Download File - JOHN J. HADDAD, Ph.D.

Development of Novel Immunotherapeutics 171
the groin lymph nodes of 19 melanoma patients with stage IV disease, using a
programmable infusion pump. The plasmid was given in repeated cycles, generally
up to four times; each cycle lasting 96 hours and being two weeks apart.
The trial was a dose-ranging, with maximal dose of 1.5 mg of plasmid per
infusion cycle. Plasmid infusion into lymph nodes was well tolerated, with few
adverse events mostly local (transient lymphadenopathy) and rare systemic
adverse events (mainly fatigue and pyrexia). Only 4 out of 19 patients showed
measurable elevation of the immune response as assessed by tetramer assay–
based measurement of peptide-specific T cells. Interestingly, other five patients
had preexisting immunity against Melan-A and showed no further increase in the
frequency of specific T cells. Despite the fact that there was no objective tumor
regression in any of the patients treated, there was a significant correlation
between clinical outcome in terms of TTP and Melan-A immunity at baseline or
after immunization. Patients that developed an immune response in both circumstances
had a double TTP than the nonimmune patients. A lack of correlation
with the basic immune competency measurements (percentage of CD4 þ ,
CD8 þ T cells and ex vivo mitogenic test) argued against the possibility of a bias
or that Melan-A/MART-1-specific immunity is simply an epiphenomenon
(linked to the overall immune competence and thus clinical status). Nevertheless,
the statistical significance of this retrospective analysis disappears if patients
with preexisting immunity against Melan-A are excluded from the analysis. In
the absence of a detailed analysis of the immunological response (for example,
the profile of T cells before and after immunization), we cannot rule out that, in
fact, despite the lack of further expansion of the antigen-specific population
in these patients, the vaccine may have acted by converting the T cells to
an effector phenotype. Conversely, only four patients apparently displayed de
novo induction of specific immunity against the dominant Melan-A26–35 epitope
evaluated in this trial.
Overall, the conclusions were the following:
l Melan-A/MART-1 and tyrosinase are most likely key melanoma antigens
that offer a viable platform for developing immunotherapies—concordant
with independent findings (14).
l The immunization methodology needs significant improvement in order to
allow induction of robust, reproducible, persisting, and multivalent
immune responses.
l The range and quality of assays in support of the exploratory trials need to
be enhanced.
l Evaluation of multiple PD biomarkers in exploratory phase is of paramount
importance to development of first-in-class products. Example in
case, the need to have a comprehensive evaluation of magnitude and
profile of immune response. This is key to establish a causal link between
the investigational drug and the clinical effect during early development, a
prerequisite for successful identification of the right opportunity in clinic