Abstract
We translated two cancer vaccine strategies from mice into human clinical trials. (1) In preclinical studies on TARP, an antigen expressed in most prostate cancers, we mapped epitopes presented by HLA-A*0201, modified them to increase affinity and immunogenicity in HLA transgenic mice, and induced human T cells that killed human cancer cells (“epitope enhancement”). In a clinical trial, HLA-A2+ prostate cancer patients with PSA biochemical recurrence (Stage D0) were vaccinated with two peptides either in Montanide-ISA51 or on autologous dendritic cells (DCs). In stage D0, the Prostate-Specific Antigen (PSA) slope is prognostic of time to radiographic evidence of metastases and death. With no difference between arms, 74% of combined subjects had a decreased PSA slope at 1 year compared to their own baseline slopes (p = 0.0004). For patients vaccinated with DCs, response inversely correlated with a tolerogenic DC signature. A randomized placebo-controlled phase II trial is underway. (2) HER2 is a driver surface oncogene product expressed in multiple tumors. We made an adenoviral vector vaccine expressing the extracellular and transmembrane domains of HER2 and cured mice with large established HER2+ tumors, dependent on antibodies to HER2, not T cells. The mechanism differed from that of trastuzumab. We tested a human version in advanced metastatic cancer patients naïve to HER2-directed therapies. At the second and third dose levels, 45% of evaluable patients showed clinical benefit. Circulating tumor cells also declined in some vaccinated patients. Thus, cancer vaccines developed in mice were successfully translated to humans with promising early results.
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Cancer vaccines may target either the antibody (humoral) or T cell arm of the immune system (Fig. 1). Antibodies can detect only antigens on the surface of intact tumor cells, whereas T cells can detect any protein antigen made in the cell because the major histocompatibility complex (MHC) molecules (such as HLA in humans) act as an internal surveillance mechanism or spy within the cell to detect fragments of all proteins made in the cell and carry them to the surface where they can be seen by T cell receptors (TCRs) [1, 2]. Thus, most cancer vaccines attempt to induce cytotoxic T cells that can kill tumor cells. Here, we will give examples of both types of cancer vaccines that we have developed based on mouse model preclinical studies and translated to human clinical trials with promising early results. With the increased focus on immunotherapy due to the success of checkpoint inhibitors and adoptive T cell therapy [3,4,5,6, 7, 8], as well as with the licensing of the first human therapeutic cancer vaccine, Sipuleucel-T [9, 10], there is a revived interest in cancer vaccines [11,12,13,14,15], especially to induce immune responses in otherwise less-immunogenic tumors. Such cancer vaccines may also be aided by combinations with checkpoint inhibitors, or inhibitors of other negative regulatory cells and molecules, to allow the resulting T cells to have their maximum effect [14,15,16,17,18,19,20,21,22,23].
Because cancers that are detected clinically have already evaded potential immunosurveillance, their antigens may not be optimal immunogens. We developed an approach we call epitope enhancement to modify amino acid sequences of epitopes to make them more immunogenic [24,25,26,27,28,29,30] (Fig. 2). This involves identifying amino acid residues critical for binding of the peptide to the MHC molecule without affecting TCR recognition, using a combination of predictions of primary and secondary anchor residues [31,32,33,34,35] and of empirical assays, as well as residues that interfere with binding, and then making substitutions to increase affinity of the peptide for the MHC molecule. Then, the modified sequences have to be tested for binding affinity, immunogenicity in HLA-transgenic mice, and most importantly, for the ability to induce T cells that recognize not only the enhanced sequence but also the wild-type natural sequence since that is the sequence in the virus or tumor cell. We applied this to both viral and tumor antigens. For the current study, we first mapped epitopes binding to HLA-A*0201, the most common human class I MHC molecule, in the sequence of TARP (T cell receptor gamma chain alternative reading frame protein) originally discovered by Ira Pastan’s lab [36]. This protein is encoded by a different reading frame from the TCR gamma chain so the amino acid sequence is unrelated to T cell proteins. TARP was found to be expressed in about 95% of prostate cancers and about half of breast cancers, and at all stages and Gleason types of prostate cancer. We then modified the sequences to increase affinity for HLA-A*0201 and tested these in a binding assay and for immunogenicity in HLA-A2 transgenic mice [37]. One TARP epitope, 27–35, was already high affinity and none of the modifications increased that affinity. However, TARP 29–37, an overlapping but independent epitope, bound only moderately well to HLA-A*0201 but could be improved by replacing the C-terminal residue with valine to make 29-37-9V. That enhanced peptide induced T cells reactive with the wild-type TARP sequence, whereas some others, such as TARP-29-37-3A, did not [37]. Finally, these were tested for induction of human T cells in vitro and found to induce human T cells that could kill human cancer cells (MCF-7) expressing both TARP and HLA-A*0201, and not ones with either alone [37].
Based on these results, we initiated a phase I clinical trial (NCT00972309) to test safety and immunogenicity of these two peptides in HLA-A*0201+ prostate cancer patients. We divided the subjects into two arms, one receiving the peptides emulsified together with GM-CSF in Montanide-ISA51 given subcutaneously, and one receiving the same peptides pulsed together with keyhole limpet hemocyanin (KLH) as a source of help onto autologous dendritic cells (DCs), given intradermally [38]. Autologous DCs were prepared monocytes from an apheresis pack cultured for 4 days with GM-CSF and IL-4 and then matured with interferon-gamma and lipopolysaccharide. We elected to treat stage D0 prostate cancer, the stage in which primary tumor had been definitively eradicated with surgery or radiation, but now a rising PSA in the absence of radiographically evident metastases is a biochemical indication of micro-metastatic tumor recurrence. This has the advantage that the tumor burden is small, such as in an adjuvant setting, but there is a parameter (PSA) one can measure to monitor effects on tumor growth without waiting for tumor to be detectable radiographically. In this setting, it has been shown that the rate of rise (slope or doubling time) of the PSA is a valid predictor of clinical outcome measured as time to radiographic progression or to death and response to therapy [39,40,41,42,43,44]. The practical problem with the widely used doubling time is that if the rate of PSA rise goes to 0, a desirable outcome, the doubling time becomes infinite, not a useful number for statistics, and if the PSA starts actually decreasing, an even better outcome, the doubling time becomes negative, not a meaningful number (Fig. 3). On the other hand, the slope, proportional to the reciprocal of the doubling time, is a continuous variable, whether positive, 0, or negative. Thus, we used the slope (log (PSA)) as our measure, compared to the patient’s own pretreatment slope measured at ≥ 4 time points over > 3 months during the 12 months prior to vaccination. Patients were immunized five times at 3-week intervals from week 3-week 15, and PSA values followed for at least 1 year. Slope (log(PSA)) was determined at each time point from week 3 to that time point, and compared with that person’s pre-treatment slope to determine the change in slope. Because the two arms were not statistically different, we were advised to combine them to increase statistical power. Of 40 patients treated on both arms, 71.8% had a decreased slope (log(PSA)) at 24 weeks (p = 0.0012) and 74.2% had a decreased slope at 48 weeks (p = 0.0004) [38]. 15% of the patients actually developed a negative slope, that is a decreasing PSA. This decreased tumor growth rate was corroborated by an independent analysis of tumor growth rate constant obtained by fitting the PSA values to an exponential growth curve [45], which found that the tumor growth rate constant fell in half (p = 0.003). Thus, the vaccine appeared to slow tumor growth in nearly ¾ of patients [38].
When T cell responses were measured as interferon-gamma ELISPOT responses to the two vaccine peptides and the wild-type version of 29–37, 77.5% of patients made a new response not present at baseline (considered positive if ≥ 3-fold over background at at least two time points and statistically significant), but the magnitude of response did not correlate with clinical response [38]. Thus, the vaccine was safe and immunogenic, and showed preliminary evidence of clinical benefit, but we did not have an immune correlate of clinical activity. We hypothesized that differences in T cell function or avidity might correlate better, but a mechanistic correlate has not yet been identified. We had found earlier that human T cells raised against the TARP peptides could kill human tumor cells expressing TARP and HLA-A*0201, indicating that the epitopes were endogenously processed and presented in the tumor cells [37], but T cells from TARP-immunized patients in this study have not yet been tested for lytic activity. Nevertheless, based on the phase I results, a randomized placebo-controlled phase II trial (NCT02362451) has been opened. This trial extends the vaccine peptides to cover all of the TARP sequence (so called multi-epitope TARP), in addition to the original 2 peptides, to avoid limitations to HLA-A*0201. The phase II trial is being conducted with autologous DCs because this arm showed a more significant change in slope on its own that the Montanide arm in the phase I study and because making seven emulsions would have been impractical.
However, another parameter was discovered that might help explain which patients responded, at least in the arm that received autologous monocyte-derived DCs [46]. It was found that a combination of genes that correlated with a tolerogenic DC phenotype was inversely associated with a greater decrease in PSA slope and with poor immunological response [46]. By ROC curves, this gave 85% power to discriminate among PSA responders vs non-responders, and 98% power to discriminate among immunological responders and non-responders. Moreover, a simplified combination of four parameters, increased CD14 levels, increased IL-10 and CCL2 secretion, and decreased CCL22 secretion, correlated with similar predictive power [46]. This ability of the DC properties to predict DC vaccine effectiveness has important implications for optimizing DC-based vaccines.
We now turn to a vaccine that functions through an antibody response. In this case, it is fortunate that the driver oncogene product, HER2, is expressed on the surface of cancer cells where antibodies can detect it on intact cells [47]. One can think of it as a receptor that is constitutively driving the cells to proliferate. We know that antibodies to HER2 can be effective at least in some breast tumors because trastuzumab and other anti-HER2 antibodies are approved for this use. However, no vaccine has been developed to induce a patient to make her/his own antibodies to HER2 that are effective. However, there are peptide-based and other vaccines under study to induce T cell responses to HER2 [48, 49]. For mouse preclinical studies, we made an adenovirus vector expressing the extracellular (EC) and transmembrane (TM) domains of rodent HER2 [50], and immunized HER2-transgenic mice [50, 51] and mice bearing large established TUBO tumors [52]. The TUBO tumors derive from a BALB/c mouse transgenic for the rodent HER2 oncogene, and express high levels of HER2. We were gratified to see that even tumors 2 cm in diameter regressed completely within about 3 weeks after one dose of the vaccine [52]. Large established lung metastases also completely regressed. Thus, this vaccine fulfilled the key requirement that it could treat large established tumors, not just prevent ones injected after the vaccination. We had intended to make a vaccine to induce a T cell response, but it turned out to our surprise that the mechanism was completely dependent on antibodies. CD8 T cells were not necessary, as they could be depleted prior to vaccination, and as beta-2 microglobulin knockout mice (without MHC class I molecules), which lack CD8 T cells, were protected as well as wild-type mice. CD4 T cells could be depleted after the first 2 days, when they were needed to provide help for an antibody response, without affecting tumor rejection, so effector CD4 T cells were also not required. However, the vaccine did not work in JH knockout B-cell deficient mice. In addition, serum from immunized mice could transfer the protection [52]. Thus, the protection was purely antibody-mediated. However, unlike trastuzumab, which was shown to require Fc receptors [53], the protection was just as effective in FcR deficient mice. Moreover, serum from the immunized mice could kill a pure population of TUBO tumor cells in vitro (in the absence of cells that could mediate antibody-dependent cellular cytotoxicity), and at 1:100 or 1:20 dilution, immune serum could inhibit phosphorylation of HER2 on the cell surface, suggesting that it worked by inhibiting oncogene function, not by cytotoxicity. Thus, the mechanism was different from that of trastuzumab, and the vaccine might work in patients who had failed trastuzumab. The vaccine also had the advantage that it did not require multiple expensive intravenous infusions of immunoglobulin every few weeks for the life of the patient. Polyclonal antibodies induced by the vaccine might also be more resistant to escape mutations than a monoclonal antibody.
Based on these preclinical results, we translated this vaccine to humans, making a cGMP version of the adenovirus expressing the EC and TM domains of human HER2. By omitting the intracellular domain, we avoided any chance of oncogenicity or reversion to an oncogenic phenotype. To avoid neutralization of the adenovirus in adenovirus-seropositive people, we used the adenovirus to transduce autologous DCs as the vaccine, and showed that this approach also worked in mice [50]. Patients with advanced HER2+ metastatic cancers who had failed all standard therapies available were immunized at 4–8 week intervals from week 0 to week 24 with escalating doses of autologous transduced DCs, and followed for 2 years after the last dose of vaccine for safety assessment. Because of the approximately 7% cardiotoxicity rate in patients receiving long-term trastuzumab therapy, we wanted to avoid testing safety of the adenovirus vaccine in patients previously exposed to trastuzumab or other HER2-directed therapy. Thus, part I of the trial (NCT01730118) was designed to treat patients naïve to these agents, mostly patients with non-breast tumors that expressed 1+ to 3+ levels of HER2 who were not eligible for trastuzumab. If safety was shown in these, then in Part II, we would proceed to treat breast cancer patients with 3+ levels of HER2 who had failed other HER2-directed therapies. Enrollment in Part I of the trial has been completed and we have seen no evidence of cardiotoxicity, despite frequent monitoring of left ventricular ejection fraction. At the lowest dose of 5 million autologous DCs, we saw no clinical responses (and no antibody responses), but at 10 and 20 million DCs, 5/11 evaluable patients, with metastatic cancers that had failed all standard therapies, showed evidence of clinical benefit (either complete response, partial response, or stable disease lasting ≥ 6 months) (Wood et al., manuscript in preparation). Several patients have also shown significant decreases in the number of circulating tumor cells, often almost complete disappearance. Antibody responses for later dose groups are pending, as are T cell responses. Based on this evidence and the safety profile, we have received approval to extend the treatment to 40 million DCs and to start enrollment in Part II of the study involving treatment of breast and other cancer patients who have progressed on licensed HER2-targeted therapies. If these promising results are borne out, then the next step would be a phase II efficacy trial.
In conclusion, we have translated two types of cancer vaccines from mice to human clinical trials. One vaccine is to induce T cells to a cell-internal prostate antigen, TARP, using an epitope-enhanced cancer vaccine and demonstrating the utility of the concept of epitope enhancement. This vaccine appears to slow tumor growth in nearly three quarters of stage D0 prostate cancer patients, and is now in phase II trials. The second vaccine is to induce antibodies to a cell-surface tumor antigen, HER2, that is a driver oncogene product accessible to antibodies. This vaccine has shown preliminary evidence of clinical benefit in patients with advanced metastatic HER2+ cancers that have failed all other therapies, including complete response, partial response and stable disease lasting ≥ 6 months, and decrease in circulating tumor cells. Both vaccines make use of autologous DCs, and we have seen that certain qualities of such DCs are critical for the success of such cancer vaccines. We conclude that both categories of cancer vaccines (targeting both arms of the adaptive immune system) can be translated from preclinical murine models to human clinical trials with promising early results.
Abbreviations
- DC:
-
Dendritic cell
- GM-CSF:
-
Granulocyte-macrophage colony-stimulating factor
- HLA:
-
Human leukocyte antigen
- KLH:
-
Keyhole limpet hemocyanin
- MHC:
-
Major histocompatibility complex
- PSA:
-
Prostate-specific antigen
- TARP:
-
T cell receptor gamma-chain-alternate reading frame protein
- TCR:
-
T cell receptor
References
Germain RN, Margulies DH (1993) The biochemistry and cell biology of antigen processing and presentation. Annu Rev Immunol 11:403–450
Pamer E, Cresswell P (1998) Mechanisms of MHC class I–restricted antigen processing. Annu Rev Immunol 16:323–358
Phan GQ, Yang JC, Sherry RM et al (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 100:8372–8377
Morgan RA, Dudley ME, Wunderlich JR et al (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126–129
Fox BA, Schendel DJ, Butterfield LH et al (2011) Defining the critical hurdles in cancer immunotherapy. J Transl Med 9:214. doi:10.1186/1479-5876-9-214
Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454. doi:10.1056/NEJMoa1200690
Wolchok JD, Chan TA (2014) Cancer: antitumour immunity gets a boost. Nature 515:496–498. doi:10.1038/515496a
Sharma P, Allison JP (2015) The future of immune checkpoint therapy. Science 348:56–61. doi:10.1126/science.aaa8172
Kantoff PW, Higano CS, Shore ND et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363:411–422. doi:10.1056/NEJMoa1001294
Cheever MA, Higano CS (2011) PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin Cancer Res 17:3520–3526. doi:10.1158/1078-0432.CCR-10-3126
Finn OJ (2003) Cancer vaccines: between the idea and the reality. Nat Rev Immunol 3:630–641
Finn OJ (2008) Cancer immunology. N Engl J Med 358:2704–2715. doi:10.1056/NEJMra072739
Berzofsky JA, Terabe M, Oh S, Belyakov IM, Ahlers JD, Janik JE, Morris JC (2004) Progress on new vaccine strategies for the immunotherapy and prevention of cancer. J Clin Investig 113:1515–1525
Berzofsky JA, Wood LV, Terabe M (2013) Cancer vaccines: 21st century approaches to harnessing an ancient modality to fight cancer. Expert Rev Vaccines 12:1115–1118. doi:10.1586/14760584.2013.836906
Gatti-Mays ME, Redman JM, Collins JM, Bilusic M (2017) Cancer vaccines: enhanced immunogenic modulation through therapeutic combinations. Hum Vaccin Immunother. doi:10.1080/21645515.2017.1364322
Sutmuller RPM, Van Duivenvoorde LM, Van Elsas A, Schumacher TNM, Wildenberg ME, Allison JP, Toes REM, Offringa R, Melief CJM (2001) Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25+ regulatory T cells in antitumor therapy reveals alternative cytotoxic T lymphocyte responses. J Exp Med 194:823–832
Cheever MA, Schlom J, Weiner LM, Lyerly HK, Disis ML, Greenwood A, Grad O, Nelson WG (2008) Translational Research Working Group developmental pathway for immune response modifiers. Clin Cancer Res 14:5692–5699. doi:10.1158/1078-0432.CCR-08-1266
Terabe M, Ambrosino E, Takaku S, O’Konek JJ, Venzon D, Lonning S, McPherson JM, Berzofsky JA (2009) Synergistic enhancement of CD8 + T cell-mediated tumor vaccine efficacy by an anti-transforming growth factor-beta monoclonal antibody. Clin Cancer Res 15:6560–6569. doi:10.1158/1078-0432.CCR-09-1066
Terabe M, Robertson FC, Clark K, De Ravin E, Bloom A, Venzon D, Kato S, Mirza A, Berzofsky JA (2017) Blockade of only TGF-β 1 and 2 is sufficient to enhance the efficacy of vaccine and PD-1 checkpoint blockade immunotherapy. OncoImmunology. doi:10.1080/2162402X.2017.1308616
Le DT, Lutz E, Uram JN et al (2013) Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother 36:382–389. doi:10.1097/CJI.0b013e31829fb7a2
Le DT, Jaffee EM (2013) Harnessing immune responses in the tumor microenvironment: all signals needed. Clin Cancer Res 19:6061–6063. doi:10.1158/1078-0432.CCR-13-2424
Vreeland TJ, Clifton GT, Herbert GS, Hale DF, Jackson DO, Berry JS, Peoples GE (2016) Gaining ground on a cure through synergy: combining checkpoint inhibitors with cancer vaccines. Expert Rev Clin Immunol. doi:10.1080/1744666X.2016.1202114
Parchment RE, Voth AR, Doroshow JH, Berzofsky JA (2016) Immuno-pharmacodynamics for evaluating mechanism of action and developing immunotherapy combinations. Semin Oncol 43:501–513. doi:10.1053/j.seminoncol.2016.06.008
Berzofsky JA (1993) Epitope selection and design of synthetic vaccines: molecular approaches to enhancing immunogenicity and crossreactivity of engineered vaccines. Ann NY Acad Sci 690:256–264
Ahlers JD, Takeshita T, Pendleton CD, Berzofsky JA (1997) Enhanced immunogenicity of HIV-1 vaccine construct by modification of the native peptide sequence. Proc Natl Acad Sci USA 94:10856–10861
Sarobe P, Pendleton CD, Akatsuka T, Lau D, Engelhard VH, Feinstone SM, Berzofsky JA (1998) Enhanced in vitro potency and in vivo immunogenicity of a CTL epitope from hepatitis C virus core protein following amino acid replacement at secondary HLA-A2.1 binding positions. J Clin Investig 102:1239–1248
Ahlers JD, Belyakov IM, Thomas EK, Berzofsky JA (2001) High affinity T-helper epitope induces complementary helper and APC polarization, increased CTL and protection against viral infection. J. Clin. Investig 108:1677–1685
Berzofsky JA, Ahlers JD, Belyakov IM (2001) Strategies for designing and optimizing new generation vaccines. Nat Rev Immunol 1:209–219
Okazaki T, Pendleton DC, Lemonnier F, Berzofsky JA (2003) Epitope-enhanced conserved HIV-1 peptide protects HLA-A2-transgenic mice against virus expressing HIV-1 antigen. J. Immunol 171:2548–2555
Okazaki T, Pendleton CD, Sarobe P, Thomas EK, Harro C, Schwartz D, Iyengar S, Berzofsky JA (2006) Epitope-enhancement of a CD4 HIV epitope toward the development of the next generation HIV vaccine. J Immunol 176:3753–3759
Berzofsky JA, Cease KB, Cornette JL, Spouge JL, Margalit H, Berkower IJ, Good MF, Miller LH, DeLisi C (1987) Protein antigenic structures recognized by T cells: potential applications to vaccine design. Immunol Rev 98:9–52
Rammensee HG, Friede T, Stevanoviic S (1995) MHC ligands and peptide motifs: first listing. Immunogenetics 41:178–228
Ruppert J, Sidney J, Celis E, Kubo RT, Grey HM, Sette A (1993) Prominent role of secondary anchor residues in peptide binding to HLA-A2.1 molecules. Cell 74:929–937
Roberts CGP, Meister GE, Jesdale BT, Lieberman J, Berzofsky JA, DeGroot AS (1996) Prediction of HIV peptide epitopes by a novel algorithm. AIDS Res Hum Retroviruses 12:593–610
Zhang C, Anderson A, DeLisi C (1998) Structural principles that govern the peptide-binding motifs of class I MHC molecules. J Mol Biol 281:929–947
Wolfgang CD, Essand M, Vincent JJ, Lee B, Pastan I (2000) TARP: a nuclear protein expressed in prostate and breast cancer cells derived from an alternate reading frame of the T cell receptor gamma chain locus. Proc Natl Acad Sci USA 97:9437–9442
Oh S, Terabe M, Pendleton CD et al (2004) Human CTL to wild type and enhanced epitopes of a novel prostate and breast tumor-associated protein, TARP, lyse human breast cancer cells. Can Res 64:2610–2618
Wood LV, Fojo A, Roberson BD et al (2016) TARP vaccination is associated with slowing in PSA velocity and decreasing tumor growth rates in patients with Stage D0 prostate cancer. Oncolmmunology. doi:10.1080/2162402X.2016.1197459
Freedland SJ, Humphreys EB, Mangold LA, Eisenberger M, Dorey FJ, Walsh PC, Partin AW (2005) Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA 294:433–439. doi:10.1001/jama.294.4.433
Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC (1999) Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281:1591–1597
Freedland SJ, Humphreys EB, Mangold LA, Eisenberger M, Dorey FJ, Walsh PC, Partin AW (2007) Death in patients with recurrent prostate cancer after radical prostatectomy: prostate-specific antigen doubling time subgroups and their associated contributions to all-cause mortality. J Clin Oncol 25:1765–1771. doi:10.1200/JCO.2006.08.0572
Antonarakis ES, Zahurak ML, Lin J, Keizman D, Carducci MA, Eisenberger MA (2012) Changes in PSA kinetics predict metastasis- free survival in men with PSA-recurrent prostate cancer treated with nonhormonal agents: combined analysis of 4 phase II trials. Cancer 118:1533–1542. doi:10.1002/cncr.26437
Slovin SF, Wilton AS, Heller G, Scher HI (2005) Time to detectable metastatic disease in patients with rising prostate-specific antigen values following surgery or radiation therapy. Clin Cancer Res 11:8669–8673. doi:10.1158/1078-0432.CCR-05-1668
Lee AK, Levy LB, Cheung R, Kuban D (2005) Prostate-specific antigen doubling time predicts clinical outcome and survival in prostate cancer patients treated with combined radiation and hormone therapy. Int J Radiat Oncol Biol Phys 63:456–462. doi:10.1016/j.ijrobp.2005.03.008
Stein WD, Gulley JL, Schlom J et al (2011) Tumor regression and growth rates determined in five intramural NCI prostate cancer trials: the growth rate constant as an indicator of therapeutic efficacy. Clin Cancer Res 17:907–917. doi:10.1158/1078-0432.CCR-10-1762
Castiello L, Sabatino M, Ren J, Terabe M, Khuu H, Wood LV, Berzofsky JA, Stroncek DF (2017) Expression of CD14, IL10, and tolerogenic signature in dendritic cells inversely correlate with clinical and immunologic response to TARP vaccination in prostate cancer patients. Clin Cancer Res 23:3352–3364. doi:10.1158/1078-0432.CCR-16-2199
Foy TM, Fanger GR, Hand S, Gerard C, Bruck C, Cheever MA (2002) Designing HER2 vaccines. Semin Oncol 29:53–61
Knutson KL, Schiffman K, Disis ML (2001) Immunization with a HER-2/neu helper peptide vaccine generates HER- 2/neu CD8 T-cell immunity in cancer patients. J Clin Investig 107:477–484
Holmes JP, Gates JD, Benavides LC et al (2008) Optimal dose and schedule of an HER-2/neu (E75) peptide vaccine to prevent breast cancer recurrence: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Cancer 113:1666–1675
Sakai Y, Morrison BJ, Burke JD, Park JM, Terabe M, Janik JE, Forni G, Berzofsky JA, Morris JC (2004) Vaccination by genetically modified dendritic cells expressing a truncated neu oncogene prevents development of breast cancer in transgenic mice. Can Res 64:8022–8028
Park JM, Terabe M, Sakai Y, Munasinghe J, Forni G, Morris JC, Berzofsky JA (2005) Early Role of CD4 + Th1 cells and antibodies in HER-2 adenovirus-vaccine protection against autochthonous mammary carcinomas. J Immunol 174:4228–4236
Park JM, Terabe M, Steel JC, Forni G, Sakai Y, Morris JC, Berzofsky JA (2008) Therapy of advanced established murine breast cancer with a recombinant adenoviral ErbB-2/neu vaccine. Cancer Res 68:1979–1987
Clynes RA, Towers TL, Presta LG, Ravetch JV (2000) Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 6:443–446
Acknowledgments
We thank all the laboratory members and clinical staff who made these studies possible.
Funding
This work was supported by National Cancer Institute Center for Cancer Research Intramural funding under project Z01-SC-004020 to Jay A. Berzofsky.
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Jay A. Berzofsky—planned and supervised all the preclinical and clinical projects and wrote the manuscript. Masaki Terabe—oversaw and supervised the preclinical research. Jane Trepel—planned and supervised the testing of circulating tumor cells. Ira Pastan—discovered the TARP antigen, provided unpublished information, and helped plan the clinical trials. David F. Stroncek—supervised the preparation of DCs for the clinical trials and planned and supervised the study of DC phenotype as a correlate of DC vaccine efficacy. John C. Morris—Prepared the original Adeno-HER2 vaccine and planned and supervised some of the preclinical studies of that vaccine, as well as helping to plan the HER2 clinical protocol. Lauren V. Wood—wrote both clinical protocols and carried out the clinical trials.
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The animal protocols were approved by the NCI Animal Care and Use Committee accredited by the AAALAC and followed all the AAALAC regulations for animal care and use. The human protocols (NCI 09-C-0139 and 13-C-0016) were all approved by the NCI-NIH Institutional Review Board and the US Food and Drug Administration, and met all the United States ethical standards required for human studies.
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After appropriate explanation provided by the protocol principal investigator, all human subjects signed informed consent documents approved by the NCI-NIH Institutional Review Board.
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This paper is a Focussed Research Review based on a presentation given at the Fifth International Conference on Cancer Immunotherapy and Immunomonitoring (CITIM 2017), held in Prague, Czech Republic, 24th–27th April 2017. It is part of a series of Focussed Research Reviews and meeting report in Cancer Immunology, Immunotherapy.
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Berzofsky, J.A., Terabe, M., Trepel, J.B. et al. Cancer vaccine strategies: translation from mice to human clinical trials. Cancer Immunol Immunother 67, 1863–1869 (2018). https://doi.org/10.1007/s00262-017-2084-x
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DOI: https://doi.org/10.1007/s00262-017-2084-x