The rationale for immunotherapy, is dependent on the idea that
cancer must be recognised by the immune system. Cancer cells are derived from the
patient’s own tissue, therefore there has been some reluctance in believing that the
immune response can effectively control or even eradicate neoplasia. In the age of
molecular biology, great advances have occurred which demonstrated not only
immunological control of neoplasia, but also specific markers which are the target of
immune recognition. Such markers are useful not only for measuring the immune
response a patient may have against their tumor, but also for development of antitumor
The Mutator Phenotype
Cancer cells have a very high rate of mutation. This is partly accounted for by the fact
that many cancers have mutations in tumor suppressor genes such as p53. Cells with
mutated DNA are blocked from proliferating by p53, a protein that was also called
“guardian of the genome” because of its key function in maintaining genomic integrity
(1). If p53 it self is mutated or inactivated then the cell is able to acquire additional
mutations. Once this happens the cell is said to have a mutator phenotype (2). The
ability of cancer cells to mutate allows them to utilize any biological strategy they need in
order to survive and in most cases to kill the host.
Here is a sample of what mutations allow the cancer cells to do:
1. Resist normal antiproliferative signals such as TGF-β by mutating the receptor (3) or
transduction proteins linked to its signalling (4).
2. Evade apoptosis by mutating apoptosis-inducing receptors such as Fas (5).
3. Evade apoptosis by increasing activity of naturally occurring anti-apoptotic proteins
such as bcl-2 (6) or FLIP (7).
4. Proliferate in absence of external growth factor by a constitutively active:
a) Tyrosine kinases (8),
b) GTP protein (9),
c) Growth factor receptor (10,11).
5. Express the enzyme telomerase which allows cells to overcome the Hayflick limit and
continue dividing without the problem of telomere shortening (11a). The mutations of cancer cells allow them to be different than the noncancerous cells from which they originated. Targeting mutations that the cancer requires for proliferation and/or viability should be therapeutic since if the cancer cells mutate to evade the intervention, they will not be able to proliferate and/or remain viable. The flaw in this statement is that the cancer cells can try a new mutation. Or, cancer cells may mutate by altering the way in which they express the proteins on the cell surface, thus “hiding” them from our intervention. However, an immunotherapy that targets several mutations which
are needed for proliferation and/or viability will hopefully be efficacious, at least
Immune Recognition of Mutant Proteins
Although these molecular mutations exist, the question is whether immune response can
be induced against them. For the immune system to recognise mutant forms of protein,
these proteins must be expressed on the surface of the cancer cell. Classical immunology
teaches that intracellular proteins are digested into peptides and presented on MHC class
I to CD8 T cells. There have been some new papers describing the role of non-classical
MHC and molecules such as Rae-1 presenting tumor antigens to NK and gamma-delta T
cells (12-14). Regardless of the method of activation, immune response to tumor
antigens can be measured by T cell proliferation/cytokine production in response to in
vitro stimulation with the antigen, or by antibody responses.
Are there naturally occurring immune responses to oncogenically mutated proteins? Yes!
Immune Response to P53
Immune responses to wild-type p53 are not usually detectable, however antibody
response to mutant p53 was detected in patients with colorectal cancer (15), esophageal
cancer (16), breast cancer (17), ovarian cancer (18), and several other types (reviewed in
Interestingly, in some of these cases presence of antibody to mutated p53
corresponds with poor prognosis. An explanation for this may be that these antibodies
can not fix complement and therefore are unable to lyze the tumor. If this is the case,
than such antibodies may be deleterious to anticancer immune response by formation of
antigen-antibody complexes which have previously been demonstrate to stimulate the
cancer-promoting Th2 immune response (20, 21).
T cell responses have also been detected to both wild type and mutant p53 proteins. In
1995 Ropke et al used limiting dilution analysis to demonstrate the existence of MHC
class I restricted CD8 cells in the peripheral blood of healthy volunteers, which recognize
p53 peptides. These cells were found at a frequency of 1in 2 × 104 to 1.5 × 105 cells.
(22). In a more recent paper, p53-specific CD8 responses where seen only from
lymphocytes of patients bearing p53-overexpressing tumors (23). Why would healthy
individuals have T cells specific for a self peptide? A possible answer is that immune
response does not only recognize self vs non-self but also higher levels of self proteins.
In the case of p53, immunity can be increased by vaccination. DNA vaccines comprising
of the p53 gene under control of a strong promoter can elicit immunity to mutant p53
peptides in a murine model. The relevance of this experiment is seen by the observation
that immunized mice have protective antitumor immunity. Furthermore, immunogenicity
can be enhance by fusing a portion of the p53 gene with an endoplasmic reticulum
targeting sequence (24).
Immune Response to Telomerase
Telomerase is a ribonucleoprotein with enzymatic activity that is expressed in over 90%
of cancers and on very few non-cancerous cells. Targeting of telomerase has been
attempted by at the gene level by antisense oligonucleotides (25), as well as at the protein
level by pharmacological inhibitors (26). Unfortunately, both of these strategies are in
preclinical phases of development and potential problems of delivery and toxicity exist.
A more attractive idea would be to stimulate immune response against telomerase. The
first problem is that telomerase is expressed embryonically, and therefore a possibility
exists that it is hard, if not impossible to break tolerance against it. Fortunately, it is possible. By transfecting dendritic cells with mRNA encoding the polypeptide portion of
telomerase called TERT, and then immunizing mice with these dendritic cells,
investigators were able to induce CD8 cytotoxic T cells which recognized and lysed a
variety of different tumors. Human DC transfected with TERT were able to stimulate
human CD8 cells to lyse tumor cell lines in vitro (27). Vonderheide et al recently
demonstrated that it is equally feasible to raise TERT-specific CD8 cells from cancer
patients and healthy controls by ex vivo stimulation with TERT peptides. These cells are
able to lyse cell lines and primary tumor samples in an HLA-A2 restricted manner (28).
Ras is a molecular switch involved in proliferation and activation of a variety of cells.
Activated Ras signalling occurs when Ras is bound to GTP. GTPase activating proteins
(GAP) are responsible for changing Ras from its activated GTP bound form to its inactive
GDP bound form. Many types of cancers are associated with a mutant Ras that is
constitutively active. Several approaches have been used to target mutated Ras proteins
including antisense (29-31) and viruses which selectively kill cells expressing activated
Ras (32). Serum antibodies have been detected in women with precervical cancer lesions
but not in healthy women. Interestingly, the antibodies were directed against wild-type
Ras (33). A common activating Ras mutation in colon cancer is the substitution of
aspartic acid at amino acid position 12. Out of 160 patients with colon cancer 51
possessed antibodies to this form of Ras whereas only 1 out of 40 healthy controls had
this type of antibody. The isotype of the antibody was IgA which is a noncomplement
fixing type of antibody (34).
MHC class II restricted T cells have been found in peripheral blood of healthy individuals
which specifically recognize Ras with a substitution for aspartic acid on residue 12 (35).
These T cells are CD4 positive and do not possess cytotoxic activity. Therefore it would
be more desirable to determine whether CD8 cells can be raised to mutant Ras. By
immunizing patients with mutant Ras peptides followed by in vitro restimulation, it was
possible to raise both CD4 and CD8 cell lines which had specificity for mutant but not
wild-type Ras (36). In a feasibility study immunization with mutant Ras peptides
together with the dendritic cell stimulating cytokine GM-CSF, it was possible to induce
CD8 response to mutant Ras as demonstrated by positive skin reaction (37).
Terry Boon and colleagues screened tumor cDNA libraries using T cell clones from
tumor patients. This lead to the identification of MAGE, a protein expressed in
melanoma cells and some other types of cancer but not expressed in normal tissue with
the exception of the testis and the placenta (38). Subsequently, other tumor specific
genes of the MAGE family (more recently called cancer-testis antigens) were identified
such as BAGE (39) and GAGE (40). About 50% of melanoma patients express one or
more of these genes. Expression of MAGE is suppressed by DNA methylation in adult
tissues. Treatment of noncancerous cells such as primary fibroblasts with the DNA
methylation inhibitor 5-aza-2’-deoxycytidine induces re-expression of MAGE (41).
MUC-1, an antigen associated with epithelial cancers is also re-expressed due to
hypomethylation of the gene only in the cancerous state (41a). While de-methylation is
used by cancer cells to turn on MAGE expression, cancer cells also specifically methylate
portions of the gene for MHC class I (42) in order to decrease immune recognition of
potentially immunogenic antigens. In a personal communication, although I forgot the
source, it was stated that the suppressed levels of TAP in cancer cell lines is due to DNA
Peptides derived from the MAGE protein have been demonstrated to induce specific
immune response in the clinical setting, occasionally with therapeutic benefit. Out of 25
HLA-A1 positive metastatic melanoma patients vaccinated with MAGE-3 peptides, 7 had
significant tumor regressions with two patients remaining free of disease for more than
three years (43,44). Partial regression of metastasis in melanoma was also achieved by
treatment of patients with dendritic cells pulsed with MAGE peptides (45,46). In vivo
expansion of MAGE-specific CTLs in response to vaccination has been demonstrated in
a clinical setting using tetramer technology (47). Antibody responses have been detected
to MAGE and other members of the cancer-testis antigen family in patients with
oesophageal, gastric and breast carcinomas (48).
There are many, many other antigens that are found on tumors. The purpose of this book
is to throw ideas around, therefore I did not bother to go through all of the tumor specific
antigens. There are also antigens which are not tumor specific but tumor associated. One
example is tyrosinase, an enzyme which is involved in melanin production by normal
melanocytes. This enzyme is also expressed in melanoma cells and therefore contributes
to their immunogenicity (49). The fact that immune responses can be induced to
tyrosinase support the idea previously stated that the immune response may not only
discriminate between self and non-self but also between levels of self protein, or even
perhaps the context in which self protein is seen by the immune response. Other tumor
associated antigens include prostate specific antigen (PSA) and prostatic acid
phosphatase (PAP). Immune response to both of these proteins by vaccination has been
elicited, and in the case of PAP demonstrated some clinical efficacy (50-52).
Glycolipids on the surface of cancer cells such as the gangliosides GM2 and GD3 seem
to be specific to cancer cells. Complement-fixing antibodies to both of these gangliosides
have been elicited in human cancer patients although therapeutic effects are still
Peptides from the protein product of the chronic myeloid leukaemia-specific oncogene,
bcr-abl, have been demonstrated immunogenic (55-58). In this type of leukaemia,
treatment of post-bone marrow transplant relapsed patients with donor-specific
leukocytes is effective in inducing long-term remission (59). The possibility of immune
response against bcr-abl derived peptides mediating these remissions should be
investigated. If it is possible to induce therapeutic immune response to bcr-abl derived
peptides, this would be an ideal target since leukemic cells in which expression of this
gene is blocked by antisense oligonucleotides undergo apoptosis (60). The key role of
bcr-abl in leukaemia is further demonstrated by observations that transfection of normal
human CD34 stem cells with this oncogene induces leukaemia-like properties in these
So what does this tell us?
First, there is such a thing as cancer-specific proteins. Sure, some may say that immune
response does not control cancer because if there indeed is recognition of all these
cancer-specific antigens, then why does cancer arise. To this I dare the detractor to ask a
transplant surgeon what the rate of tumors is in immune suppressed patients. The rate of
tumors in these patients are much higher compared to the normal population. And the
tumor types are diverse and not restricted only to hematological one.
Second, immune response to these proteins can be induced.
Third, in subsets of individuals immune response correlates with prognosis. In the case
of some patients with antibodies to p53, immune response can correlate with poor
prognosis, whereas in patients vaccinated with peptides of MAGE, immune response can
lead to regression. Several questions need to be answered:
1. Why is it that immune response allows for cancers to begin in the first place?
2. What are the mechanisms by which tumor cells evade immune responses?
3. Are there better methods of immunization for increased clinical efficacy?
4. Is the systemic immune response of the cancer patient too weak to destroy the
offending antigen, even if recognition occurs?
5. What combinations of treatments can be used for maximal therapeutic gain?
Actually, there are probably a lot more questions, but throughout this book I hope to
answer some of them.
1. Lane DP. Cancer. p53, guardian of the genome.
Nature. 1992 Jul 2;358(6381):15-6.
2. Jackson AL, Loeb LA. The contribution of endogenous sources of DNA damage to
the multiple mutations in cancer. Mutat Res. 2001 Jun 2;477(1-2):7-21.
3. Kim SJ, Im YH, Markowitz SD, Bang YJ. Molecular mechanisms of inactivation of
TGF-beta receptors during carcinogenesis. Cytokine Growth Factor Rev. 2000 Mar-Jun;11(1-2):159-68.
4. Muro-Cacho CA, Rosario-Ortiz K, Livingston S, Munoz-Antonia T. Defective
transforming growth factor beta signaling pathway in head and neck squamous cell
carcinoma as evidenced by the lack of expression of activated Smad2.
Clin Cancer Res. 2001 Jun;7(6):1618-26.
5. Boldrini L, Faviana P, Pistolesi F, Gisfredi S, Di Quirico D, Lucchi M, Mussi A,
Angeletti CA, Baldinotti F, Fogli A, Simi P, Basolo F, Fontanini G. Alterations of Fas
(APO-1/CD 95) gene and its relationship with p53 in non small cell lung cancer.
Oncogene. 2001 Oct 4;20(45):6632-7.
6. Mullauer L, Gruber P, Sebinger D, Buch J, Wohlfart S, Chott A. Mutations in
apoptosis genes: a pathogenetic factor for human disease.
Mutat Res. 2001 Jul;488(3):211-31.
7. Kim K, Fisher MJ, Xu SQ, el-Deiry WS. Molecular determinants of response to
TRAIL in killing of normal and cancer cells.
Clin Cancer Res. 2000 Feb;6(2):335-46.
8. Blume-Jensen P, Hunter T. Oncogenic kinase signalling.
Nature. 2001 May 17;411(6835):355-65.
9. Adjei AA. Blocking oncogenic Ras signaling for cancer therapy.
J Natl Cancer Inst. 2001 Jul 18;93(14):1062-74.
10. Menard S, Tagliabue E, Campiglio M, Pupa SM. Role of HER2 gene overexpression
in breast carcinoma. J Cell Physiol. 2000 Feb;182(2):150-62.
11. Chan R, Muller WJ, Siegel PM. Oncogenic activating mutations in the neu/erbB-2
oncogene are involved in the induction of mammary tumors.
Ann N Y Acad Sci. 1999;889:45-51.
11a. Buys CH. Telomeres, telomerase, and cancer.
N Engl J Med. 2000 Apr 27;342(17):1282-3.
12. Pardoll DM. Immunology: stress, nk receptors, and immune surveillance.
Science. 2001 Oct 19;294(5542):534-6.
13. Diefenbach A, Jensen ER, Jamieson AM, Raulet DH. Rae1 and H60 ligands of the
NKG2D receptor stimulate tumour immunity.
Nature. 2001 Sep 13;413(6852):165-71.
14. Cerwenka A, Baron JL, Lanier LL. Ectopic expression of retinoic acid early
inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class Ibearing tumor in vivo. Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11521-6.
15. Forslund A, Kressner U, Lindmark G, Inganas M, Lundholm K. Serum anti-p53 in
relation to mutations across the entire translated p53 gene in colorectal carcinomas.
Int J Oncol. 2001 Sep;19(3):501-6.
16. Ralhan R, Arora S, Chattopadhyay TK, Shukla NK, Mathur M. Circulating p53
antibodies, p53 gene mutational profile and product accumulation in esophageal
squamous-cell carcinoma in India. Int J Cancer. 2000 Mar 15;85(6):791-5.
17. Angelopoulou K, Yu H, Bharaj B, Giai M, Diamandis EP. p53 gene mutation, tumor
p53 protein overexpression, and serum p53 autoantibody generation in patients with
breast cancer. Clin Biochem. 2000 Feb;33(1):53-62.
18. Abendstein B, Marth C, Muller-Holzner E, Widschwendter M, Daxenbichler G,
Zeimet AG. Clinical significance of serum and ascitic p53 autoantibodies in epithelial
ovarian carcinoma. Cancer. 2000 Mar 15;88(6):1432-7.
19. Soussi T. p53 Antibodies in the sera of patients with various types of cancer: a
review. Cancer Res. 2000 Apr 1;60(7):1777-88.
20. Berger S, Chandra R, Ballo H, Hildenbrand R, Stutte HJ Immune complexes are
potent inhibitors of interleukin-12 secretion by human monocytes. Eur J Immunol. 1997
21. Berger S, Ballo H, Stutte HJ. Distinct antigen-induced cytokine pattern upon
stimulation with antibody-complexed antigen consistent with a Th1-->Th2-shift.
Res Virol. 1996 Mar-Jun;147(2-3):103-8.
22. Ropke M, Regner M, Claesson MH. T cell-mediated cytotoxicity against p53-
protein derived peptides in bulk and limiting dilution cultures of healthy donors.
Scand J Immunol. 1995 Jul;42(1):98-103.
23. Ferries E, Connan F, Pages F, Gaston J, Hagnere AM, Vieillefond A, Thiounn N,
Guillet J, Choppin J. Identification of p53 peptides recognized by CD8 T
lymphocytes from patients with bladder cancer. Hum Immunol. 2001 Aug;62(8):791-8.
24. Ciernik IF, Berzofsky JA, Carbone DP. Induction of cytotoxic T lymphocytes and
antitumor immunity with DNA vaccines expressing single T cell epitopes.
J Immunol. 1996 Apr 1;156(7):2369-75.
25. Schindler A, Fiedler U, Meye A, Schmidt U, Fussel S, Pilarsky C, Herrmann J, Wirth
MP. Human telomerase reverse transcriptase antisense treatment downregulates the
viability of prostate cancer cells in vitro. Int J Oncol. 2001 Jul;19(1):25-30.
26. Hayakawa N, Nozawa K, Ogawa A, Kato N, Yoshida K, Akamatsu Ki, Tsuchiya M,
Nagasaka A, Yoshida S. Isothiazolone derivatives selectively inhibit telomerase from
human and rat cancer cells in vitro. Biochemistry. 1999 Aug 31;38(35):11501-7.
27. Nair SK, Heiser A, Boczkowski D, Majumdar A, Naoe M, Lebkowski JS, Vieweg J,
Gilboa E. Induction of cytotoxic T cell responses and tumor immunity against unrelated
tumors using telomerase reverse transcriptase RNA transfected dendritic cells.
Nat Med. 2000 Sep;6(9):1011-7.
28. Vonderheide RH, Schultze JL, Anderson KS, Maecker B, Butler MO, Xia Z, Kuroda
MJ, von Bergwelt-Baildon MS, Bedor MM, Hoar KM, Schnipper DR, Brooks MW,
Letvin NL, Stephans KF, Wucherpfennig KW, Hahn WC, Nadler LM. Equivalent
Induction of Telomerase-specific Cytotoxic T Lymphocytes from Tumor-bearing Patients
and Healthy Individuals. Cancer Res. 2001 Dec 1;61(23):8366-70.
29. Cunningham CC, Holmlund JT, Geary RS, Kwoh TJ, Dorr A, Johnston JF, Monia B,
Nemunaitis J. A Phase I trial of H-ras antisense oligonucleotide ISIS 2503 administered
as a continuous intravenous infusion in patients with advanced carcinoma.
Cancer. 2001 Sep 1;92(5):1265-71.
30. Adjei AA. Blocking oncogenic Ras signaling for cancer therapy.
J Natl Cancer Inst. 2001 Jul 18;93(14):1062-74.
31. Wickstrom E. Oligonucleotide treatment of ras-induced tumors in nude mice.
Mol Biotechnol. 2001 May;18(1):35-55.
32. Coffey MC, Strong JE, Forsyth PA, Lee PW. Reovirus therapy of tumors with
activated Ras pathway. Science. 1998 Nov 13;282(5392):1332-4.
33. Pedroza-Saavedra A, Cruz A, Esquivel F, De La Torre F, Berumen J, Gariglio P,
Gutierrez L. High prevalence of serum antibodies to Ras and type 16 E4 proteins of
human papillomavirus in patients with precancerous lesions of the uterine cervix.
Arch Virol. 2000;145(3):603-23.
34. Takahashi M, Chen W, Byrd DR, Disis ML, Huseby ES, Qin H, McCahill L, Nelson
H, Shimada H, Okuno K, et al. Antibody to ras proteins in patients with colon cancer.
Clin Cancer Res. 1995 Oct;1(10):1071-7.
35. Gedde-Dahl T 3rd, Eriksen JA, Thorsby E, Gaudernack G. T-cell responses against
products of oncogenes: generation and characterization of human T-cell clones specific
for p21 ras-derived synthetic peptides. Hum Immunol. 1992 Apr;33(4):266-74.
36. Abrams SI, Khleif SN, Bergmann-Leitner ES, Kantor JA, Chung Y, Hamilton JM,
Schlom J. Generation of stable CD4+ and CD8+ T cell lines from patients immunized
with ras oncogene-derived peptides reflecting codon 12 mutations.
Cell Immunol. 1997 Dec 15;182(2):137-51.
37. Hunger RE, Brand CU, Streit M, Eriksen JA, Gjertsen MK, Saeterdal I, Braathen
LR, Gaudernack G. Successful induction of immune responses against mutant ras in
melanoma patients using intradermal injection of peptides and GM-CSF as adjuvant.
Exp Dermatol. 2001 Jun;10(3):161-7.
38. van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde
B, Knuth A, Boon T. A gene encoding an antigen recognized by cytolytic T lymphocytes
on a human melanoma.
Science. 1991 Dec 13;254(5038):1643-7.
39. Boel P, Wildmann C, Sensi ML, Brasseur R, Renauld JC, Coulie P, Boon T, van der
Bruggen P. BAGE: a new gene encoding an antigen recognized on human melanomas by
cytolytic T lymphocytes.
Immunity. 1995 Feb;2(2):167-75.
40. Van den Eynde B, Peeters O, De Backer O, Gaugler B, Lucas S, Boon T. A new
family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes
on a human melanoma. J Exp Med. 1995 Sep 1;182(3):689-98.
41. De Smet C, De Backer O, Faraoni I, Lurquin C, Brasseur F, Boon T. The activation
of human gene MAGE-1 in tumor cells is correlated with genome-wide demethylation.
Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7149-53.
41a. Zrihan-Licht S, Weiss M, Keydar I, Wreschner DH. DNA methylation status of the
MUC1 gene coding for a breast-cancer-associated protein. Int J Cancer. 1995 Jul 28;62(3):245-
42. Serrano A, Tanzarella S, Lionello I, Mendez R, Traversari C, Ruiz-Cabello F,
Garrido F. Rexpression of HLA class I antigens and restoration of antigen-specific CTL
response in melanoma cells following 5-aza-2’-deoxycytidine treatment.
Int J Cancer. 2001 Oct 15;94(2):243-51.
43. Marchand, M., Weynants, P., Rankin, E., Arienti, F., Belli, F., Parmiani, G.,
Cascinelli, N., Bourlond, A., Vanwijck, R., & Humblet, Y. (1995). Int. J. Cancer 63,
44. Marchand, M., van Baren, N., Weynants, P., Brichard, V., Dréno, B., Tessier, M.-H.,
Rankin, E., Parmiani, G., Arienti, F., & Humblet, Y. (1999). Int. J. Cancer 80, 219 230.
45. Nestle, F. O., Alijagic, S., Gilliet, M., Sun, Y., Grabbe, S., Dummer, R., Burg, G., &
Schadendorf, D. (1998). Nat. Med. 4, 328 332.
46. Thurner, B., Haendle, I., Roder, C., Dieckmann, D., Keikavoussi, P., Jonuleit, H.,
Bender, A., Maczek, C., Schreiner, D., & von den Driesch, P. (1999). J. Exp. Med. 190,
47. Coulie PG, Karanikas V, Colau D, Lurquin C, Landry C, Marchand M, Dorval T,
Brichard V, Boon T. A monoclonal cytolytic T-lymphocyte response observed in a
melanoma patient vaccinated with a tumor-specific antigenic peptide encoded by gene
MAGE-3. Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10290-5.
48. Mashino K, Sadanaga N, Tanaka F, Yamaguchi H, Nagashima H, Inoue H,
Sugimachi K, Mori M. Expression of multiple cancer-testis antigen genes in
gastrointestinal and breast carcinomas. Br J Cancer. 2001 Sep 1;85(5):713-20.
49. Fishman P, Merimski O, Baharav E, Shoenfeld Y. Autoantibodies to tyrosinase: the
bridge between melanoma and vitiligo. Cancer. 1997 Apr 15;79(8):1461-4.
50. Meidenbauer N, Harris DT, Spitler LE, Whiteside TL. Generation of PSA-reactive
effector cells after vaccination with a PSA-based vaccine in patients with prostate cancer.
Prostate. 2000 May 1;43(2):88-100.
51. Small EJ, Fratesi P, Reese DM, Strang G, Laus R, Peshwa MV, Valone FH.
Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic
cells. J Clin Oncol. 2000 Dec 1;18(23):3894-903.
52. Tjoa BA, Simmons SJ, Elgamal A, Rogers M, Ragde H, Kenny GM, Troychak MJ,
Boynton AL, Murphy GP. Follow-up evaluation of a phase II prostate cancer vaccine
trial. Prostate. 1999 Jul 1;40(2):125-9.
53. Chapman PB, Morrissey DM, Panageas KS, Hamilton WB, Zhan C, Destro AN,
Williams L, Israel RJ, Livingston PO. Induction of antibodies against GM2 ganglioside
by immunizing melanoma patients using GM2-keyhole limpet hemocyanin + QS21
vaccine: a dose-response study. Clin Cancer Res. 2000 Mar;6(3):874-9.
54. Kim SK, Ragupathi G, Cappello S, Kagan E, Livingston PO. Effect of
immunological adjuvant combinations on the antibody and T-cell response to vaccination
with MUC1-KLH and GD3-KLH conjugates. Vaccine. 2000 Oct 15;19(4-5):530-7.
55. ten Bosch GJ, Toornvliet AC, Friede T, Melief CJ, Leeksma OC. Recognition of
peptides corresponding to the joining region of p210BCR-ABL protein by human T cells.
Leukemia. 1995 Aug;9(8):1344-8.
56. Bocchia M, Korontsvit T, Xu Q, Mackinnon S, Yang SY, Sette A, Scheinberg DA.
Specific human cellular immunity to bcr-abl oncogene-derived peptides. Blood. 1996 May
57. Pinilla-Ibarz J, Cathcart K, Korontsvit T, Soignet S, Bocchia M, Caggiano J, Lai L,
Jimenez J, Kolitz J, Scheinberg DA. Vaccination of patients with chronic myelogenous
leukemia with bcr-abl oncogene breakpoint fusion peptides generates specific immune
responses. Blood. 2000 Mar 1;95(5):1781-7.
58. Chen W, Peace DJ, Rovira DK, You SG, Cheever MA. T-cell immunity to the
joining region of p210BCR-ABL protein. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1468-72.
59. Dazzi F, Szydlo RM, Goldman JM. Donor lymphocyte infusions for relapse of
chronic myeloid leukemia after allogeneic stem cell transplant: where we now stand.
Exp Hematol. 1999 Oct;27(10):1477-86.
60. Maekawa T, Kimura S, Hirakawa K, Murakami A, Zon G, Abe T. Sequence
specificity on the growth suppression and induction of apoptosis of chronic myeloid
leukemia cells by BCR-ABL anti-sense oligodeoxynucleoside phosphorothioates.
Int J Cancer. 1995 Jul 4;62(1):63-9.
61. Zhao RC, Jiang Y, Verfaillie CM. A model of human p210(bcr/ABL)-mediated
chronic myelogenous leukemia by transduction of primary normal human CD34 cells
with a BCR/ABL-containing retroviral vector. Blood. 2001 Apr 15;97(8):2406-12.