Abstract
Evaluation of: Odunsi K, Qian F, Matsuzaki J et al. Vaccination with an NY-ESO-1 peptide of HLA class I/II specificities induces integrated humoral and T cell responses in ovarian cancer. Proc. Natl Acad. Sci. USA 104[31], 12837–12842 (2007).
NY-ESO-1 is a cancer testis antigen, a family in which MAGE is a better-known example. It was discovered 10 years ago and has rapidly progressed into clinical trials with over 30 studies present to date. Being an embryological related antigen present on the testes, it is also present on the ovaries and this paper reports the testing of an epitope of this antigen that is recognized by both HLA class-I and class-II restricted CD8+ T cells. In this study, 18 HLA- DP4+ ovarian cancer patients with minimal disease burden were given repeated vaccinations with this peptide mixed with an incomplete Freund’s adjuvant (Montanide ISA51). The claim in the paper is that this protocol induces integrated humoral and T-cell responses in ovarian cancer. However, there are a number of concerns regarding the actual data.
In spite of decades of work and a plethora of candidates, no human cancer vaccine has yet been registered, even though proof of principle has been shown in randomized cancer studies using autologous preparation for the vaccine in early colorectal cancer and resected renal cell patients Citation[1,2]. There has, therefore, been a search for methods that can induce an effective immune response that does not require autologous tumor preparations: a search for new tumor-specific antigens revealed MAGE and MART, which were melanoma associated Citation[3–5]. Disappointment with the development of melanoma vaccines has led researchers to seek antigens that may well be shared by other solid tumor types. To date, a vaccine for prostate cancer has come the closest to receiving approval Citation[6,7]. NY-ESO is a member of the cancer-testis family of antigens and is present in the testes but not in normal tissue; in addition, it is present in an aberrant version in many tumor types. Ovarian cancer has long been thought to be a suitable target for immunotherapy because of its predictable and usually contained disease spread as well as numerous reports of responses to various forms of immunotherapy Citation[8].
In the paper evaluated here, owing to the high expression of NY-ESO-1 on ovarian cancer cells, Odunsi et al. have selected a peptide that is a natural helper epitope, recognized in the context of class II (HLA-DPB1*0401 and *0402) as well as having HLA-2 and HLA-24 class I motifs embedded in its sequence Citation[9]. Therefore, they determined whether the peptide could elicit specific CD4+ and CD8+ T-cell responses in ovarian cancer patients with minimal disease burden by using incomplete Freund’s adjuvant (Montanide ISA51) in patients with specific HLA-DP4+ backgrounds. Nine patients were either HLA-2+ or HLA-24+. The data show that three patients were baseline positive for antibodies to NY-ES0-1 and that the titers increased significantly over the course of immunization in two of these, whereas the third become seronegative 1 year after completing immunization. Two baseline seronegative patients converted to seropositive during the course of immunization; one after seven vaccinations and the other after eleven vaccinations. Nothing is mentioned about the other patients who presumably did not respond. Induction of specific CD4 cells is analyzed by INF-γ, The enzyme-linked immunosorbent spot assays and intracellular staining after a single in vitro stimulation with the peptide. Two patients had pre-existing peptide-reactive CD4+ T-cells, which increased in both patients during the course of immunization. In total, 13 of the remaining 16 patients developed a reactive CD4 cell response during the course of immunization. All this concludes that the number of patients positive at the end of the study (83%) was significantly greater than that at the start of therapy.
Odunsi et al. then studied whether these cells where able to recognize tumor targets, by production of INF-γ and TNF-α, using a number of cell lines. However, although this is consistent with recognition of naturally processed protein, the cell lines were not the same as those expressing NY-ESO or the negative control. Furthermore, NY-ESO was not knocked down with siRNA. Therefore, the results certainly cannot be taken as proof. Specificity was further examined using CD8 cell lines, which did have identical usage of Vβ and Jβ genes consistent with similar peptide recognition on tumor cells. By contrast, there was a functional clustering of T-cell receptor usage by CD4 T-cell lines. Another observation was the fact that these responses were long lived with responses being detected at 6 and 12 months.
Although this was a Phase I study, the median time to disease progression from start of vaccination was 19 months, with the number of vaccines administered being thought to relate to disease-free survival. However, this could also be affected by the reduced number of vaccines in patients with progressive disease. One patient with a recurrent tumor following vaccination was shown to have heavy infiltration of CD8 and CD4 cells, although there was no longer any expression of the NY-ESO-1 antigen by immunohistochemistry or reverse transcriptase-PCR.
The main problem with Odunsi et al.’s paper is that the title suggests that the induction of humoral and cellular responses is integrated, and it is very difficult to appreciate the evidence for this even in a supplementary information table – which is poorly described, with no statistics to describe correlations between humoral and cellular responses.
Expert commentary & five–year view
Despite the previously mentioned limitations, this study shows that it is possible to induce antitumor antigen-specific responses in both CD8 and CD4 cells and that this may have a beneficial effect on outcome. However, the authors are quick to point out that Treg cells, which are enhanced in ovarian cancer, are not affected by this vaccination and that antigen escape remains a potential problem necessitating the need for multiple antigens in future studies.
In addition they show that, in order to induce good immune responses, multiple vaccinations are required. Indeed, it took seven vaccinations over 160 days or more before some responses were detected. However, the great variability among patients regarding which responses will occur makes it difficult to form clear assessments, as it is unclear from this study whether the variability can be explained by age, disease stage or the amount and type of therapy given previously.
Conclusion
Nevertheless, this paper exemplifies nicely the complexity of developing a vaccine immunotherapy for cancer and, in this case, ovarian cancer in particular. It is becoming widely acceptable that cancer vaccines may be more effective when given with other treatment modalities and that these need to be incorporated into future trials. For instance, low-dose chemotherapy may help control the Treg cells as well as help with other aspects of tumor control Citation[10–13]. Other modalities, such as antiangiogenics and anti-inflammatories, have also been shown to enhance vaccine responses and outcome. In conclusion, I would expect that in 5 years there will be vaccines approved for at least one solid tumor. Paradoxically, I doubt that this will be melanoma, but a vaccine for ovarian cancer may be a realistic therapeutic modality, even if none is registered by this time.
Key issues
| • | Relevant antitumor immunity can be raised in patients with advanced ovarian cancer who have had previous treatment. | ||||
| • | Importantly, there appears to be an association between the number of vaccinations and a desired immune response, as well as clinical outcome, which is similar to that reported in other vaccine studies. | ||||
| • | Odunsi et al. stress that there may be limitations in therapeutic vaccines using singular antigens as targets and not addressing the presence of significantly increased Treg cells, which occur in ovarian cancer, that will downregulate any response induced by the vaccine. | ||||
| • | Future studies that address these issues with the vaccine integrated into the overall management of the disease may produce a much more dramatically improved outcome. | ||||
Financial & competing interests disclosure
The author had no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
- Vermorken JB, Claessen AM, van Tinteren H et al. Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial. Lancet353(9150), 345–350 (1999).
- Jocham D, Richter A, Hoffmann L et al. Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: Phase III, randomised controlled trial. Lancet363(9409), 594–599 (2004).
- Van den Eynde BJ, Boon T. Tumor antigens recognized by T lymphocytes. Int. J. Clin. Lab. Res.27(2), 81–86 (1997).
- Kawakami Y, Robbins PF, Rosenberg SA. Human melanoma antigens recognized by T lymphocytes. Keio. J. Med.45(2), 100–108 (1996).
- Castelli C, Rivoltini L, Andreola G, Carrabba M, Renkvist N, Parmiani G. T-cell recognition of melanoma-associated antigens. J. Cell. Physiol.182(3), 323–331 (2000).
- Ward S, Dalgleish A. Therapeutic cancer vaccines. Vaccine (2007) (Epub ahead of print).
- Dalgleish A. Overcoming technical challenges in the development of cancer vaccines. IDrugs10(7), 463–467 (2007).
- Sabbatini P, Odunsi K. Immunologic approaches to ovarian cancer treatment. J. Clin. Oncol.25(20), 2884–2893 (2007).
- Odunsi K, Qian F, Matsuzaki J et al. Vaccination with an NY-ESO-1 peptide of HLA class I/II specificities induces integrated humoral and T cell responses in ovarian cancer. Proc. Natl Acad. Sci. USA104(31), 12837–12842 (2007).
- Dalgleish AG, Whelan MA. Cancer vaccines as a therapeutic modality: the long trek. Cancer Immunol. Immunother.55(8), 1025–1032 (2006).
- den Brok MH, Sutmuller RP, Nierkens S et al. Synergy between in situ cryoablation and TLR9 stimulation results in a highly effective in vivo dendritic cell vaccine. Cancer Res.66(14), 7285–7292 (2006).
- Bae SH, Park YJ, Park JB, Choi YS, Kim MS, Sin JI. Therapeutic synergy of human papillomavirus E7 subunit vaccines plus cisplatin in an animal tumor model: causal involvement of increased sensitivity of cisplatin-treated tumors to CTL-mediated killing in therapeutic synergy. Clin. Cancer Res.13(1), 341–349 (2007).
- Nishisaka N, Maini A, Kinoshita Y et al. Immunotherapy for lung metastases of murine renal cell carcinoma: synergy between radiation and cytokine-producing tumor vaccines. J. Immunother.22(4), 308–314 (1999).