Exploitation of differential homeostatic proliferation of T-cell subsets following chemotherapy to enhance the efficacy of vaccine-mediated antitumor responses

Abstract

The 5-year survival rate for stage IB-III non-small-cell lung cancer (NSCLC) remains 15%. Surgical resection followed by adjuvant chemotherapy with cisplatin and vinorelbine is one standard-of-care. We sought to determine in a preclinical model whether (a) the combination of cisplatin and vinorelbine could positively modulate components of the immune system independent of antitumor activity, and (b) there were synergistic effects of this drug combination and vaccine immunotherapy. We examined the effect of cisplatin/vinorelbine on gene expression, cell-surface phenotype, and CTL-mediated cytolysis of murine lung carcinoma cells in vitro; we also assessed the effects of cisplatin/vinorelbine on immune subsets and function of Tregs in vivo. Finally, we evaluated the potential synergy between chemotherapy and a recombinant yeast-CEA vaccine in a murine model transgenic for CEA with mice bearing lung tumors. These studies demonstrate that exposure of lung tumor cells to the platinum doublet cisplatin/vinorelbine modulates tumor cell phenotype and increases sensitivity to CTL-mediated cytolysis. These studies also demonstrate that cisplatin/ vinorelbine (a) induces sub-myeloablative leucopenia that differentially modulates reconstitution of Treg versus effector T-cell subsets and (b) can be employed synergistically with vaccine, exploiting homeostatic peripheral expansion of T cells. Antitumor studies show for the first time that cisplatin/vinorelbine combined with vaccine increases the survival of mice with established NSCLC. These findings provide the rationale for the potential clinical benefit of the combined use of vaccine with cisplatin/vinorelbine chemotherapy regimens.

Cancer vaccines inducing antibody production: more pros than cons

“…Interestingly, in the same study cyclophosphamide administration supported the vaccine success paralleled by enhanced T-cell (CD8 + and CD4 + ) activity against the tumor cells. This is in line with the recently reported phenomenon that chemotherapy may enhance the efficacy of tumor vaccines due to increased sensitivity towards cytotoxic effector T cell (CTL)-mediated killing [94]. Furthermore, Monzavi-Karbassi et al report that the improved efficacy of the mimotope vaccine upon pretreatment with chemotherapy involves the induction of leucopenia affecting Treg levels at the tumor site [93].…”

Selective Treg reconstitution during lymphopenia normalizes DC costimulation and prevents graft-versus-host disease

“…In stark contrast, antitumor responses may benefit from conditions favoring fast-phase LIP during immune reconstitution (59). In general, antitumor responses in mouse (60) and man (61) are enhanced by a reduction in absolute Treg numbers and thus the Treg/DC ratio.…”

Antitumor Effects of Cisplatin Combined with Tecemotide Immunotherapy in a Human MUC1 Transgenic Lung Cancer Mouse Model

“…Cyclophosphamide has been shown to reduce both the number of Tregs (25)(26)(27)(28)(29) and their immunosuppressive functionality in mice (28) and humans (26). Preclinical data suggest that cisplatin, administered at full therapeutic doses, has a similar effect on Tregs (30,31) and may prove useful in combination with immunotherapy. Cisplatin has been shown to alter the phenotype of tumor cells (32)(33)(34), resulting in increased sensitivity to CTL.…”