Characteristics of reovirus-mediated chemoimmunotherapy of murine L1210 leukemia

Abstract

We have previously demonstrated the ability of reovirus to function synergistically with chemotherapy in the treatment of murine EL-4 lymphoma. This study characterizes this treatment regimen in the therapy of L1210 leukemia. Animals with an estimated tumor burden of 10(7) cells were treated with 9 mg/kg 1,3-bis(2-chloroethyl)-1-nitrosourea. Reovirus type 3, which had been quantitated either by particles or plaque-forming units (pfu), was administered 48 h after chemotherapy. Complete remission of tumor was observed in 80% of the animals which received either 10(11) particles or 10(9) pfu of reovirus. Cured animals were resistant to challenge with homologous tumor, but were susceptible to challenge with heterologous tumor. Reovirus undergoes limited replication at the tumor site, and virus-specific antibody appears only after disappearance of reovirus-infected cells and virus from the ascites fluid. Reovirus appears to function therapeutically by inducing a tumor-specific cytolytic immune response.

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU)/interleukin-2 chemoimmunotherapy of murine L1210 leukemia

“…Attempts to reduce this toxicity while maintaining therapeutic effectiveness were successful when IL-2 was used in combination with chemotherapy [12,16]. We observed similar synergy when BCNU was used with reovirus as the immunotherapeutic agent [1]. However, in those studies BCNU was used at a dramatically reduced dose, which eliminated high background BCNU therapy without altering the effectiveness of the combined therapy.…”

“…The tumor cells were removed, washed and the erythrocytes lysed as described above, The cell concentration was adjusted to 5 × 106 viable cells/ml in D-PBS and 0.2 ml was injected i. p. into each mouse. Cox [ 1 ]. BCNU was injected i. p. at a dose of 9 mg/kg body weißt.…”

“…1,3-Bis(2-chloroethyl)-l-nitrosourea (BCNU) was selected as the chemotherapy component in this study because it is a cytoreductive agent and may also have immunomodulatory effects. We have found BCNU to be very effective in the therapy of murine tumors when used in combination with reovirus as the immunotherapeutic agent [1]. It has been reported that BCNU stimulates increased tumoricidal macrophage and CTL activity and higher percentages of Thl cells in tumor-bearing animals [11,10,15].…”

Recent Developments in the Virus Therapy of Cancer

“…(54) demonstrated that L1210 tumor cells pretreated with reovirus and the chemotherapeutic agent 1,3‐bis(2‐chloroethyl)‐1‐nitrosourea (BCNU) and then injected into syngeneic mice were rejected. Subsequently, our studies and those of others have shown that reovirus and BCNU can be used to treat L1210‐ or EL‐4‐bearing mice to elicit a significant cure rate (55, 56). Challenging cured mice with homologous tumor results in 100% survival, whereas challenge with heterologous tumor results in the death of all animals.…”