Patients with advanced colorectal cancer mounted a robust response to an experimental vaccine and low-dose cyclophosphamide, and strong responses were associated with improvements in survival in a phase I/II clinical trial of modified vaccinia virus Ankara–5T4 (TroVax).1
This is the first randomized study to show a clear benefit of immunotherapy in advanced colorectal cancer—and to suggest this approach may be superior to (and less toxic than) continuous palliative chemotherapy in these patients.— Martin Scurr, PhD
Tweet this quote
Martin Scurr, PhD, of Cardiff University in the United Kingdom, led the TaCTiCC trial that was presented at the 2017 ASCO-SITC (Society for Immunotherapy of Cancer) Clinical Immuno-Oncology Symposium. He and his fellow investigators reported that both low-dose cyclophosphamide and the vaccine independently induced “highly beneficial antitumor immune responses, resulting in significant survival of end-stage colorectal cancer patients, without any major toxicity.”
Perhaps even more interesting was the effect of low-dose cyclophosphamide alone, which also produced strong immune responses.
“Both cyclophosphamide and [the vaccine] induced highly beneficial antitumor immune responses that resulted in significantly prolonged survival of end-stage colorectal cancer patients, without toxicity. This is the first randomized study to show a clear benefit of immunotherapy in advanced colorectal cancer—and to suggest this approach may be superior to (and less toxic than) continuous palliative chemotherapy in these patients,” he said.
About the Vaccine
The study vaccine incorporates a tumor-associated antigen, 5T4, and a pox virus vector, modified vaccinia virus Ankara. The 5T4 antigen is found in a wide range of solid cancers, including up to 90% of colorectal tumors, and its presence is correlated with a poor prognosis.
Immunotherapeutic Vaccine in Colorectal Cancer
- A novel therapeutic vaccine employs a highly attenuated strain of vaccinia virus, modified vaccinia virus Ankara, and encodes the tumor antigen 5T4, which is found on 90% of colorectal cancers.
- In a phase I/II trial of advanced colorectal cancer patients, modified vaccinia virus Ankara–5T4 plus low-dose cyclophosphamide (delivered prior to vaccination) led to robust immune responses that were associated with improved progression-free and overall survival.
- Low-dose cyclophosphamide alone also produced strong immune responses that were associated with prolonged remission.
Current immunotherapies have been largely ineffective in colorectal cancer. The researchers hypothesized that combining a modified vaccinia virus Ankara–based vaccine targeting 5T4 with low-dose cyclophosphamide to deplete Foxp3-positive regulatory T cells could improve immunologic responses and patient outcomes.
“To broaden the immune response to the vaccine, we used low-dose cyclophosphamide, which has been implicated in stimulating an immune response by depleting the suppressive arm of the immune response, the regulatory T cells (Tregs),” he explained. “One of the primary readouts is to see if we can deplete Tregs, defined as Foxp3-positive cells on CD4-positive T cells.”
Study Design
The academic-led study was an open-label phase I/II clinical trial involving 52 patients with inoperable metastatic colorectal cancer. Almost all patients had received capecitabine and fluorouracil, and many had received other approved colorectal cancer agents.
Patients were randomized to receive no treatment (n = 8), metronomic low-dose cyclophosphamide at 50 mg twice daily during treatment weeks 1 and 3 (n = 9), modified vaccinia virus Ankara–5T4 only (n = 17), or low-dose cyclophosphamide followed by modified vaccinia virus Ankara–5T4 (n = 18). Patients in the vaccine arms started treatment on day 22, after they were given cyclophosphamide. They received 5 injections 2 weeks apart and then the sixth injection 4 weeks after the fifth one. The primary endpoint was boosted anti-5T4 responses at treatment day 43, as measured by increased T-cell and/or antibody responses.
Immunologic Responses
“After we gave the cyclophosphamide, we saw that patients with the greatest reduction in regulatory T cells had a progression-free survival advantage,” Dr. Scurr reported. “Just giving low-dose cyclophosphamide alone caused an immune response.”
Cyclophosphamide depleted regulatory T cells in 21 of 27 patients during treatment week 3 (P = .0028). Among 27 cyclophosphamide-treated patients, 12 reached the cutoff for a reduction of at least 39.4%. This magnitude of depletion correlated with a prolonged progression-free survival in cyclophosphamide-containing cohorts, compared to cyclophosphamide-treated patients not attaining the 39.4% cutoff. Median progression-free survival was 5.0 vs 2.4 months for these subsets (hazard ratio [HR]= 0.48, P = .09).
Vaccination induced a more than twofold increase in anti-5T4 immune responses in 16 of 35 patients treated with the modified vaccinia virus Ankara–5T4. These patients experienced significantly prolonged median progression-free survival (5.6 vs 2.4 months; HR = 0.21, P = .0002) and overall survival (20.0 vs 11.2 months; HR = 0.32, P = .0076).
While cyclophosphamide “can boost antibody responses generated to the vaccine,” Dr. Scurr said, the combination of low-dose cyclophosphamide and the vaccine was not significantly superior to either agent alone, in terms of generating an immune response or for improving progression-free or overall survival, compared to no treatment at all, he added.
“Not being treated with anything is by far the most detrimental factor,” he emphasized. “With low-dose cyclophosphamide, plus or minus [the vaccine], survival is better than with no treatment in [previously treated] colorectal cancer.”
The modified vaccinia virus Ankara–5T4 vaccine is being evaluated as a therapeutic cancer vaccine in a number of tumor types. ■
Disclosure: Dr. Scurr reported no potential conflicts of interest. The study was independently conducted.
Reference
