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. 2008:2:237-45.
doi: 10.4137/cmo.s538. Epub 2008 Apr 29.

Therapeutic anti-tumor vaccines: from tumor inhibition to enhancement

Paula Chiarella  1 , Verónica Reffo, Juan Bruzzo, Oscar D Bustuoabad, Raúl A Ruggiero
Affiliations

Therapeutic anti-tumor vaccines: from tumor inhibition to enhancement

Paula Chiarella et al. Clin Med Oncol. 2008.

Abstract

Numerous immunization trials have proved successful in preventing the growth of experimental animal tumors and human hepatocarcinomas induced by hepatitis B virus. These results have prompted researchers and physicians to use vaccines in a therapeutic mode but the results have, in general, been disappointing even when strongly immunogenic murine tumors were concerned. Data presented herein suggest that immunotherapy induced by a single dose of a dendritic cell-based vaccine against a murine established tumor or against residual tumor cells after debulking the primary tumor, can render not only inhibitory or null but also stimulatory effects on tumor growth. These different effects might be dependent on where the system is located in the immune response curve that relates the quantity of the immune response to the quantity of target tumor cells. We suggest that high ratios render tumor inhibition, medium and very low ratios render null effects and low ratios-between medium and very low ones-render tumor stimulation. Since the magnitude of these ratios would depend on the antigenic profile of the tumor, the immunogenic strength of the vaccine used and the immunological state of the host, studies aimed to determine the magnitude of these variables in each particular case, seem to be necessary as a pre-condition to design rational immunotherapeutic approaches to cancer. In contrast, if these studies are neglected, the worst thing that an immunotherapist could face is not merely a null effect but enhancement of tumor growth.

Keywords: immunostimulation; immunotherapy; tumor.

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Figures

Figure 1
Figure 1
Representative experiment showing the expression of the molecular markers of maturation MHCII, CD80, CD86 and CD40 in dendritic cells (DC) pulsed with MC-C tumor lysate for two days in culture (mature DC or mDC), revealed with fluoresceinated specific antibodies. Controls were dendritic cells pulsed with none (immature DC or iDC).
Figure 2
Figure 2
High titer of TNF-α in the supernatant of DC pulsed with MC-C tumor lysate for two days in culture. Supernatants of dendritic cells pulsed with LPS or none, served as control. The values represent the mean ± standard error of 4 experiments.
Figure 3
Figure 3
Growth of MC-C initiated with a s.c. inoculum of 5 × 105 MC-C tumor cells in mice receiving a vaccine consisting in a single dose of 3 × 105 mDC intra footpad, in a preventive mode, 10 days prior tumor inoculation (A) or in a therapeutic mode, at 5 (B), 8 (C), 12 (D), 18 (E), 25 (F) and 35 (G) days after tumor inoculation, when tumor volumes were 10 mm3, 50 mm3, 250 mm3, 600 mm3, 1000 mm3 and ≥2000 mm3, respectively. Growth of MC-C inoculated in mice receiving iDC or none served as controls. In E and F growth of MC-C tumor in nude mice was registered in addition to that in vaccinated and control euthymic mice.*p < 0.05; **p < 0.02; ***p < 0.01; §: p < 0.001.
Figure 4
Figure 4
Survival curves of vaccinated and control mice from Figure 3A–G.
Figure 5
Figure 5
Growth of 2 × 106 residual tumor cells left behind at the operation site after partially debulking a s.c. MC-C tumor measuring 600 mm3 (A) or 2400 mm3 (B) at the time of surgery, in mice receiving a vaccine of mDC 3 days after surgery (vaccinated) or in controls receiving none after surgery. *p < 0.05
Figure 6
Figure 6
Survival curves of vaccinated and control mice from Figure 5A–B.
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