) on day 1-28 of a 28-day
cycle. Treatment cycles were repeated until disease progression by RECIST
criteria or intolerable toxicity. Pharmacodynamic (PD) effects of treatment
on circulating B and T lymphocytes subsets were assessed by multiparameter
flow cytometry at baseline and after 2 cycles. Results: We enrolled 21
patients (thyroid-5, salivary gland-5, colon-4, sarcoma-2, and others-5);
median age-58 (29-74); male-13; ECOG PS of 0, 1, 2 (3/17/1). Salient
grade 3/4 toxicities included rash (67%), anemia (19%) and vomiting (5%)
without dose limiting toxicities. The median number of completed cycles
was3(1-�15) and best response in 14 of 18 evaluable patients was
stable disease (range 2- �14 months); median PFS was 116 days (14-
�498). The RP2D of E and L was defined as 10mg and 25mg once daily,
respectively. PD endpoint analysis after 2 cycles of treatment showed a
significant increase in activated cytotoxic T cell subset (CD8�ICOS1�) in
patients with salivary or thyroid cancers compared to other tumor types
(�2051.0 vs. �394 vs. -1687.4 respectively; p�0.0303) and a trend for
an increase in patients with non-progressing tumors (�661.7 vs. -384.1;
p�0.0988). Other significant correlations were: Changes in total B-cells
(CD3-CD19�) with PFS; NK cells with age (p�0.0211) and activated T
cells (CD3�CD69�; CD3�CD62L-; p�0.01) with gender. Conclusions:
The combination of E and L is well tolerated at the recommended single
agent doses and showed promising efficacy in neuroendocrine and salivary
adenoidcystic carcinoma. Modulation of activated T cell subsets
(CD8�ICOS1�) correlates with efficacy of these agents.
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