Establishment of tumor‐specific immunotherapy model utilizing vaccinia virus‐reactive helper T cell activity

Abstract

It was previously demonstrated that preimmunization of mice with live vaccinia virus (VV) and subsequent immunization with VV-infected (modified), syngeneic tumor cells resulted in enhanced induction of tumor-specific immunity through a cellular collaboration between VV-reactive helper T (VV-Th) cells and tumor-specific effector cell precursors. On the basis of this augmenting system, a tumor-specific immunotherapy model was established in which a growing tumor regressed. C3H/HeN mice were pretreated with cyclophosphamide to eliminate nonspecific suppressor T cell activity and subsequently inoculated (primed) s.c. with live VV, leading to augmented induction of VV-Th cell activities. Four weeks later, the mice were inoculated i.d. with syngeneic X5563 myeloma cells. Six days after the tumor cell inoculation, live VV was injected into the tumor mass three times at 2-day intervals. Seven of ten mice which had received VV priming and subsequent VV injection into the tumor mass exhibited complete tumor regression. On the contrary, mice which had received mere intratumoral VV injection in the absence of VV priming failed to exhibit appreciable tumor regression. Mice whose tumor had completely regressed (regressor mice) by the above VV immunotherapy were shown to have acquired systemic anti-tumor immunity, which was confirmed by a challenge with syngeneic tumor cells after the tumor regression. In vitro analysis of these immune mice revealed that potent tumor-specific cytotoxic T lymphocyte responses were preferentially induced, but with no detectable anti-tumor antibody responses. Such a potent tumor-specific immunity was not observed in mice which had received an intratumoral VV injection in the absence of VV priming. Thus the results clearly indicate that the tumor regression was accompanied by concurrent generation of a potent tumor-specific immunity, suggesting that the cellular collaboration between VV-Th cells and tumor-specific effector cell precursors is also functioning in this VV-immunotherapy protocol, likewise the immunoprophylactic model. Therefore, the present model provides an effective maneuver for tumor-specific immunotherapy and this system will be theoretically applicable to human cancer treatment.

Immunotherapy of the rat 13762SC mammary adenocarcinoma by vaccinia virus augmentation of tumor immunity

“…We will now be able to investigate whether we can get improved anti-tumor efficacy by using repeated immunizations over time, which is the approach reported by several others [36][37][38][39]41,43]. Clearly, models in which animals are immunized against a tumor prior to tumor challenge are not applicable as a model for human tumor immunotherapy, insofar as tumor challenge takes place in the face of a previous antitumor response which is then reactivated.…”

“…through provision of additional helper determinants on the cell surface. Many workers have confirmed this finding, demonstrating that membranes and/or oncolysates from virus-infected tumor cells induce antitumor immunity [1,3,4,16,37,40]. 0262-0898/90 $3"00 © 1990 Taylor & Francis Ltd. recognized in association with weak tumor immunogens, the immune response against the tumor cell may be enhanced.…”

Potential of oncolytic viruses in the treatment of multiple myeloma

“…Animals vaccinated with tumor cells infected ex vivo with VacV and then lethally irradiated can completely reject secondary challenge with uninfected MM cells, 109 – 113 and vaccination of tumor-bearing animals can result in remission of established MM. 114 This effect appears to be mediated by cytotoxic T cells, although the exact subset has not been identified. 111 , 113 Unfortunately, this methodology requires prevaccination of tumor-naïve individuals with VacV to achieve maximal efficacy, which could severely limit its translational potential.…”