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induced by chemotherapy [49]. Since various cytotoxic
chemotherapies, such as cisplatin, are know lead to cell
cycle arrest and p53 induction by tumors [50], we were
interested in evaluating the combination of p53-specific
STAR fusion proteins and cisplatin in our animal efficacy
models.
Initial studies confirmed the cisplatin induced expres-
sion of p53 (aa 264-272)/HLA-A
0201 complexes on the
high aggressive human melanoma A375 subclone
(A375C15NL1) and human NSCLC A2-A549-L1 cells
following in vitro incubation. In the subcutaneous
A375C15NL1 melanoma mouse xenograft model, mono-
therapy with ALT-802 (i.e., twice-weekly dosing for 4
weeks) or cisplatin (i.e., every 2 weeks) exhibits similar
antitumor effects. However, combined therapy with ALT-
802 and cisplatin exhibited significantly better antitumor
activity than that of ALT-802 monotherapy (Figure 31.5C)
(W. Xu, J. Wen, unpublished data). Similarly, the combi-
nation of ALT-801 treatment (i.e., three doses per weekly
cycle, a 10-day rest, and another three doses per weekly
cycle) with a single-dose cisplatin showed enhanced effi-
cacy in this model compared to ALT-801 or cisplatin
treatment alone. The synergistic effects of cisplatin and
fusion protein treatment are possibly due to cisplatin-
mediated increases in p53 peptide antigen display on
the tumors and subsequent enhanced tumor targeting of
the p53-specific scTCR domain. Since cisplatin is a com-
ponent of standard-of-care therapy for advanced bladder
cancer, NSCLC and several other cancers and been used in
biochemotherapy regimens with high-dose IL-2 for treat-
ment of melanoma [48], it is of interest to further evaluate
the beneficial effects of ALT-801 and ALT-802 in combi-
nation with cisplatin in the clinical setting.
tolerated dose (MTD) level exhibiting the general spec-
trum of side effects of high-dose IL-2 therapy but with a
much lesser degree of severity and less grade III/IV effects
on liver and kidney function. ALT-801 treatment resulted
in immune stimulation with increased serum interferon-
g
(IFN-
g
)butnotTNF-
a
4-8 h postdose and elevated NK
cell activation following the initial dosing cycle. The
serum half-life of ALT-801 was about 4 h consistent
with the animal pharmacokinetic data, indicating that
the half-life of fusion protein is considerably longer
than the
15min distribution and 85min elimination
half-lives reported for recombinant human IL-2 [52].
Furthermore, the maximum serum ALT-801 concentra-
tions observed were consistent with the ALT-801 dose,
in contrast to the mere 30% serum recovery observed in
subjects receiving IL-2 therapy. ALT-801 treatment exhib-
its evidence of dose-dependent clinical benefit to cancer
patients with 40% of the patients having stable disease,
several with tumor shrinkage and one patient with a
complete response (CR). The patient with the CR has
been disease-free for 2 years postdosing without other
anticancer therapy. This suggests that ALT-801 can pro-
vide a durable response in patients with metastatic malig-
nances and mirrors that of high-dose IL-2 treatment but
without the severe toxicities associated with Proleukin
therapy. In addition, stable disease was observed in various
indications (neuroendocrine, prostate, head and neck can-
cer) that are not typically sensitive to IL-2 treatment,
suggesting tumor targeting with the scTCR domain can
broaden the therapeutic utility of the cytokine. These data
are also consistent with our observations in the preclinical
studies described earlier.
<
31.5.2 ALT-801/Chemotherapy Phase II Studies
With the encouraging Phase I results and the demonstrated
synergybetweenALT-801andcisplatininmousetumor
efficacy studies, Phase Ib/II studies are underway for an
ALT-801/cisplatintreatmentregimeninpatientswithmeta-
static melanoma (Clinicalt rials.gov: NCT0 1029873) and
an ALT-801/cisplatin/gemcitabine treatment regimen in
patients with muscle invasive or metastatic bladder cancer
(Clinicaltrials.gov: NCT01326871). We are pa rticul arly
interested in advanced/metastatic bladder cancer since no
new drugs for this indication have been approved in the past
20 years and current antibody-based cancer therapies have
yet to demonstrate significant improvement over standard-
of-care chemotherapy [53,54]. Notably, mutation and sub-
sequent tumor cell overexpression of p53 may represent an
important yet unexploited target for advanced/metastatic
bladder cancer [32,55]. Recent analysis of over 3400 blad-
der cancer patients revealed a highly significant correlation
between detectable p53 overexpression in tumors and both
tumor grade/stage and tumor progression and mortality in
31.5 CLINICAL DEVELOPMENT OF ALT-801
31.5.1 Monotherapy Clinical Study with ALT-801
With the favorable preclinical testing results, the clinical
objective for ALT-801 is to determine if this fusion protein
has potential as a targeted immunotherapeutic with better
antitumor potency, a lower toxicity profile and more
convenient dosing schedule compared to that of human
recombinant IL-2. It is also of particular interest to expand
clinical utility of IL-2-based immunotherapy beyond its
twoFDA-approvedindications, metastatic melanoma and
renal cell carcinoma. Toward these aims, we have com-
pleted an open-label, dose-escalating Phase I/IIa clinical
trial (Clinicaltrials.gov: N CT00496860) in which 26
patients with various metastatic, refractory malignancies
wereenrolledandinfusedwithatleastoneandasmanyas
eight doses of ALT-801 per treatment course [51]. Results
indicate that ALT-801 is well tolerated at the maximum-
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