Efficacy of GM-CSF-producing Tumor Vaccine after Docetaxel Chemotherapy in Mice Bearing Established Lewis Lung Carcinoma

Abstract

In this report, we evaluated the efficacy of a GM-CSF-producing tumor vaccine given before and after docetaxel in mice bearing established lung tumors. Mice bearing established 3LL tumors were treated with docetaxel and tumor vaccines transduced with either control or GM-CSF adenoviral vectors. Docetaxel (5-20 mg/kg) treatment alone had only a minimal effect on growth of established 3LL tumors in vivo, although docetaxel was cytotoxic to 3LL cells in vitro. When mice bearing established 3LL tumors were pretreated with docetaxel followed by vaccination with irradiated GM-CSF- transduced 3LL tumor cells, significant tumor regression and prolonged survival were observed compared with chemotherapy alone. Delaying docetaxel treatment until after tumor vaccination abrogated the vaccine's anti-tumor effects. Mice that survived treatment were able to resist a lethal rechallenge of 3LL tumor cells. Memory CTL specific for an epitope (MUT-1) derived from 3LL were detected in surviving mice. Docetaxel induced a mild lymphodepletion in mice, both CD4 and CD8 subsets were reduced in LN and spleens. Interestingly, docetaxel also diminished the number of memory CD8+ T cells (CD122+) and possible CD4+ CD25+ Foxp3+ natural Treg cells. Docetaxel treatment did not affect antigen-driven proliferation of naive T cells but significantly promoted survival of activated T cells. Thus, augmentation of vaccine induced antitumor immunity in docetaxel-treated mice primarily due to the enhanced survival of antigen-experienced T cells.

The importance of correctly timing cancer immunotherapy

“…+ T-cells and Tregs [63]. Similar results have been observed in melanoma patients who received dacarbazine (DTIC) 1 day before tumor-antigen vaccination [68].…”

“…In an established 3LL lung tumor model, administration of docetaxel before but not after vaccination with a GM-CSF-producing tumor vaccine could significantly induce tumor regression and prolonged survival [63]. This is due to the docetaxel-associated enhanced survival of activated antigenexperienced T-cells induced by the vaccine over that of preexisting memory CD8…”

“…Above all, in cases where the treatment modalities stimulate the functionality or stability of tumor-specific CD8 + T-cells, administration of immunotherapy following conventional therapy can improve the antitumor immune responses [63,67]. In an established 3LL lung tumor model, administration of docetaxel before but not after vaccination with a GM-CSF-producing tumor vaccine could significantly induce tumor regression and prolonged survival [63].…”

Enhancement of antitumor immunity by low-dose total body irradiationis associated with selectively decreasing the proportion and number of T regulatorycells

“…10 In brief, cultured F10 cells, as well as the control 3LL cells, were collected and washed with phosphate-buffered saline, and then labeled with 5-and 6-carboxyfluorescein diacetate succinimidyl ester (Molecular Probes, Eugene, OR, USA). Labeling reactions were stopped with complete RPMI 1640 medium.…”

Enhancing efficacy of therapeutic vaccinations by combination with other modalities

“…In an experimental melanoma model, systemic cyclophosphamide combined with local intratumoral injection of dendritic cells led to complete tumor regression [23]. In preclinical murine studies, the chemotherapy agents cyclophosphamide, doxorubicin, paclitaxel, and docetaxel [24] enhanced antitumor immune response to a whole tumor-cell vaccine [25]. The immune enhancement may occur through several possible mechanisms.…”