Part III: Can Cancer be a Curable Disease in the Near Future?

What are good targets against which to generate a therapeutic immune

response?

The keynote address was given by Stephen Hoffman of Celera. Confident on

immunological interventions will ultimately have a greater impact on cancer therapy
than monoclonal antibodies like biosimilar monoclonal antibody, Hoffman contends
that protein targets as yet unidentified will demonstrate that immunological therapies
can have an impact on the diseases of not just some, but most patients with cancer. He
argued that the inadequate responses to current cancer vaccine targets observed to
date relate to a lack of breadth of immune response against synthetic peptide or
subunit targets, for example, HLA restriction of response is such that all individuals
simply cannot respond to the same epitopes.

Conversely, whole-cell vaccines, which might overcome the issue of breadth of

response, present the opposite problem, that of failing to focus the immune response
to the correct target. In the presence of too many proteins, unimportant proteins dilute
or even suppress the immune response to the intended target. The proteomic approach
being taken by Celera to identify quantifiable, differentially expressed, novel proteins
as targets for cancer vaccines employing high throughput liquid chromatography and
mass spectrometry was described. This approach will likely identify far more
candidate proteins than can ever be explored as potential therapeutics. Criteria for
validating novel targets have been established, beginning with the magnitude of
differential expression in a normal organ versus tumor tissue, followed by a detailed
analysis of the in vitro and in vivo immune responses to the potential immunogen. It
remains unknown whether any protein in a tumor can be a potential target for an
immune response and the approach taken here should ultimately be able to determine
this.

At the opposite end of the spectrum of discovery followed by application, Claudine

Bruck (GlaxoSmithKline Biologicals) outlined her teams experience with bringing
candidate tumor antigens to clinical application. Three different potential cancer
vaccine targets, each chosen with important theoretical considerations in mind were
presented: MAGE 3, specific for melanoma but expressed only at low levels, was
chosen for tumor specificity.

For tissue specificity, a variety of prostate specific antigens, also expressed in normal
prostate tissue but that of a dispensable organ are available (of which PSA is the
prototype), and Her2/Neu is a prototype for considerable differential over-expression
in tumor tissue. The learning from a clinical study of vaccination against MAGE 3
was shared: Clinical responses have been seen in some patients, mostly in those with
non-visceral disease in fact, some of the responding patients have continued to
receive vaccinations on a compassionate basis with continued and improving response.
Disappointingly however, measures of immune response including assessment
of antibody levels and quantitation of interferon gamma-producing T cells showed no
correlation with clinical response.

Bruck raised an important and recurring issue regarding the appropriate patient
population in which to test cancer vaccines. There are clear advantages to including
either patients with low disease burden or without measurable disease but at high risk
of relapse. However, such studies are lengthy and costly in addition to presenting
problems of data interpretation should standards of care change during such an
ongoing study.

Bruck also warned against drawing conclusions on correlation between immune

responses observed to vaccination in advanced cancer patients and survival: clearly,
those patients already in poorer health may respond less well to vaccinations, so that a
good prognosis after immunotherapy might merely reflect better pre-existing immune
responsiveness.

Reference: Adele Fielding, Molecular Medicine Program, Mayo Clinic

Author Author

Creative Biolabs is a professional biotech service provider. Sinceits establishment in

2005, it has been focused on the research and development of antibody, including de
novo antibody sequencing, recombinant antibody production, antibody purification,
and so on.

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