The aim of this study was to determine if cells primed in vivo could be rendered more effective in killing tumor by secondary sensitization in vitro. C57BL/6 mice were primed with a viable antigenic syngeneic Friend leukemia (FBL-3). The immune spleen cells secondarily sensitized by 5-day culture with irradiated FBL-3 (CiFx) became significantly more effective than fresh noncultured immune cells (Ci) in in vitro cytotoxicity, tumor neutralization (Winn assay), and immunotherapy of an early leukemia. However, in chemoimmunotherapy of advanced leukemia, CiFx were no more effective than Ci. Moreover, Ci cultured with irradiated C57BL/6 spleen cells (CiCx), i.e., without secondary sensitization in vitro, became markedly less effective than noncultured Ci. C57BL/6 mice inoculated with 5 × 106 FBL-3 on day 0 received on day 5 cyclophosphamide (CY) plus Ci, CiFx, or CiCx. CY alone doubled the median survival time (MST) to day 26. As an adjunct to CY, Ci or CiFx prolonged the MST to day 53 and day 55 and cured 16/72 and 20/66 mice, respectively, whereas CiCx prolonged the MST to only day 33 and cured 1/36 mice. To determine if the lack of enhanced effect after secondary sensitization in vitro reflects the nature of primary exposure to antigen, other priming regimens were studied. When mice were primed with irradiated FBL-3 or with cross-reacting MSV, CiFx were more effective than Ci in chemoimmunotherapy. Thus, enhancement by secondary in vitro sensitization of primed cells to eradicate advanced leukemia is dependent upon the method of priming and cannot be predicted by results of the in vitro tumor cytotoxicity, tumor neutralization, or immunotherapy of early leukemia. Moreover, primed cells lose effectiveness in tumor therapy if cultured without secondary stimulation.

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