Biotech Values

[p3analyze]

"believe results from trials like these wildly vary depending on the mouse models"

You are right. Unlike the previous one, this CEGE pub showed that administering docetaxel shortly after vaccination (within 2 days) but not too much later actually expand the antigen specific T cells. I am not diagreeing with Gold's statement that docetaxel spreads antigen, but I guess Gold could have fielded Monnane's Treg question better and show his depth of knowledge in the field. The following excerpt from a GVAX + Docetaxel animal study provided some evidence of docetaxel actually slightly increased circulating antigen-specific T cells. Sorry to clutter the board. But again, it might not help to promote a competitor..


http://www.springerlink.com/content/yv4376824q35g136/fulltext.pdf


The combination of a chemotherapeutic agent such as
docetaxel with a vaccine like B16.GM could result in
chemotherapy-related inhibition of the activation or
premature death of immune cells that are stimulated to
divide rapidly by the vaccine. A series of studies were
conducted to determine whether docetaxel could inhibit
antigen (Ag)-specific T cell activation after vaccination
with a GM-CSF-secreting tumor cell vaccine. An
adoptive T cell transfer system was developed in which
OVA is expressed on the surface of the tumor cells
(B16.OVA) to serve as a surrogate tumor-associated
antigen. Matching, i.e., OVA-expressing, B16.GM
vaccine cells (B16.GM-OVA) were also developed. Ovaspecific
T-cell receptor transgenic (TCR) precursor
frequencies of 2–3% were detected in the spleen and
lymph nodes of mice that were adoptively transferred
with approximately 1.5•106 OVA-specific T cells only
at day 0, and their frequency was unchanged in mice
bearing B16-OVA tumors that were treated with either
HBSS or docetaxel (Fig. 5a, c). In contrast, a large
increase in the fraction of OT-1-specific T cells was seen
in the spleens of mice 6 days after vaccination with
B16.GM-OVA cells compared to control mice (18% vs.
6% of CD8+ T cells) (Fig. 5a), and a slightly greater,
but not significant, expansion was detected in mice
treated with the combination of B16.GM-OVA vaccine
and docetaxel (22%). By day 10 post-vaccination, the
percentage of Ova-specific T cells in mice vaccinated
with B16.GM-OVA returned to control levels, whereas
the percentage of ova-specific T cells remained slightly
elevated in mice treated with the vaccine plus docetaxel
(13% vs. 5% in the vaccine-only treatment group).


Pre-vaccination administration of docetaxel, which
leads to moderate lymphopenia, might also result in
the induction of a stronger anti-tumor T cell response
after vaccination. Several studies have shown that a
lymphopenic environment, as a result of chemotherapy,
radiation therapy or RAG deficiency, is conducive to
the expansion and survival of antigen-specific T cells,
presumably by eliminating the inhibitory effects of
the CD4+CD25+ T regulatory cells [34–37]. However,
whether docetaxel increases the potency of GM-CSFsecreting
tumor cell vaccines by removal of
CD4+CD25+ regulatory T cells or simply reducing
tumor burden and increasing antigen accessibility
through direct tumor cytolytic effects or by both mechanisms
remains to be investigated.
In contrast to the observation of Machiels et al. [33],
in which post-vaccination administration of paclitaxel
did not enhance anti-tumor activity of a vaccine, postvaccination
administration of docetaxel in this study
significantly increased the survival of mice. The dissimilar
outcome may reflect the different timing of chemotherapy
treatment. Machiels et al. administered
paclitaxel 7 days after vaccination, whereas in our
studies docetaxel was administered 2 days after vaccine
[33]. It is possible that administration of docetaxel
7 days after vaccination eradicates the rapidly dividing T
cells stimulated by the vaccination. However, since docetaxel
has a short half-life in vivo [38, 39], residual drug
levels will be very low when given 2 days after vaccination,
before T cells start their vaccine-induced proliferation.
Docetaxel is an approved therapy for prostate cancer,
and a GM-CSF-secreting tumor cell vaccine (GVAX) is
currently being evaluated in a phase 3 clinical trial in
hormone-resistant prostate cancer patients. When
undertaking combination therapy with these two treatment
modalities for prostate cancer, particular attention
should be given to the timing of administration of the
two therapies. Docetaxel is typically given every 3 weeks
in current treatment regimens, in part to allow for the
recovery of drug-induced neutropenia. One could
envisage a regimen in which a GM-CSF-secreting tumor
cell vaccine such as the GVAX prostate cancer vaccine is
administered 2–3 days after each docetaxel treatment.
Using this treatment schedule, docetaxel would kill the
proliferating tumor cells, increasing antigen accessibility,
or remove CD4+CD25+ regulatory T cells or both, but
be cleared from the circulation in time to have a minimal
effect on the vaccine-induced anti-tumor immune response.
The data reported herein demonstrate that administration
of docetaxel either prior to or after vaccination
enhances the anti-tumor efficacy of the vaccine resulting
in prolonged survival at docetaxel dose levels that induce
neutropenia. Furthermore, vaccine-induced T cell responses
are unaffected by docetaxel administration.
These findings provide a rationale for testing docetaxel
chemotherapy in combination with GM-CSF-secreting
tumor cell vaccines in patients with cancer.