Treatment in the Adjuvant Setting

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The basis for emphasis on vaccination in the adjuvant setting is best demonstrated in preclinical models. The syngeneic murine tumor models involving EL4 lymphoma are particularly informative in terms of trial design (9). EL4 lymphoma naturally expresses GD2 ganglioside, which is recognized by MAb 3F8. Vaccines containing GD2 covalently conjugated to keyhole limpet hemocyanine (KLH) and mixed with immunological adjuvant QS21 are optimal for vaccination against GD2. Relatively higher levels of MAb administered 2 or 4 d after intravenous tumor challenge or moderate titers induced by vaccination that were present by day 4 after tumor challenge were able to eradicate disease in most mice. If MAb administration was deferred until day 7 or 10 after iv challenge, little or no benefit could be demonstrated. If the number of cells in the EL4 challenge was decreased, giving a longer window of opportunity, the vaccinations could be initiated after tumor challenge and good protection seen (9). These results are consistent with the need to initiate immunization with vaccines inducing antibodies in the adjuvant setting, when the targets are circulating tumor cells and micrometastases.

Comparable benefit is also seen when a subcutaneous foot-pad tumor challenge model, which more closely mirrors the clinical setting, is used (see Fig. 1). Vaccination or MAb

Fig. 1. Survival of groups of 10 mice challenged in the foot-pad with 105 EL4 lymphoma cells on day 0. The foot was amputated on day 24 or 31, and mice were treated after amputation with GD2-KLH plus QS-21 vaccine, 3F8 MAb, or various negative control treatments.

administration after amputation of the foot-pad primary tumor results in cure of most mice. There are comparable syngeneic models demonstrating the antitumor efficacy of MAbs or vaccines against other glycolipids (GD3, GM3), mucin antigens (Tn, TF, and MUC1) and a protein antigen (gp75) (reviewed in 1 and 2). These trials all share one thing in common: Benefit is seen primarily in minimal disease settings, comparable to the adjuvant setting in the clinic.

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