Randomized phase II clinical trial of chemo-immunotherapy in advanced nonsmall cell lung cancer

Abstract

The purpose of this study was to compare chemotherapy-naive patients with stage IV nonsmall cell lung cancer patients treated with chemotherapy or chemoimmunotherapy. We tested doxetacel plus cisplatinum as chemotherapy protocol. An immunomodulatory adjuvant system was added as chemoimmunotherapy to the previously mentioned protocol. This system contains three well-known and complementary conditioners of protective immune-responses: cyclophosphamide low-dose, granulocyte macrophage-colony stimulant factor and magnesium silicate granuloma. Eighty-eight patients were randomly assigned to receive every 3-weeks one of the treatments under comparison. Patients received four cycles of treatment unless disease progression or unacceptable toxicity was documented. The maximum follow-up was one year. In each arm, tumor response (rate,duration), median survival time, 1-year overall survival, safety, and immunity modifications were assessed. Immunity was evaluated by submitting peripheral blood mononuclear cells to laboratory tests for nonspecific immunity: a) phytohemaglutinin-induced lymphocyte proliferation, b) prevalence of T-Regulatory (CD4+CD25+) cells and for specific immunity: a) lymphocyte proliferation induced by tumor-associated antigens (TAA) contained in a previously described autologous thermostable hemoderivative. The difference (chemotherapy vs. chemoimmunotherapy) in response rate induced by the two treatments (39.0% and 35.0%) was not statistically significant. However, the response duration (22 and 31 weeks), the median survival time (32 and 44 weeks) and 1-year survival (33.3% and 39.1%) were statistically higher with chemoimmunotherapy. No difference in toxicity between both arms was demonstrated. A switch in the laboratory immunity profile, nonspecific and specific, was associated with the chemoimmunotherapy treatment: increase of proliferative lymphocyte response, decrease of tolerogenic T-regulatory cells and eliciting TAA-sensitization.

Keywords: cancer therapy; cancer vaccine; immunomodulatory cancer treatment; immunotherapy adjuvants; lung cancer chemoimmunotherapy; lung cancer chemotherapy.

Figure 1

Stage IV nonsmall cell lung cancer at one-year follow-up. Observed survival in the chemotherapy arm (CHT; 41 patients): Doxetacel + cisplatinum and the chemoimmunotherapy arm (CHIMT; 40 patients): CHT + immunomodulatory adjuvant system. Survival rates at 95% confidence intervals (CIs) were estimated and the comparisons between the two treatment procedures were carried out using the two-tailed log-rank test. P-value for log-rank test was calculated. The sample size for Survival (log-rank) was assessed using the approach of Schoenfeld and Richter. Abbreviations: MST, median survival time; 1-OS, one year overall survival.