Harnessing naturally occurring tumor immunity: a clinical vaccine trial in prostate cancer.
BACKGROUND
Studies of patients with paraneoplastic neurologic disorders (PND) have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC) vaccine.


RESULTS
We have modeled PND tumor immunity in a clinical trial in which apoptotic allogeneic prostate tumor cells were used to generate an apoptotic tumor-autologous dendritic cell vaccine. Twenty-four prostate cancer patients were immunized in a Phase I, randomized, single-blind, placebo-controlled study to assess the safety and immunogenicity of this vaccine. Vaccinations were safe and well tolerated. Importantly, we also found that the vaccine was immunogenic, inducing delayed type hypersensitivity (DTH) responses and CD4+ and CD8+ T cell proliferation, with no effect on FoxP3+ regulatory T cells. A statistically significant increase in T cell proliferation responses to prostate tumor cells in vitro (p = 0.002), decrease in prostate specific antigen (PSA) slope (p = 0.016), and a two-fold increase in PSA doubling time (p = 0.003) were identified when we compared data before and after vaccination.


CONCLUSIONS
An apoptotic cancer cell vaccine modeled on naturally occurring tumor immune responses in PND patients provides a safe and immunogenic tumor vaccine.


BACKGROUND
ClinicalTrials.gov NCT00289341.
Frank
Mayu O
MO
Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, New York, United States of America.
Kaufman
Julia
J
Tian
Suyan
S
Suárez-Fariñas
Mayte
M
Parveen
Salina
S
Blachère
Nathalie E
NE
Morris
Michael J
MJ
Slovin
Susan
S
Scher
Howard I
HI
Albert
Matthew L
ML
Darnell
Robert B
RB
D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D064987:Cell- and Tissue-Based Therapy; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000276:immunology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D014611:Vaccination
D019496:Cancer Vaccines; D017430:Prostate-Specific Antigen
J Immunother. 2006 Sep-Oct;29(5):545-57
16971810
Gynecol Oncol. 2005 Nov;99(2):462-71
16137749
Cancer Res. 2001 Dec 1;61(23):8513-9
11731436
Prostate Cancer Prostatic Dis. 2004;7(1):63-72
14999241
Cancer Res. 2008 Jul 15;68(14):5955-64
18632651
J Exp Med. 1998 Oct 5;188(7):1359-68
9763615
Cancer Res. 2009 Jan 15;69(2):609-15
19147575
Curr Opin Immunol. 2006 Apr;18(2):206-13
16464564
J Exp Med. 1994 Apr 1;179(4):1109-18
8145033
J Exp Med. 1998 Dec 7;188(11):2163-73
9841929
Nat Med. 1998 Nov;4(11):1321-4
9809559
Curr Opin Immunol. 2007 Apr;19(2):203-8
17292599
Proc Natl Acad Sci U S A. 1996 May 14;93(10):4529-36
8643438
Cancer Res. 2004 Jul 15;64(14):4973-9
15256471
Hematol Oncol Clin North Am. 2006 Jun;20(3):689-710
16762730
J Exp Med. 1997 Nov 3;186(9):1603-8
9348319
PLoS Biol. 2005 Jun;3(6):e185
15839733
Nature. 1998 Mar 19;392(6673):245-52
9521319
J Clin Immunol. 2005 May;25(3):288-95
15981095
Nat Immunol. 2001 Nov;2(11):1010-7
11590405
Immunol Rev. 2007 Dec;220:129-50
17979844
Adv Exp Med Biol. 2008;622:221-33
18546631
Nat Immunol. 2003 Mar;4(3):201
12605223
Cancer Res. 1999 Oct 15;59(20):5160-8
10537292
Ann Neurol. 2000 Jan;47(1):9-17
10632096
Cancer Res. 2001 Sep 1;61(17):6451-8
11522640
Br J Cancer. 2004 Nov 1;91(9):1656-62
15477864
Clin Cancer Res. 2005 Jun 1;11(11):4160-7
15930352
Nature. 1998 Mar 5;392(6671):86-9
9510252
Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5271-9
17875755
Nat Biotechnol. 1998 Nov;16(11):1025-31
9831030
J Exp Med. 1994 Apr 1;179(4):1317-30
7511686
Nat Rev Immunol. 2004 Mar;4(3):223-31
15039759
Breast Cancer Res. 2004;6(4):R322-8
15217499
J Immunol. 2001 Mar 15;166(6):4254-9
11238679
J Immunol. 2001 May 15;166(10):6099-103
11342628
Annu Rev Immunol. 2004;22:329-60
15032581
N Engl J Med. 2003 Oct 16;349(16):1543-54
14561798
J Clin Immunol. 2004 Nov;24(6):653-63
15622450
Hum Gene Ther. 2001 Mar 20;12(5):575-95
11268289