Abstract Book 2010 - CIMT Annual Meeting

020 Nielsen | Therapeutic vaccination
The CDX-1307 vaccine: regulatory and clinical steps in
developing a regimen
Michaela Nielsen, Larry Thomas, Laura Vitale, Li-Zhen He, Venky Ramakrishna, Jennifer
Green, Thomas Davis
Celldex Therapeutics, Inc., Needham, Massachusetts 02494, USA
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CDX-1307 is a dendritic cell (DC)-targeting cancer
vaccine, consisting of a monoclonal antibody
against the mannose receptor, CD206, fused to the
β-chain of human chorionic gonadotropin (hCGβ).
hCGβ is frequently expressed by common epithelial
cancers, may facilitate cancer progression,
and correlates with poor prognosis. The antibody
portion of the vaccine targets it to CD206 on DCs,
where the molecule is internalized and processed
into peptides that are presented on the DC surface.
The CDX-1307 vaccine regimen was developed in
a step-wise approach. Without a suitable animal
model available, the initial Phase I study was a
dose-escalation with intradermal administration of
CDX-1307 in patients with incurable cancer. Safety
of the vaccine was established by demonstrating
tolerability in cohorts of 6 patients at 0.3, 1.0, and
2.5 mg respectively, given every two weeks for a
total of 4 doses.
Pre-clinical data and clinical experience demonstrated
that inclusion of adjuvants leads to optimal
immune responses. The cytokine GM-CSF, which
mobilizes and activates antigen-presenting cells
(APCs) and up-regulates CD206 on APCs, was thus
proposed to be added to the study regimen. After a
toxicology study with CDX-1307 + GM-CSF in hMRtransgenic
mice showed no noteworthy adverse reactions,
combination treatment with CDX-1307 and
GM-CSF was approved and initiated.
Further studies indicated that immune responses
are significantly enhanced by toll-like receptor
(TLR) agonists. Two such agents were proposed
to be added to the CDX-1307 + GM-CSF regimen
in additional cohorts: the TLR7/8 antagonist Resiquimod
(3M) or the TLR3 antagonist Hiltonol®
(Poly-ICLC). Both cohorts were approved based on
previous human experience with the antagonists,
which were proposed to be used in a concentration
below their established maximum tolerated doses
(MTD).
Our pre-clinical studies showed that combining
TLR agonists enhances the immune response and
anti-tumor activity of cancer vaccines. Therefore,
a regimen that combines GM-CSF, Resiquimod and
Hiltonol® (Poly-ICLC) was proposed. This regimen
was approved after review of toxicology data from
a rabbit local reactogenicity study with various
combinations of the three adjuvants. One particular
challenge of the combination regimen is the
local administration of four different agents, one
of which is topically administered (Resiquimod),
while the others are injected. Most rabbits that received
the three adjuvant combination developed
minor skin reactogenicity, with only one animal
developing some slowly resolving subcutaneous
edema.
The clinical data demonstrated that the combination
of the TLR agonists increased the frequency and
severity of local reactions, but they were limited to
grade 1 and 2 and resolved. In fact no dose limiting
toxicities were reported, while robust anti-hCG-β
humoral and T cell responses were reported. Evidence
of clinical impact was observed in a subset of
patients, and was noted to be associated with generation
of anti-hCG-β responses. These data provide
support for further evaluation of the CDX-1307
vaccine regimen in patients with hCG-β-expressing
tumors. A Phase II study in patients with newly diagnosed,
resectable hCGβ-positive bladder cancer
involving the full combination regimen has been
accepted by the FDA and is pending initiation.