During the last few decades, significant efforts of the interaction between immune system and immunotherapy to NSCLC have been acquired. Recent data have indicated that the lack of immunologic control is recognized as a hallmark of cancer currently. Programmed death-1 (PD-1) and its ligand PD-L1 play a key role in tumor immune escape and the formation of tumor microenvironment, closely related with tumor generation and development. Blockading the PD-1/PD-L1 pathway could reverse the tumor microenvironment and enhance the endogenous antitumor immune responses.
重點節錄
Studies indicated that PD-1/PD-L1 pathway inhibitors were most effective when combined with treatments that activating the immune system.
Preclinical evidence exists for the complementary roles of CTLA-4 and PD-1 in regulating adaptive immunity, and this provides rationale for combining drugs targeting these pathways. In a Phase I study in 46 chemotherapy-naive patients with NSCLC, four cohorts of patients received ipilimumab (3 mg/kg) plus nivolumab for four cycles followed by nivolumab 3 mg/kg intravenously every 2 weeks. The ORR was 22% and did not correlate with PD-L1 status.
In another Phase I study, 56 patients with advanced NSCLC were assigned based on histology to four cohorts to receive nivolumab (5–10 mg/kg) intravenously every 3 weeks plus one of four concurrent standard “platinum doublet” chemotherapy regimens. No dose de-escalation was required for dose-limiting toxicity. The ORR was 33–50% across arms and the 1-year OS rates were promising at 59–87%.
Current research on the combination therapy between PD-1/PD-L1 inhibitors and radiotherapy primarily focuses on animal experimentation (tumor-bearing mice). In a study of glioblastoma multiforme (GBM), investigators tested the combination of anti-PD-1 antibody with stereotactic radiotherapy in a mouse orthotopic GBM model. The results demonstrated that combination-therapy can significantly prolong the survival compared with either modality alone. Long-term survival was seen only in the combination-therapy group, with some mice alive more than 180 days.
In another study of preclinical melanoma and renal cell carcinoma mouse models, scientists found that PD-1 wild-type mice can recapitulate the radiotherapy-induced antitumor responses observed in PD-1 knockout mice after they received anti-PD-1 body therapy, thus prolonging their survivals. The combination of anti-PD-1 therapy and radiotherapy can also elicit the reduction in size of non-irradiated, secondary tumors outside the SABR radiation field (abscopal effect).
The feasibility of combination therapy was that radiotherapy maybe had an effect on up-regulation of PD-L1 on tumor cells.
Safety of drugs
The PD-1/PD-L1 inhibitors are considered to have a good safety, little toxicity and relatively well tolerated therapeutic method. In different trials (mentioned in this review), the incidence rate of immune-related adverse events (irAEs) exist large difference, but mainly focus on grade 1, 2, such as: fatigue, rash, pruritus, diarrhea, drug-related pneumonitis, vitiligo, colitis, hepatitis, hypophysitis, thyroiditis and vomit. However, there are still some reports which pointed out that a certain proportion of grade 3 or 4 irAEs occured. In a clinical trail involving a total of 296 patients, no maximum tolerated dose was defined, Grade 3 or 4 irAEs occurred in 14% of patients; three deaths resulted from pulmonary toxicity. In a clinical trial with combination therapy, the patients were followed up at least 4 months, grade 3-4 irAEs occurred in 22 of 46 (48%) and led to discontinuation in 16patients63. Three treatment-related deaths were due to respiratory failure, bronchopulmonary hemorrhage and toxic epidermal necrolysis. In another clinical trail, grade 3 or 4 treatment-related AEs were reported in 45% including pneumonitis, fatigue and acute renal failure68. The precise signaling pathways of these irAEs were still unclear. With careful vigilance, pneumonitis can often be controlled early with administration of corticosteroid.
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