Chemotherapy Plus Active Immunotherapy

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Vaccines Have Serious Side Effects

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Chemotherapeutic agents have been tested with cancer vaccines and have demonstrated synergy in several models. For instance, docetaxel administered two days prior to each of the three vaccinations of GM-CSF-secreting B16 melanoma cells results in 50% long-term survival of B16 tumor-bearing mice compared to 10% survival with either agent alone (76). While docetaxel was shown to induce neutropenia and lymphopenia, the expansion and survival of antigen-specific T cells (examined in OT-1 TCR transgenic mice using OVA-transfected B16 cells) was not impaired. In another study using neu transgenic mice, three different chemotherapeutic drugs (cyclophosphamide, doxorubicin, and paclitaxel) were tested in combination with a HER-2/neu expressing tumor vaccine and showed enhanced activity in a therapeutic setting (77). Whether drug was administered before or after vaccination affected the outcome and the optimal order of administration was found to vary from one drug to the next.

Some recent clinical studies provide yet another somewhat surprising perspective on how active immunotherapy might synergize with chemotherapy. With the caveat associated with retrospective analysis, 25 patients with glio-blastoma multiforme were vaccinated with DCs loaded with autologous tumor HLA-eluted peptides or tumor lysate (78). Thirteen of these patients went on to receive subsequent chemotherapy. An additional 13 nonvaccinated patients analyzed in this study also received chemotherapy. Of the vaccine plus chemotherapy-treated patients, 42% were two-year survivors while only 8% of patients treated with chemotherapy alone or vaccine alone survived this long. It is hypothesized that infiltrating CD8+ T cells may upregulate markers on the tumor (e.g., Fas), which render cells more susceptible to chemotherapeutic drugs that kill targets via induction of apoptosis.

In another study, a striking response rate of 62% among 21 extensive-stage small cell lung cancer patients treated with second-line chemotherapy was observed after vaccination with DCs transduced with full-length p53 (79). Thirteen of the 21 patients were platinum-resistant and 61.5% of these were responders. In a third study of patients with various metastatic cancers treated with a DNA vaccine encoding a common tumor antigen, five of six immune responders who received subsequent salvage therapy experienced unexpected clinical benefit (80). Among those benefiting from the salvage therapy were four patients with progressive disease after vaccination. Among eight patients who did not demonstrate immunity to vaccination and who survived to receive additional therapy, only one derived clinical benefit.

Clearly, determining the optimal mode of administration represents a challenge to clinical applications of vaccine/chemotherapy combinations, as the best regimen may only be understood through an extensive matrix of combination testing in clinical trials. Furthermore, as discussed by Lake and Robinson, delivery of more antigen by vaccination may not be necessary in cases where the chemotherapeutic agent alone results in sufficient antigen release via tumor cell apoptosis and secondary necrosis (81). In these situations, amplification of endogenous responses to cross-presented antigen using antibodies against, e.g., CD40, may be sufficient to realize clinical benefit (82).

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