Therapeutic Anti-Tumor Vaccines: From Tumor Inhibition to Enhancement

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

Unveiling antigens in a non-immunogenic spontaneous murine tumor using a dendritic cell based vaccine

La inmunoterapia sería un tratamiento ideal contra el cáncer porque combina eficacia y especificidad, pero hasta hoy no ha dado resultados exitosos contra tumores establecidos. En este trabajo abordamos el problema de la falta de inmunogenicidad de los tumores espontáneos como una posible causa del fracaso de la inmunoterapia. Nos preguntamos si esta falta de inmunogenicidad se debe a la ausencia de antígenos o a la existencia de mecanismos tolerogénicos que impiden a esos antígenos iniciar una respuesta inmune. Para deslindar entre ambas alternativas, utilizamos dos tumores murinos -uno espontáneo y no inmunogénico (linfoma LB) y otro inducido por metilcolantreno y fuertemente inmunogénico (fibrosarcoma MC-C)- y la técnica de inmunización con células dendríticas (DC) estimuladas con extracto acelular de tumor. Al estimular DC in vitro con extracto de LB, las DC no exhibieron maduración ni inmunizaron in vivo contra implantes de LB. Por otro lado, extractos de MC-C, hicieron madurar las DC y las convirtieron en poderosas vacunas contra implantes de MC-C pero no de LB, indicando que MC-C y LB no tienen antígenos compartidos. Por último, cuando DC fueron estimuladas con una mezcla de los extractos de LB y MC-C, expresaron marcadores de maduración y exhibieron capacidad vacunante contra LB. Estos resultados sugieren que el tumor LB tiene antígenos específicos de tumor pero carece de otras señales necesarias para la maduración de las DC. Estas señales serían aportadas por el extracto de MC-C, permitiendo de este modo iniciar una respuesta inmune contra LB.Up to date, most attempts to use immunotherapy to cause the regression of animal and human established tumors have not been successful. Former experiments have postulated that this failure could be attributed, at least in part, to a lack of immunogenicity of spontaneous tumors. In this paper, we have investigated whether this lack of immunogenicity can be attributed to the absence of tumor antigens or to the existence of tolerogenic mechanisms preventing such antigens from initiating an antitumor immune response. We have used two murine tumors -a non-immunogenic spontaneous lymphoma (LB) and a strongly immunogenic methylcholanthrene-induced fibrosarcoma (MC-C)- together with a vaccination strategy based on the inoculation of dendritic cells (DC) loaded with a tumor lysate. When DC were pulsed with LB lysate (DC+LB), no maturation of DC was achieved in vitro and no protection against LB implants after DC+LB inoculation was observed in vivo. On the other hand, when DC were pulsed with MC-C lysate (DC+MC-C), maturation of DC was observed along with a strong protection against MC-C implants after DC+MC-C inoculaton. Finally, when DC were pulsed with both LB and MC-C lysates (DC+LB+MC-C), maturation of DC and protection against LB implants were achieved. Since no immune cross reaction between MC-C and LB was ever observed, the most likely interpretation is that LB bears specific tumor antigens but lacks other signals to achieve DC maturation. These signals would be provided by MC-C which would enable DC to mature and to initiate an effective anti-LB immune response.Fil: Reffo, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Chiarella, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Bruzzo Iraola, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Bustuoabad, Oscar David. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Ruggiero, Raul Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin