Tumor-associated antigens - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 150

escalation (50 μg, 150 μg, 500 μg and 1500 μg per vaccine dose) trial [59] .
All doses administered were well tolerated without any major side effects.
Moreover, the vaccination led to functional immune responses as measured
by T-cell proliferation and delayed type hypersensitivity reactions, which
were detected in patients who were given the 500 μg and 1500 μg vaccine
doses. However, no BCR-ABL peptide-specific CTL were identified, suggest-
ing that the efficacy of the vaccine might be mediated through a CD4 + T-cell
response [60] .

In a phase II trial, 14 patients with CML were given a peptide vaccine that
included the aforementioned HLA class I peptides, along with HLA-A2
(SSKALQRPV) and HLA class II DR1, DR4, and DR11 binding peptide (IVH-
SATGFKQSSKALQRPVASDFEP) [61] . Molecular and cytogenetic responses
were reported in 7 of 14 vaccinated patients. Four patients demonstrated
peptide-specific CD8 + T-cell responses and 11 patients had CD4 + immu-
nological responses to the vaccine. Because many of these patients were
concurrently receiving interferon (IFN)-α, imatinib or donor lymphocyte
infusions as part of CML therapy, it was difficult to determine whether the
responses observed were purely a result of the vaccine or the concurrent
administration of vaccine and standard CML therapy. Bocchia et al. demon-
strated clinical responses, including cytogenetic and molecular responses,
to BCR-ABL multipeptide vaccine in all ten patients and five of six patients
who received concurrent imatinib or IFN-α therapies, respectively [62] .
Immunological responses, including delayed-type hypersensitivity, CD4 +
T cell proliferation and IFN-γ production, were also observed following
vaccination.

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Because of the recurrent CD4 + T-cell responses that were seen in the tri-
als with BCR-ABL multipeptide vaccine, Rojas et al. [63] conducted a
phase I/II vaccine study using BCR-ABL peptides linked to pan DR epit-
ope (PADRE) peptides, since the latter has been used as a vaccine adjuvant
due to its potent effects on CD4 + T-cell responses [64] . In this study, named
the EPIC trial, which included 19 imatinib-treated patients, 14 patients
demonstrated T-cell responses following vaccination and 13 patients had
molecular responses [63] . Furthermore, six patients showed CD8 + T-cell
responses and 13 patients showed CD4 + T-cell responses to BCR-ABL fol-
lowing vaccination.

Synthetic peptide analogs derived from BCR-ABL b3a2 and b2a2 proteins
that contain single or double amino acid substitutions at key HLA-A2 bind-
ing positions, which enhance peptide HLA-A2 binding, have also been
employed in BCR-ABL vaccine trials [65] . These heteroclitic peptides, along
with native HLA-A2 binding peptides, were administered to 13 patients
with CML. Clinical and immunological responses were observed following
vaccination. In a phase II study with ten CML patients using the synthetic
and native BCR-ABL peptide vaccine concurrently with imatinib, Jain et al.
[66] showed molecular responses in many patients; however, in most of the
cases the observed responses were transient.

To determine whether CML-related factors were contributing to immune
failure following vaccination, Rojas et al. [67] administered the same BCR-
ABL vaccine used in the EPIC study to five normal subjects and then mea-
sured proliferative response to the vaccine as well as IFN-γ and granzyme