Tumor-associated antigens - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 147

hTERT

Telomeres are repetitive nucleotide sequences that are found at the end
of chromosomes, which provide the chromosomes with a protective cap.
Specifically, because chromosomes shorten with every cell division, the
location of the telomeres near the end of the chromosomes protects these
terminally located genes from being degraded. Human telomerase reverse
transcriptase (hTERT) is a catalytic subunit of the enzyme telomerase, a
ribonucleoprotein that plays a role in stabilizing and maintaining chromo-
somal length by adding telomeres to the ends of chromosomes in eukary-
otes. Sine telomerase is primarily needed by highly dividing cells, it has low
expression in normal tissues with the exception of progenitor and normal
hematopoietic cells, and is activated in > 85% of tumors including myeloid
leukemia [30] . These features make hTERT a good target antigen in cancer
immunotherapy.

In an early report, immunogenicity to two HLA-A2 hTERT peptides, ILAK-
FLHWL and RLVDDFLLV, was demonstrated in normal individuals and
patients with prostate cancer [31] . hTERT-CTL specifically lysed cancer
cell lines and furthermore, in vivo immunization of HLA-A2 transgenic
mice with hTERT peptides elicited antigen-specific immune responses.
In addition to HLA-A2 peptides, other HLA class I and II peptides were
demonstrated to be valuable in targeting hTERT. Two HLA-A24 peptides,
VYAETKHFL and VYGFVRACL, were shown to elicit hTERT-specific immune
responses against HLA-A24 leukemia cell lines [32] . HLA-A24 is frequently
found in individuals of European descent and is the most common allele
found in the Japanese population. Additionally, CD4 + T-cell responses were
elicited using HLA class II epitopes derived from hTERT in the context of
several HLA-DR alleles [33] . Vaccination of HLA-DR4 mice with an HLA-
DR4 peptide elicited peptide-specific immune responses against numer-
ous hTERT-positive tumors, including the acute promyelocytic leukemia
cell line HL-60.

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Immunotherapy targeting hTERT has been primarily used in solid malig-
nancies; however, immunity to hTERT has been detected in patients with
CML and chronic lymphocytic leukemia (CLL). In CML, hTERT functional
peptide-specific CTLs were detected in patients following treatment with
IFN-α, allo-HSCT, and imatinib [34] . hTERT was also shown to be expressed
in CLL and hTERT specific cellular immunity was detected in CLL patients
[35] . With these promising data, further studies are warranted in hemato-
logical malignancies to further define the potential role of hTERT targeting
immunotherapy.

PRAME

Preferentially expressed antigen in melanoma (PRAME) is a cancer testis
antigen that was shown to be expressed in solid tumors and hematologi-
cal malignancies [36] . PRAME belongs to a class of antigens known as can-
cer testis antigens, which are non-mutated proteins normally expressed at
high levels in germinal tissues, but are absent or have very low expression in
non-germinal normal tissues. In addition to germinal tissue, PRAME is also
expressed in normal endometrial, ovarian, placental and adrenal tissues