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Effect of modified vaccinia Ankara–5t4 and low-dose cyclophosphamide on antitumor immunity in metastatic colorectal cancer: A randomized clinical trial

JAMA Oncology Oct 26, 2017

Scurr M, et al. - This trial analyzed if antitumor immunity in metastatic colorectal cancer (mCRC) could be increased using modified vaccinia Ankara–5T4 (MVA-5T4), metronomic low-dose cyclophosphamide, or a combination of both treatments. The findings disclosed a notable survival benefit in mCRC. The prior depletion of regulatory T cells by cyclophosphamide did not lead to a rise in the immune responses generated by MVA-5T4 vaccination. Nonetheless, beneficial antitumor immune responses were independently induced by cyclophosphamide and MVA-5T4. This, in turn, led to prolonged survival without toxic effects.

Methods

  • The recruitment comprised of 55 patients with inoperable mCRC and prior stable disease after standard chemotherapy, enrolled at a single center.
  • The candidates were randomized to watch and wait (n=9), cyclophosphamide treatment only (n=9), MVA-5T4 only (n=19), and a combination of MVA-5T4 and cyclophosphamide (n=18).
  • They were treated from July 9, 2012, through February 8, 2016, and follow-up was completed on December 13, 2016.
  • Data analysis was carried out on the basis of an intention to treat.
  • Patients were allocated to a cyclophosphamide group received 50 mg twice daily on treatment days 1 to 7 and 15 to 21.
  • Patients randomized to a MVA-5T4 group received an intramuscular injection at a dose of 1×109 50% tissue culture infectious dose on treatment days 22, 36, 50, 64, 78, and 106.
  • The primary meause consisted of predefined primary end point, as the magnitude of anti-5T4 immune responses (5T4-specific T-cell and antibody levels) generated at treatment week 7.
  • The analysis of the kinetics of anti-5T4 responses, progression-free survival (PFS), and overall survival (OS) were the secondary end points.

Results

  • Herein, fifty-two patients (38 men and 14 women; mean [SD] age, 64.2 [10.1] years) were recruited.
  • A marked rise was noted in the 5T4-specific antibody immune responses, in the MVA-5T4 (83.41 [36.09] relative units [RU]; P=.02) and combination treatment (65.81 [16.68] RU; P=.002) groups compared with no treatment (20.09 [7.20] RU).
  • Cyclophosphamide were found to deplete regulatory T cells in 24 of 27 patients receiving MVA-5T4, independently prolonging PFS (5.0 vs 2.5 months; hazard ratio [HR], 0.48; 95% CI, 0.21-1.11; P=.09). MVA-5T4 doubled baseline anti-5T4 responses in 16 of 35 patients.
  • This, in turn, led to substantially prolonged PFS (5.6 vs 2.4 months; HR, 0.21; 95% CI, 0.09-0.47; P<.001) and OS (20.0 vs 10.3 months; HR, 0.32; 95% CI, 0.14-0.74; P=.008).
  • There were no grade 3 or 4 adverse events.

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