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Effect of Modified Vaccinia Ankara-5T4 and Low-Dose Cyclophosphamide on Antitumor Immunity in Metastatic Colorectal
Martin Scurr1, Tom Pembroke1, Anja Bloom1
1Division of Infection and Immunity, Cardiff University, Cardiff, Wales.
Importance:
The success of immunotherapy with checkpoint inhibitors is not replicated in most cases of colorectal cancer; therefore, different strategies are urgently required. The oncofetal antigen 5T4 is expressed in more than 90% of cases of metastatic colorectal cancer (mCRC). Preliminary data using modified vaccinia Ankara-5T4 (MVA-5T4) in mCRC demonstrated that it safely induced serologic and T-cell responses.
Objective:
To determine whether antitumor immunity in mCRC could be increased using MVA-5T4, metronomic low-dose cyclophosphamide, or a combination of both treatments.
Design, Setting, And Participants:
In this randomized clinical trial, 55 patients with inoperable mCRC and prior stable disease after standard chemotherapy were enrolled at a single center and 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). Patients were enrolled and treated from July 9, 2012, through February 8, 2016, and follow-up was completed on December 13, 2016. Data were analyzed based on intention to treat.
Interventions:
Patients randomized 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.
Main Outcomes And Measures:
The predefined primary end point was the magnitude of anti-5T4 immune responses (5T4-specific T-cell and antibody levels) generated at treatment week 7. Secondary end points included analysis of the kinetics of anti-5T4 responses, progression-free survival (PFS), and overall survival (OS).
Results:
Fifty-two patients (38 men and 14 women; mean [SD] age, 64.2 [10.1] years) were included in the study analysis. The 5T4-specific antibody immune responses were significantly increased 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 depleted 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, resulting in significantly 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). No grade 3 or 4 adverse events were observed.
Conclusions And Relevance:
This initial randomized clinical immunotherapy study demonstrates a significant survival benefit in mCRC. Prior depletion of regulatory T cells by cyclophosphamide did not increase immune responses generated by MVA-5T4 vaccination; however, cyclophosphamide and MVA-5T4 each independently induced beneficial antitumor immune responses, resulting in prolonged survival without toxic effects. Larger clinical trials are planned to further validate these data.
Trial Registration:
isrctn.org Identifier: ISRCTN54669986.
Insights
This study shows that MVA-5T4 vaccination and cyclophosphamide treatment independently improve survival in metastatic colorectal cancer (mCRC) patients. Both therapies induced beneficial antitumor immune responses without significant toxicity.
Area of Science:
- Oncology
- Immunotherapy
- Colorectal Cancer Research
Background:
- Immunotherapy with checkpoint inhibitors has limited success in metastatic colorectal cancer (mCRC).
- The oncofetal antigen 5T4 is highly expressed in mCRC, making it a potential therapeutic target.
- Preliminary MVA-5T4 data in mCRC showed safe induction of immune responses.
Purpose of the Study:
- To evaluate if MVA-5T4, low-dose cyclophosphamide, or their combination can enhance antitumor immunity in mCRC.
- To assess the impact of these treatments on immune responses, progression-free survival (PFS), and overall survival (OS).
Main Methods:
- A randomized clinical trial involving 55 patients with inoperable mCRC.
- Patients were assigned to watch and wait, cyclophosphamide only, MVA-5T4 only, or combination therapy.
- Immune responses (anti-5T4 antibodies and T-cells), PFS, and OS were primary and secondary endpoints.
Main Results:
- MVA-5T4 and combination therapy significantly increased 5T4-specific antibody responses.
- MVA-5T4 monotherapy significantly prolonged PFS (5.6 vs 2.4 months) and OS (20.0 vs 10.3 months).
- Cyclophosphamide independently prolonged PFS (5.0 vs 2.5 months) without increasing MVA-5T4 immune responses; no grade 3/4 adverse events were observed.
Conclusions:
- This study demonstrates a survival benefit for MVA-5T4 and cyclophosphamide in mCRC.
- Both agents independently induced beneficial antitumor immune responses, leading to prolonged survival.
- Larger trials are planned to further validate these promising findings in mCRC immunotherapy.
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