Booster Vaccinations against Cancer Are Critical in Prophylactic but Detrimental in Therapeutic Settings

Abstract

Although cancer vaccines are in the clinic, several issues remain to be addressed to increase vaccine efficacy. In particular, whether how and how frequently a patient should be boosted remains to be defined. Here, we have assessed the ability of dendritic cell (DC)-based vaccines to induce a long-lasting tumorspecific CTL response in either prophylactic or therapeutic settings by taking advantage of transplantable and spontaneous mouse tumor models. Implementing a 24-hour ex vivo intracellular cytokine production assay, we have found that priming with a DC-based vaccine induced a long-lasting CTL response in wild-type mice, and homologous boosting better sustained the pool of central memory T cells, which associated with potent protection against B16F1 melanoma challenge. Appropriate timing of booster vaccination was also critical, as a tight boosting schedule hindered persistence of IFN-g-competent memory CD8þ T cells and mice survival in prophylactic settings. Conversely, prime/boost vaccination proved to be of no advantage or even detrimental in therapeutic settings in B16F1 and transgenic adenocarcinoma of the mouse prostate (TRAMP) models, respectively. Although DC priming was indeed needed for tumor shrinkage, restoration of immune competence, and prolonged survival of TRAMP mice, repeated boosting did not sustain the pool of central memory CTLs and was detrimental for mice overall survival. Thus, our results indicate that booster vaccinations impact antitumor immunity to different extents, depending on their prophylactic or therapeutic administration, and suggest evaluating the need for boosting in any given patient with cancer depending on the state of the disease. Cancer Res; 73(12); 3545-54. Ó2013 AACR.

Boosting anticancer vaccines

“…We have also found that boosting has a considerable impact on the pool of IFNγ-producing cytotoxic CD8 + T CM cells, which exceeds by more than 2-fold the pool detected in non-boosted mice 4 . This holds true for both exogenous and endogenous antigens, which are recognized by T cells bearing high- and low-affinity TCR, respectively 4 …”

“…When mice received booster injections at earlier time points (i.e., after a 2-week interval; tight boosting), a reduced amount of T CM cells was found in the spleen and the survival curve of these mice resembled that of mice that received only the priming injection 4 . Unexpectedly, also boosting with complete and incomplete Freund’s adjuvants (CFA and IFA, respectively), even when performed at 4-week intervals, was detrimental for the pool of T CM cells 4 . These findings are in line with a recent report showing that IFA leads to the trapping of tumor-specific CD8 + T cells at the vaccination site, where they become dysfunctional and undergo apoptosis 6 …”

“…Assuming that fully activated T EM cells immediately respond to an antigenic challenge whereas quiescent T CM cells must get activated first, 3 we have set up a long (24 h) ex vivo intracellular interferon γ (IFNγ)-specific assay to better detect the latter population 4 . Adopting this strategy, we have been able to demonstrate that, in healthy mice, a single DC-based vaccination elicits an antigen-specific immune response that lasts for at least 5 mo in the absence of subsequent antigen stimulation, confirming what has been reported for healthy humans 5 and extending this concept to T CM cells 4 …”

“…Indeed, a lag of at least 4 weeks was required to obtain the most potent T CM response, correlating with the ability of vaccinated mice to reject a challenge with B16F1 melanoma cells 4 . When mice received booster injections at earlier time points (i.e., after a 2-week interval; tight boosting), a reduced amount of T CM cells was found in the spleen and the survival curve of these mice resembled that of mice that received only the priming injection 4 . Unexpectedly, also boosting with complete and incomplete Freund’s adjuvants (CFA and IFA, respectively), even when performed at 4-week intervals, was detrimental for the pool of T CM cells 4 .…”

Dendritic Cell Therapy in an Allogeneic-Hematopoietic Cell Transplantation Setting: An Effective Strategy toward Better Disease Control?

“…No clear comparison has been made, and therefore no strong conclusions can be drawn. According to mouse studies and some clinical trials, vaccination seems to be critical, but boosting strategies of subjects with residual disease or with tumor recurrence, should be carefully revisited (68). …”